Topic: Basic Research

Abstract
<div><h4>Urinary levels of cortisol but not catecholamines are associated with those of 8-hydroxy-2\'-deoxyguanosine in uncomplicated primary hypertension.</h4><i>Tomoda F, Koike T, Nitta A, Kurosaki H, ... Oh-Hara M, Kinugawa K</i><br /><b>Objectives</b><br />The relationships between stress hormones and oxidative DNA damage have not yet been explored in human hypertension. We investigated the associations of urinary levels of cortisol or catecholamines with those of 8-hydroxy-2\'-deoxyguanosine, a marker of oxidative DNA damage in primary hypertension.<br /><b>Methods</b><br />Untreated 156 primary hypertensives without apparent cardiovascular diseases were entered into the study. Following blood sampling after an overnight fast, 24-h blood pressure monitoring and 24-h urinary sampling were performed simultaneously to determine 24-h averaged values for blood pressure and urinary levels of cortisol, catecholamines and 8-hydroxy-2\'-deoxyguanosine.<br /><b>Results</b><br />Urinary cortisol significantly correlated positively with urinary 8-hydroxy-2\'-deoxyguanosine in all studied participants (r = 0.334, P < 0.001). Contrary, either urinary adrenaline or urinary noradrenaline did not significantly correlate with urinary 8-hydroxy-2\'-deoxyguanosine (r = 0.050, P = 0.553 or r = 0.063, P = 0.435). Additionally, the positive association of urinary cortisol with urinary 8-hydroxy-2\'-deoxyguanosine remained highly significant after the adjustments for multiple confounders of oxidative stress such as age, gender, body mass index, smoking status, 24-h blood pressure, C-reactive protein and estimated glomerular filtration rate (partial r = 0.323, P < 0.001), although only approximately 10% of the variance in urinary cortisol was attributable to differences in urinary 8-OHdG (partial r2 = 0.104). Thus, our data indicate that cortisol but not catecholamines could at least partially contribute to the occurrence of oxidative DNA damage in primary hypertensives.<br /><b>Conclusion</b><br />The present study suggested the possibility that the overactivation of hypothalamic-pituitary-adrenal axis rather than sympathoadrenal system could enhance oxidative stress and attendant DNA oxidation in uncomplicated primary hypertension.<br /><br />Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>J Hypertens: 01 Oct 2023; 41:1571-1577</small></div>
Tomoda F, Koike T, Nitta A, Kurosaki H, ... Oh-Hara M, Kinugawa K
J Hypertens: 01 Oct 2023; 41:1571-1577 | PMID: 37642591
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<div><h4>The pathophysiology of excess plasma-free cholesterol.</h4><i>Gillard BK, Rosales C, Gotto AM, Pownall HJ</i><br /><b>Purpose of review</b><br />Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol is determined as a sum of free cholesterol and cholesteryl ester, two molecules with vastly different metabolic itineraries. We examine the evidence supporting the concept that the pathological effects of elevations of plasma HDL-cholesterol are due to high levels of the free cholesterol component of HDL-C.<br /><b>Recent findings</b><br />In a small population of humans, a high plasma HDL-cholesterol is associated with increased mortality. Similar observations in the HDL-receptor deficient mouse (Scarb1-/-), a preclinical model of elevated HDL-C, suggests that the pathological component of HDL in these patients is an elevated plasma HDL-FC.<br /><b>Summary</b><br />Collective consideration of the human and mouse data suggests that clinical trials, especially in the setting of high plasma HDL, should measure free cholesterol and cholesteryl esters and not just total cholesterol.<br /><br />Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>Curr Opin Lipidol: 22 Sep 2023; epub ahead of print</small></div>
Gillard BK, Rosales C, Gotto AM, Pownall HJ
Curr Opin Lipidol: 22 Sep 2023; epub ahead of print | PMID: 37732779
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<div><h4>PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation.</h4><i>Perike S, Gonzalez-Gonzalez FJ, Abu-Taha I, Damen FW, ... Wehrens XHT, McCauley MD</i><br /><b>Background</b><br />Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.<br /><b>Methods</b><br />Right atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies.<br /><b>Results</b><br />In human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (<i>P</i>=2.0×10<sup>-</sup><sup>2</sup>; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (<i>P</i>=1.4×10<sup>-</sup><sup>6</sup>; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (<i>P</i>=2.9×10<sup>-2</sup> and 6.7×10<sup>-3</sup>, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (<i>P</i>=5.0×10<sup>-</sup><sup>6</sup>; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (<i>P</i>=1.8×10<sup>-2</sup> and 4.1×10<sup>-2</sup>, respectively; n=6, 6, and 5).<br /><b>Conclusions</b><br />Patients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.<br /><br /><br /><br /><small>Circ Res: 22 Sep 2023; epub ahead of print</small></div>
Perike S, Gonzalez-Gonzalez FJ, Abu-Taha I, Damen FW, ... Wehrens XHT, McCauley MD
Circ Res: 22 Sep 2023; epub ahead of print | PMID: 37737016
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<div><h4>Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.</h4><i>Cheng YC, Hsieh ML, Lin CJ, Chang CMC, ... Kamp TJ, Hsieh PCH</i><br /><b>Background</b><br />Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs.<br /><b>Methods</b><br />We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in NOD-SCID mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated.<br /><b>Results</b><br />We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion.<br /><b>Conclusions</b><br />These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>
Cheng YC, Hsieh ML, Lin CJ, Chang CMC, ... Kamp TJ, Hsieh PCH
Circulation: 21 Sep 2023; epub ahead of print | PMID: 37732466
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<div><h4>Simultaneous Targeting of IL-1-Signaling and IL-6-Trans-Signaling Preserves Human Pulmonary Endothelial Barrier Function During a Cytokine Storm.</h4><i>Colás-Algora N, Muñoz-Pinillos P, Cacho-Navas C, Avendaño-Ortiz J, ... López-Collazo E, Millán J</i><br /><b>Background</b><br />Systemic inflammatory diseases, such as sepsis and severe COVID-19, provoke acute respiratory distress syndrome in which the pathological hyperpermeability of the microvasculature, induced by uncontrolled inflammatory stimulation, causes pulmonary edema. Identifying the inflammatory mediators that induce human lung microvascular endothelial cell barrier dysfunction is essential to find the best anti-inflammatory treatments for critically ill acute respiratory distress syndrome patients.<br /><b>Methods</b><br />We have compared the responses of primary human lung microvascular endothelial cells to the main inflammatory mediators involved in cytokine storms induced by sepsis and SARS-CoV2 pulmonary infection and to sera from healthy donors and severely ill patients with sepsis. Endothelial barrier function was measured by electric cell-substrate impedance sensing, quantitative confocal microscopy, and Western blot.<br /><b>Results</b><br />The human lung microvascular endothelial cell barrier was completely disrupted by IL (interleukin)-6 conjugated with soluble IL-6R (IL-6 receptor) and by IL-1β, moderately affected by TNF (tumor necrosis factor)-α and IFN (interferon)-γ and unaffected by other cytokines and chemokines, such as IL-6, IL-8, MCP (monocyte chemoattractant protein)-1 and MCP-3. The inhibition of IL-1 and IL-6R simultaneously, but not separately, significantly reduced endothelial hyperpermeability on exposing human lung microvascular endothelial cells to a cytokine storm consisting of 8 inflammatory mediators or to sera from patients with sepsis. Simultaneous inhibition of IL-1 and JAK (Janus kinase)-STAT (signal transducer and activator of transcription protein), a signaling node downstream IL-6 and IFN-γ, also prevented septic serum-induced endothelial barrier disruption.<br /><b>Conclusions</b><br />These findings strongly suggest a major role for both IL-6 trans-signaling and IL-1β signaling in the pathological increase in permeability of the human lung microvasculature and reveal combinatorial strategies that enable the gradual control of pulmonary endothelial barrier function in response to a cytokine storm.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 21 Sep 2023; epub ahead of print</small></div>
Colás-Algora N, Muñoz-Pinillos P, Cacho-Navas C, Avendaño-Ortiz J, ... López-Collazo E, Millán J
Arterioscler Thromb Vasc Biol: 21 Sep 2023; epub ahead of print | PMID: 37732482
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<div><h4>Aging Is Associated With Organ-Specific Alterations in the Level and Expression Pattern of von Willebrand Factor.</h4><i>Alavi P, Yousef Abdualla R, Brown D, Mojiri A, ... Bourque SL, Jahroudi N</i><br /><b>Background</b><br />VWF (von Willebrand factor) is an endothelial-specific procoagulant protein with a major role in thrombosis. Aging is associated with increased circulating levels of VWF, which presents a risk factor for thrombus formation.<br /><b>Methods</b><br />Circulating plasma, cellular protein, and mRNA levels of VWF were determined and compared in young and aged mice. Major organs were subjected to immunofluorescence analyses to determine the vascular pattern of VWF expression and the presence of platelet aggregates. An in vitro model of aging, using extended culture time of endothelial cells, was used to explore the mechanism of age-associated increased VWF levels.<br /><b>Results</b><br />Increased circulating plasma levels of VWF with elevated levels of larger multimers, indicative of VWF functional activity, were observed in aged mice. VWF mRNA and cellular protein levels were significantly increased in the brains, lungs, and livers but not in the kidneys and hearts of aged mice. Higher proportion of small vessels in brains, lungs, and livers of aged mice exhibited VWF expression compared with young, and this was concomitant with increased platelet aggregate formation. Prolonged culture of endothelial cells resulted in increased cell senescence that correlated with increased VWF expression; VWF expression was specifically detected in senescent cultured endothelial cells and abolished in response to p53 knockdown. A significantly higher proportion of VWF expressing endothelial cells in vivo exhibited senescence markers SA-β-Gal (senescence-associated β-galactosidase) and p53 in aged mouse brains compared with that of the young.<br /><b>Conclusions</b><br />Aging elicits a heterogenic response in endothelial cells with regard to VWF expression, leading to organ-specific increase in VWF levels and alterations in vascular tree pattern of expression. This is concomitant with increased platelet aggregate formation. The age-associated increase in VWF expression may be modulated through the process of cell senescence, and p53 transcription factor contributes to its regulation.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 21 Sep 2023; epub ahead of print</small></div>
Alavi P, Yousef Abdualla R, Brown D, Mojiri A, ... Bourque SL, Jahroudi N
Arterioscler Thromb Vasc Biol: 21 Sep 2023; epub ahead of print | PMID: 37732483
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<div><h4>Single-Cell RNA Sequencing Reveals Cellular Adaptation of Human Aortic Endothelial Cells to Antiproliferative Therapies Is Modulated by Flow-Induced Shear Stress.</h4><i>Salazar-Martín AG, Kalluri AS, Villanueva MA, Hughes TK, ... Shalek AK, Edelman ER</i><br /><b>Background</b><br />Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular adaptation may be a potential marker for cardiovascular disease and a predictor of poor response to endovascular pharmacological interventions such as drug-eluting stents. Here, we report single-cell transcriptional profiling of ECs exposed to multiple stimulus classes to evaluate EC adaptation.<br /><b>Methods</b><br />Human aortic ECs were costimulated with both pathophysiological flows mimicking shear stress levels found in the human aorta (laminar and turbulent, ranging from 2.5 to 30 dynes/cm<sup>2</sup>) and clinically relevant antiproliferative drugs, namely paclitaxel and rapamycin. EC state in response to these stimuli was defined using single-cell RNA sequencing.<br /><b>Results</b><br />We identified differentially expressed genes and inferred the TF (transcription factor) landscape modulated by flow shear stress using single-cell RNA sequencing. These flow-sensitive markers differentiated previously identified spatially distinct subpopulations of ECs in the murine aorta. Moreover, distinct transcriptional modules defined flow- and drug-responsive EC adaptation singly and in combination. Flow shear stress was the dominant driver of EC state, altering their response to pharmacological therapies..<br /><b>Conclusions</b><br />We showed that flow shear stress modulates the cellular capacity of ECs to respond to paclitaxel and rapamycin administration, suggesting that while responding to different flow patterns, ECs experience an impairment in their transcriptional adaptation to other stimuli.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 21 Sep 2023; epub ahead of print</small></div>
Salazar-Martín AG, Kalluri AS, Villanueva MA, Hughes TK, ... Shalek AK, Edelman ER
Arterioscler Thromb Vasc Biol: 21 Sep 2023; epub ahead of print | PMID: 37732484
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<div><h4>A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression.</h4><i>Chen Z, Giotti B, Kaluzova M, Puigdelloses Vallcorba M, ... Tsankov AM, Hambardzumyan D</i><br /><AbstractText>Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here we show that PDGFB-driven GBM cells induce the expression of the potent pro-inflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-kB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, reduced exhausted CD8+ T cells, and thereby extends the survival of tumor-bearing mice. In contrast to IL-1β, IL-1α exhibits anti-tumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss of interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Nf1-silenced tumors have a constitutively-active NF-kB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1β could be considered as an effective therapy specifically for proneural GBM.</AbstractText><br /><br /><br /><br /><small>J Clin Invest: 21 Sep 2023; epub ahead of print</small></div>
Chen Z, Giotti B, Kaluzova M, Puigdelloses Vallcorba M, ... Tsankov AM, Hambardzumyan D
J Clin Invest: 21 Sep 2023; epub ahead of print | PMID: 37733448
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<div><h4>Basic Mechanisms of Brain Injury and Cognitive Decline in Hypertension: Dementia Series.</h4><i>Baggeroer CE, Cambronero FE, Savan NA, Jefferson AL, Santisteban MM</i><br /><AbstractText>Dementia affects almost 50 million adults worldwide, and remains a major cause of death and disability. Hypertension is a leading risk factor for dementia, including Alzheimer disease and Alzheimer disease-related dementias. Although this association is well-established, the mechanisms underlying hypertension-induced cognitive decline remain poorly understood. By exploring the mechanisms mediating the detrimental effects of hypertension on the brain, studies have aimed to provide therapeutic insights and strategies on how to protect the brain from the effects of blood pressure elevation. In this review, we focus on the basic mechanisms contributing to the cerebrovascular adaptions to elevated blood pressure and hypertension-induced microvascular injury. We also assess the cellular mechanisms of neurovascular unit dysfunction, focusing on the premise that cognitive impairment ensues when the dynamic metabolic demands of neurons are not met due to neurovascular uncoupling, and summarize cognitive deficits across various rodent models of hypertension as a resource for investigators. Despite significant advances in antihypertensive therapy, hypertension remains a critical risk factor for cognitive decline, and several questions remain about the development and progression of hypertension-induced cognitive impairment.</AbstractText><br /><br /><br /><br /><small>Hypertension: 21 Sep 2023; epub ahead of print</small></div>
Baggeroer CE, Cambronero FE, Savan NA, Jefferson AL, Santisteban MM
Hypertension: 21 Sep 2023; epub ahead of print | PMID: 37732479
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<div><h4>Targeted activation of hERG channels rescues electrical instability induced by the hERG R56Q+/- Long QT Syndrome variant.</h4><i>Venkateshappa R, Hunter DV, Muralidharan P, Nagalingam RS, ... Tibbits GF, Claydon TW</i><br /><b>Aims</b><br />Long QT Syndrome Type 2 (LQTS2) is associated with inherited variants in the cardiac hERG K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant, and its phenotypic rescue by the type 1 hERG activator, RPR260243.<br /><b>Methods and results</b><br />These approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean APD90. However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of action potential duration (APD90) during rate transitions, and increases the incidence of 2:1 block. During paired S1-S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness.<br /><b>Conclusion</b><br />Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 21 Sep 2023; epub ahead of print</small></div>
Venkateshappa R, Hunter DV, Muralidharan P, Nagalingam RS, ... Tibbits GF, Claydon TW
Cardiovasc Res: 21 Sep 2023; epub ahead of print | PMID: 37739930
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<div><h4>Galectin-3 contributes to acute cardiac dysfunction and toxicity by increasing oxidative stress and fibrosis in doxorubicin-treated mice.</h4><i>Seropian IM, Fontana Estevez FS, Villaverde A, Cacciagiú L, ... Miksztowicz V, González GE</i><br /><b>Background</b><br />Doxorubicin (DOX) leads to cardiovascular toxicity through direct cardiomyocyte injury and inflammation. We aimed to study the role of Galectin-3 (Gal-3), a β-galactosidase binding lectin associated with inflammation and fibrosis in DOX-induced acute cardiotoxicity in mice.<br /><b>Methods</b><br />Male C57 and Gal-3 knockout (KO) mice were given a single dose of DOX (15 mg/kg, i.p) or placebo. Serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and cardiac thiobarbituric acid-reactive substance (TBARS) were measured at 3 days to assess cardiac injury and oxidative stress. Cardiac remodeling and function were studied by echocardiography and catheterization at 7 days. Myocardial fibrosis was quantified in picrosirius red stained slices.<br /><b>Results</b><br />Absence of Gal-3 tended to reduce the mortality after DOX. DOX significantly increased CPK, LDH, AST and TBARS while treated Gal-3 KO mice showed reduced injury and oxidative stress. After 7 days, adverse remodeling, fibrosis and dysfunction in treated-C57 mice were severely affected while those effects were prevented by absence of Gal-3.<br /><b>Conclusion</b><br />In summary, genetic deletion of Gal-3 prevented cardiac damage, adverse remodeling and dysfunction, associated with reduced cardiac oxidative stress and fibrosis. Understanding the contribution of GAL-3 to doxorubicin-induced cardiac toxicity reinforces its potential use as a therapeutic target in patients with several cancer types.<br /><br />Copyright © 2023 Elsevier Ireland Ltd. All rights reserved.<br /><br /><small>Int J Cardiol: 21 Sep 2023:131386; epub ahead of print</small></div>
Seropian IM, Fontana Estevez FS, Villaverde A, Cacciagiú L, ... Miksztowicz V, González GE
Int J Cardiol: 21 Sep 2023:131386; epub ahead of print | PMID: 37741348
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<div><h4>Recovery of Extracorporeal Lungs Using Cross-Circulation with Injured Recipient Swine.</h4><i>Chen P, Van Hassel J, Pinezich MR, Diane M, ... Bacchetta M, Vunjak-Novakovic G</i><br /><b>Objective</b><br />Lung transplantation remains limited by the shortage of healthy organs. Cross-circulation with a healthy swine recipient provides a durable physiologic environment to recover injured donor lungs. In a clinical application, a recipient awaiting lung transplantation could be placed on cross-circulation to recover damaged donor lungs, enabling eventual transplantation. Our objective was to assess the ability of recipient swine with respiratory compromise to tolerate cross-circulation and support recovery of donor lungs subjected to extended cold ischemia.<br /><b>Methods</b><br />Swine donor lungs (n = 6) were stored at 4°C for 24 hours, while recipient swine (n = 6) underwent gastric aspiration injury prior to cross-circulation. Longitudinal multiscale analyses (blood gas, bronchoscopy, radiography, histopathology, cytokine quantification) were performed to evaluate recipient swine and extracorporeal lungs on cross-circulation.<br /><b>Results</b><br />Recipient swine lung injury resulted in sustained, impaired oxygenation (PaO<sub>2</sub>/FiO<sub>2</sub> ratio 205 ± 39 mmHg versus 454 ± 111 mmHg at baseline). Radiographic, bronchoscopic, and histologic assessments demonstrated bilateral infiltrates, airway cytokine elevation, and significantly worsened lung injury scores. Recipient swine provided sufficient metabolic support for extracorporeal lungs to demonstrate robust functional improvement (0 hours, PaO<sub>2</sub>/FiO<sub>2</sub> 138 ± 28.2 mmHg; 24 hours, 539 ± 156 mmHg). Multiscale analyses demonstrated improved gross appearance, aeration, and cellular regeneration in extracorporeal lungs by 24 hours.<br /><b>Conclusions</b><br />We demonstrate that acutely injured recipient swine tolerate cross-circulation and enable recovery of donor lungs subjected to extended cold storage. This proof-of-concept study supports feasibility of cross-circulation for recipients with isolated lung disease, who are candidates for this clinical application.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>J Thorac Cardiovasc Surg: 21 Sep 2023; epub ahead of print</small></div>
Chen P, Van Hassel J, Pinezich MR, Diane M, ... Bacchetta M, Vunjak-Novakovic G
J Thorac Cardiovasc Surg: 21 Sep 2023; epub ahead of print | PMID: 37741314
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<div><h4>Iron deficiency in myocardial ischemia: molecular mechanisms and therapeutic perspectives.</h4><i>Corradi F, Masini G, Bucciarelli T, De Caterina R</i><br /><AbstractText>Systemic iron deficiency (SID), even in the absence of anemia, worsens the prognosis and increases mortality in heart failure (HF). Recent clinical-epidemiological studies, however, have shown that a myocardial iron deficiency (MID) is frequently present in cases of severe HF even in the absence of SID and without anemia. In addition, experimental studies have shown a poor correlation between the state of systemic and myocardial iron. MID in animal models may lead to severe mitochondrial dysfunction, alterations of mitophagy and mitochondrial biogenesis, with profound alterations in cardiac mechanics and the occurrence of a fatal cardiomyopathy, all effects prevented by intravenous administration of iron. This shifts the focus to the myocardial state of iron, in the absence of anemia, as an important factor in prognostic worsening and mortality in HF. There is now epidemiological evidence that SID worsens prognosis and mortality also in patients with acute and chronic coronary heart disease, and experimental evidence that MID aggravates acute myocardial ischemia as well as post-ischemic remodeling. Intravenous administration of ferric carboxymaltose or ferric dextrane improves post-ischemic adverse remodeling. We here review such evidence, propose that MID worsens ischemia/reperfusion injury, and discuss possible molecular mechanisms, such as chronic hyperactivation of HIF1-α; exacerbation of cytosolic and mitochondrial calcium overload, amplified increase of mitochondrial [NADH]/[NAD+] ratio, and depletion of energy status and NAD+ content with inhibition of sirtuin 1-3 activity. Such evidence now portrays iron metabolism as a core factor not only in heart failure, but also in myocardial ischemia.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 19 Sep 2023; epub ahead of print</small></div>
Corradi F, Masini G, Bucciarelli T, De Caterina R
Cardiovasc Res: 19 Sep 2023; epub ahead of print | PMID: 37722377
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<div><h4>Endoplasmic reticulum stress impairs trophoblast syncytialization through upregulation of HtrA4 and causes early-onset preeclampsia.</h4><i>Yuan X, Liu X, Zhu F, Huang B, ... Tang J, Tong C</i><br /><b>Objective</b><br />Syncytiotrophoblasts form via mononuclear cytotrophoblast fusion during placentation and play a critical role in maternal-fetal communication. Impaired syncytialization inevitably leads to pregnancy-associated complications, including preeclampsia. Endoplasmic reticulum stress (ERS) is reportedly linked with preeclampsia, but little is known about its association with syncytialization. High temperature requirement factor A4 (HtrA4), a placental-specific protease, is responsible for protein quality control and placental syncytialization. This study aimed to investigate the relationship among HtrA4, ERS, and trophoblast syncytialization in the development of early-onset preeclampsia (EO-PE).<br /><b>Methods</b><br />HtrA4 expression and ERS in preeclamptic placentas and control placentas were analyzed by Western blotting and qRT-PCR. HtrA4 and ERS localization in placentas was determined by immunohistochemistry and immunofluorescence. BeWo cells were used to stimulate the effects of HtrA4 and ERS on syncytialization.<br /><b>Results</b><br />HtrA4 expression was upregulated in EO-PE and positively correlated with ERS. HtrA4 activity was increased in preeclampsia. Under normoxia, HtrA4 overexpression in BeWo cells did not alter the ERS level. In addition, treatment with hypoxia/reoxygenation (H/R) or an ERS inducer increased HtrA4 expression. HtrA4 upregulation suppressed the levels of syncytin-2 and β-HCG in the presence of forskolin (FSK), and this change was exaggerated after ERS activation. In addition, treatment with an ERS inhibitor markedly suppressed FSK-treated cell fusion in a manner related to downregulation of HtrA4 expression.<br /><b>Conclusion</b><br />Our results suggest that ERS enables syncytialization of placental development by upregulating HtrA4, but that excessive HtrA4 expression and preexisting ERS impair syncytialization and cause EO-PE.<br /><br />Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>J Hypertens: 19 Sep 2023; epub ahead of print</small></div>
Yuan X, Liu X, Zhu F, Huang B, ... Tang J, Tong C
J Hypertens: 19 Sep 2023; epub ahead of print | PMID: 37728094
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<div><h4>Insulin-Like Growth Factor 1 Receptor Deficiency Alleviates Angiotensin II-Induced Cardiac Fibrosis Through the Protein Kinase B/Extracellular Signal-Regulated Kinase/Nuclear Factor-κB Pathway.</h4><i>Zhu J, Li Q, Sun Y, Zhang S, ... Sun Z, Zhang L</i><br /><AbstractText><br /><b>Background:</b><br/>The renin-angiotensin system plays a crucial role in the development of heart failure, and Ang II (angiotensin II) acts as the critical effector of the renin-angiotensin system in regulating cardiac fibrosis. However, the mechanisms of cardiac fibrosis are complex and still not fully understood. IGF1R (insulin-like growth factor 1 receptor) has multiple functions in maintaining cardiovascular homeostasis, and low-dose IGF1 treatment is effective in relieving Ang II-induced cardiac fibrosis. Here, we aimed to investigate the molecular mechanism of IGF1R in Ang II-induced cardiac fibrosis. Methods and Results Using primary mouse cardiac microvascular endothelial cells and fibroblasts, in vitro experiments were performed. Using C57BL/6J mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9)-mediated IGF1R heterozygous knockout (<i>Igf1r</i><sup>+/-</sup>) mice, cardiac fibrosis mouse models were induced by Ang II for 2 weeks. The expression of IGF1R was examined by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot. Mice heart histologic changes were evaluated using Masson and picro sirius red staining. Fibrotic markers and signal molecules indicating the function of the Akt (protein kinase B)/ERK (extracellular signal-regulated kinase)/nuclear factor-κB pathway were detected using quantitative reverse transcription polymerase chain reaction and Western blot. RNA sequencing was used to explore IGF1R-mediated target genes in the hearts of mice, and the association of IGF1R and G-protein-coupled receptor kinase 5 was identified by coimmunoprecipitation. More important, blocking IGF1R signaling significantly suppressed endothelial-mesenchymal transition in primary mouse cardiac microvascular endothelial cells and mice in response to transforming growth factor-β1 or Ang II, respectively. Deficiency or inhibition of IGF1R signaling remarkably attenuated Ang II-induced cardiac fibrosis in primary mouse cardiac fibroblasts and mice. We further observed that the patients with heart failure exhibited higher blood levels of IGF1 and IGF1R than healthy individuals. Moreover, Ang II treatment significantly increased cardiac IGF1R in wild type mice but led to a slight downregulation in <i>Igf1r</i><sup><i>+/-</i></sup> mice. Interestingly, IGF1R deficiency significantly alleviated cardiac fibrosis in Ang II-treated mice. Mechanistically, the phosphorylation level of Akt and ERK was upregulated in Ang II-treated mice, whereas blocking IGF1R signaling in mice inhibited these changes of Akt and ERK phosphorylation. Concurrently, phosphorylated p65 of nuclear factor-κB exhibited similar alterations in the corresponding group of mice. Intriguingly, IGF1R directly interacted with G-protein-coupled receptor kinase 5, and this association decreased ≈50% in <i>Igf1r</i><sup><i>+/-</i></sup> mice. In addition, <i>Grk5</i> deletion downregulated expression of the Akt/ERK/nuclear factor-κB signaling pathway in primary mouse cardiac fibroblasts. <br /><b>Conclusions:</b><br/>IGF1R signaling deficiency alleviates Ang II-induced cardiac fibrosis, at least partially through inhibiting endothelial-mesenchymal transition via the Akt/ERK/nuclear factor-κB pathway. Interestingly, G-protein-coupled receptor kinase 5 associates with IGF1R signaling directly, and it concurrently acts as an IGF1R downstream effector. This study suggests the promising potential of IGF1R as a therapeutic target for cardiac fibrosis.</AbstractText><br /><br /><br /><br /><small>J Am Heart Assoc: 18 Sep 2023:e029631; epub ahead of print</small></div>
Zhu J, Li Q, Sun Y, Zhang S, ... Sun Z, Zhang L
J Am Heart Assoc: 18 Sep 2023:e029631; epub ahead of print | PMID: 37721135
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<div><h4>DNA Damage and Nuclear Morphological Changes in Cardiac Hypertrophy Are Mediated by SNRK Through Actin Depolymerization.</h4><i>Stanczyk P, Tatekoshi Y, Shapiro JS, Nayudu K, ... Chang HC, Ardehali H</i><br /><b>Background</b><br />Proper nuclear organization is critical for cardiomyocyte function, because global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy; however, the mechanism for this process is not well delineated. AMPK (AMP-activated protein kinase) family of proteins regulates metabolism and DNA damage response (DDR). Here, we examine whether a member of this family, SNRK (SNF1-related kinase), which plays a role in cardiac metabolism, is also involved in hypertrophic remodeling through changes in DDR and structural properties of the nucleus.<br /><b>Methods</b><br />We subjected cardiac-specific <i>Snrk</i><sup>-/-</sup> mice to transaortic banding to assess the effect on cardiac function and DDR. In parallel, we modulated SNRK in vitro and assessed its effects on DDR and nuclear parameters. We also used phosphoproteomics to identify novel proteins that are phosphorylated by SNRK. Last, coimmunoprecipitation was used to verify Destrin (DSTN) as the binding partner of SNRK that modulates its effects on the nucleus and DDR.<br /><b>Results</b><br />Cardiac-specific <i>Snrk</i><sup>-/-</sup> mice display worse cardiac function and cardiac hypertrophy in response to transaortic banding, and an increase in DDR marker pH2AX (phospho-histone 2AX) in their hearts. In addition, in vitro <i>Snrk</i> knockdown results in increased DNA damage and chromatin compaction, along with alterations in nuclear flatness and 3-dimensional volume. Phosphoproteomic studies identified a novel SNRK target, DSTN, a member of F-actin depolymerizing factor proteins that directly bind to and depolymerize F-actin. SNRK binds to DSTN, and DSTN downregulation reverses excess DNA damage and changes in nuclear parameters, in addition to cellular hypertrophy, with SNRK knockdown. We also demonstrate that SNRK knockdown promotes excessive actin depolymerization, measured by the increased ratio of G-actin to F-actin. Last, jasplakinolide, a pharmacological stabilizer of F-actin, rescues the increased DNA damage and aberrant nuclear morphology in SNRK-downregulated cells.<br /><b>Conclusions</b><br />These results indicate that SNRK is a key player in cardiac hypertrophy and DNA damage through its interaction with DSTN. This interaction fine-tunes actin polymerization to reduce DDR and maintain proper cardiomyocyte nuclear shape and morphology.<br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>
Stanczyk P, Tatekoshi Y, Shapiro JS, Nayudu K, ... Chang HC, Ardehali H
Circulation: 18 Sep 2023; epub ahead of print | PMID: 37721051
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<div><h4>Targeted delivery of miR125a-5p and human Factor VIII attenuates molecular mediators of hemophilic arthropathy.</h4><i>Senthilkumar MB, Sarangi P, Amit S, Senguttuvan S, Kumar N, Jayandharan GR</i><br /><AbstractText>Hemophilic arthropathy (HA) due to repeated bleeding into the joint cavity is a major cause of morbidity in patients with hemophilia. The molecular mechanisms contributing to this condition are not well characterized. MicroRNAs (miRs) are known to modulate the phenotype of multiple joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Since miR125a is known to modulate disease progression in OA and RA, we performed a targeted screen of miR125a-5p and its target genes in a murine model of chronic HA. A digital PCR analysis demonstrated significant downregulation of miR125a-5p (2-fold vs control joint). Further molecular evaluation revealed elevated expression of the immunological markers STAT1 (7.6-fold vs control joint) and TRAF6 (10.6 fold vs control joint), which are direct targets of miR125a-5p. We then studied the impact of targeted overexpression of miR125a-5p using an Adeno-associated virus (AAV) vector in modulating the molecular mediators of HA. AAV5-miR125a vectors were administered intra-articularly either alone or in combination with a low dose of AAV8-based human factor 8 (F8) gene in a murine model of HA. We observed significantly increased expression of miR125a-5p in AAV5-miR125a administered mice (~12 fold vs injured joint) or in combination with AAV8-F8 vectors (~44 fold vs injured joint). The activity assay revealed ~17 %-20 % FVIII levels in mice that received low dose liver-directed F8 gene therapy. Further immunohistochemical analysis, demonstrated a decrease in inflammatory markers (STAT1 and TRAF6) and cartilage-degrading matrix metalloproteinases (MMPs) 3, 9, 13 in the joints of treated animals. These data highlight the crucial role of miR125a-5p in the development of HA.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Thromb Res: 17 Sep 2023; 231:8-16</small></div>
Senthilkumar MB, Sarangi P, Amit S, Senguttuvan S, Kumar N, Jayandharan GR
Thromb Res: 17 Sep 2023; 231:8-16 | PMID: 37741049
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<div><h4>LKB1 delays atherosclerosis by inhibiting phenotypic transformation of vascular smooth muscle cells.</h4><i>Chen K, Zhu C, Zhang Q, Zeng Z, ... Zhou Z, Zeng R</i><br /><b>Background:</b><br/>and objective</b><br />Although liver kinase B1 (LKB1) is a well-known tumor suppressor gene, and its encoded protein has important biological functions, it is not clear whether LKB1 can inhibit atherosclerosis by regulating vascular smooth muscle cells (VSMCs). The purpose of this study is to explore the relationship among LKB1, VSMCs and atherosclerosis.<br /><b>Methods and results</b><br />ApoE<sup>-/-</sup> mice with VSMCs-specific overexpression of LKB1 were constructed by adeno-associated virus transfection technique, and then fed with high-fat diet for eight weeks. The effect of LKB1 overexpression on atherosclerosis in mice was investigated by oil red O staining, HE staining, immunofluorescence and Western Blot. The results showed that the expression of LKB1 mRNA and protein in arterial tissue of mice increased significantly after overexpression of LKB1. The degree of atherosclerosis, smooth muscle fiber proliferation and lipid accumulation were significantly alleviated in the overexpression group. The results of Western Blot showed that the expression of α-SMA was increased, while the expression of OPN and CD68 was significantly decreased in the overexpression group (P < 0.05). The Immunofluorescence results of Image Pro Plus software analysis showed that the co-localization relationship between α-SMA and CD68 was more obvious in the control group (P < 0.01).<br /><b>Conclusion</b><br />Our results suggested that LKB1 can delay the progression of atherosclerosis by inhibiting the phenotypic transition of VSMCs.<br /><br />Copyright © 2023. Published by Elsevier B.V.<br /><br /><small>Int J Cardiol: 16 Sep 2023:131363; epub ahead of print</small></div>
Chen K, Zhu C, Zhang Q, Zeng Z, ... Zhou Z, Zeng R
Int J Cardiol: 16 Sep 2023:131363; epub ahead of print | PMID: 37722454
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<div><h4>Elimination of CaMKIIδ Autophosphorylation by CRISPR-Cas9 Base Editing Improves Survival and Cardiac Function in Heart Failure in Mice.</h4><i>Lebek S, Caravia XM, Chemello F, Tan W, ... Bassel-Duby R, Olson EN</i><br /><b>Background</b><br />Cardiovascular diseases are the main cause of worldwide morbidity and mortality, highlighting the need for new therapeutic strategies. Autophosphorylation and subsequent overactivation of the cardiac stress-responsive enzyme CaMKIIδ (Ca<sup>2+</sup>/calmodulin-dependent protein kinase IIδ) serves as a central driver of multiple cardiac disorders.<br /><b>Methods</b><br />To develop a comprehensive therapy for heart failure, we used CRISPR-Cas9 adenine base editing to ablate the autophosphorylation site of CaMKIIδ. We generated mice harboring a phospho-resistant CaMKIIδ mutation in the germline and subjected these mice to severe transverse aortic constriction, a model for heart failure. Cardiac function, transcriptional changes, apoptosis, and fibrosis were assessed by echocardiography, RNA sequencing, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and standard histology, respectively. Specificity toward <i>CaMKIIδ</i> gene editing was assessed using deep amplicon sequencing. Cellular Ca<sup>2+</sup> homeostasis was analyzed using epifluorescence microscopy in Fura-2-loaded cardiomyocytes.<br /><b>Results</b><br />Within 2 weeks after severe transverse aortic constriction surgery, 65% of all wild-type mice died, and the surviving mice showed a dramatically impaired cardiac function. In contrast to wild-type mice, CaMKIIδ phospho-resistant gene-edited mice showed a mortality rate of only 11% and exhibited a substantially improved cardiac function after severe transverse aortic constriction. Moreover, CaMKIIδ phospho-resistant mice were protected from heart failure-related aberrant changes in cardiac gene expression, myocardial apoptosis, and subsequent fibrosis, which were observed in wild-type mice after severe transverse aortic constriction. On the basis of identical mouse and human genome sequences encoding the autophosphorylation site of <i>CaMKIIδ</i>, we deployed the same editing strategy to modify this pathogenic site in human induced pluripotent stem cells. It is notable that we detected a >2000-fold increased specificity for editing of <i>CaMKIIδ</i> compared with other <i>CaMKII</i> isoforms, which is an important safety feature. Although wild-type cardiomyocytes showed impaired Ca<sup>2+</sup> transients and an increased frequency of arrhythmias after chronic β-adrenergic stress, <i>CaMKIIδ</i>-edited cardiomyocytes were protected from these adverse responses.<br /><b>Conclusions</b><br />Ablation of CaMKIIδ autophosphorylation by adenine base editing may offer a potential broad-based therapeutic concept for human cardiac disease.<br /><br /><br /><br /><small>Circulation: 15 Sep 2023; epub ahead of print</small></div>
Lebek S, Caravia XM, Chemello F, Tan W, ... Bassel-Duby R, Olson EN
Circulation: 15 Sep 2023; epub ahead of print | PMID: 37712250
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<div><h4>Cardiomyocyte and endothelial cells play distinct roles in the tumor necrosis factor (TNF)-dependent atrial responses and increased atrial fibrillation vulnerability induced by endurance exercise training in mice.</h4><i>Lakin R, Polidovitch N, Yang S, Parikh M, ... Christoffels VM, Backx PH</i><br /><b>Aims</b><br />Endurance exercise is associated with an increased risk of atrial fibrillation (AF). We previously established that adverse atrial remodeling and AF susceptibility induced by intense exercise in mice requires the mechanosensitive and pro-inflammatory cytokine tumor necrosis factor (TNF). The cellular and mechanistic basis for these TNF-mediated effects is unknown.<br /><b>Methods and results</b><br />We studied the impact of TNF excision, in either atrial cardiomyocytes or endothelial cells (using Cre-recombinase expression controlled by Nppa or Tie2 promoters, respectively), on the cardiac responses to six weeks of intense swim exercise training. TNF ablation, in either cell type, had no impact on the changes in heart rate, autonomic tone or left ventricular structure and function induced by exercise training. Tnf excision in atrial cardiomyocytes did, however, prevent atrial hypertrophy, fibrosis, and macrophage infiltration as well as conduction slowing and increased AF susceptibility arising from exercise training. By contrast, endothelial-specific excision only reduced the training-induced atrial hypertrophy. Consistent with these cell-specific effects of Tnf excision, the loss of TNF in cardiomyocytes was able to prevent the activation of p38MAPKinase, a strain-dependent downstream mediator of TNF signaling, without affecting the atrial stretch as assessed by atrial pressures induced by exercise. Despite TNF\'s established role in innate immune responses and inflammation, neither acute nor chronic exercise training caused measurable NLRP3 inflammasome activation.<br /><b>Conclusions</b><br />Our findings demonstrate that adverse atrial remodeling and AF vulnerability induced by intense exercise requires TNF in atrial cardiomyocytes whereas the impact of endothelial-derived TNF is limited to hypertrophy modulation. The implications of the cell autonomous effects of TNF and crosstalk between cells in the atria are discussed.<br /><b>Translational perspective</b><br />Endurance sport is associated with atrial fibrillation (AF) and mouse models show intense exercise training promotes atrial hypertrophy, fibrosis, inflammation, and AF vulnerability, which requires the mechanosensitive inflammatory cytokine tumor necrosis factor (TNF). We demonstrate that Tnf ablation in atrial cardiomyocytes protects fully against atrial changes induced by exercise, whereas endothelial-specific ablation only prevents atrial hypertrophy. Since atrial filling pressures increase markedly during exercise and most clinical conditions linked to AF (hypertension, heart failure, valvular/metabolic diseases), we discuss how atrial stretch may mediate cell autonomous effects of TNF and arrhythmogenic tissue changes in the atria.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 15 Sep 2023; epub ahead of print</small></div>
Lakin R, Polidovitch N, Yang S, Parikh M, ... Christoffels VM, Backx PH
Cardiovasc Res: 15 Sep 2023; epub ahead of print | PMID: 37713664
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<div><h4>Confounding Effects of Tamoxifen: Cautionary and Practical Considerations for the Use of Tamoxifen-Inducible Mouse Models in Atherosclerosis Research.</h4><i>Dubner AM, Lu S, Jolly AJ, Noble T, ... Majesky MW, Weiser-Evans MCM</i><br /><b>Background</b><br />In recent years, fate-mapping lineage studies in mouse models have led to major advances in vascular biology by allowing investigators to track specific cell populations in vivo. One of the most frequently used lineage tracing approaches involves tamoxifen-inducible Cre<sup>ERT</sup>-LoxP systems. However, tamoxifen treatment can also promote effects independent of Cre recombinase activation, many of which have not been fully explored.<br /><b>Methods</b><br />To elucidate off-target effects of tamoxifen, male and female mice were either unmanipulated or injected with tamoxifen or corn oil. All mice received PCSK9-adeno-associated virus injections and a modified Western diet to induce hypercholesterolemia. After 2 weeks, serum cholesterol and liver morphology were assessed. To determine the duration of any tamoxifen effects in long-term atherosclerosis experiments, mice received either 12 days of tamoxifen at baseline or 12 days plus 2 sets of 5-day tamoxifen boosters; all mice received PCSK9-adeno-associated virus injections and a modified Western diet to induce hypercholesterolemia. After 24 weeks, serum cholesterol and aortic sinus plaque burden were measured.<br /><b>Results</b><br />After 2 weeks of atherogenic treatment, mice injected with tamoxifen demonstrated significantly reduced serum cholesterol levels compared with uninjected- or corn oil-treated mice. However, there were no differences in PCSK9-mediated knockdown of LDL (low-density lipoprotein) receptors between the groups. Additionally, tamoxifen-treated mice exhibited significantly increased hepatic lipid accumulation compared with the other groups. Finally, the effects of tamoxifen remained for at least 8 weeks after completion of injections, with mice demonstrating persistent decreased serum cholesterol and impaired atherosclerotic plaque formation.<br /><b>Conclusions</b><br />In this study, we establish that tamoxifen administration results in decreased serum cholesterol, decreased plaque formation, and increased hepatic lipid accumulation. These alterations represent significant confounding variables in atherosclerosis research, and we urge future investigators to take these findings into consideration when planning and executing their own atherosclerosis experiments.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 14 Sep 2023; epub ahead of print</small></div>
Dubner AM, Lu S, Jolly AJ, Noble T, ... Majesky MW, Weiser-Evans MCM
Arterioscler Thromb Vasc Biol: 14 Sep 2023; epub ahead of print | PMID: 37706321
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<div><h4>Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?</h4><i>Flora GD, Nayak MK, Ghatge M, Chauhan AK</i><br /><AbstractText>Current antithrombotic therapies used in clinical settings either target the coagulation pathways or platelet activation receptors (P2Y12 or GPIIb/IIIa), as well as the cyclooxygenase (COX) enzyme through aspirin. However, they are associated with bleeding risk and are not suitable for long-term use. Thus, novel strategies which provide broad protection against platelet activation with minimal bleeding risks are required. Regardless of the nature of agonist stimulation, platelet activation is an energy-intensive and ATP-driven process characterized by metabolic switching towards a high rate of aerobic glycolysis, relative to oxidative phosphorylation (OXPHOS). Consequently, there has been considerable interest in recent years in investigating whether targeting metabolic pathways in platelets, especially aerobic glycolysis and OXPHOS, can modulate their activation, thereby preventing thrombosis. This review briefly discusses the choices of metabolic substrates available to platelets that drive their metabolic flexibility. We have comprehensively elucidated the relevance of aerobic glycolysis in facilitating platelet activation and the underlying molecular mechanisms that trigger this switch from OXPHOS. We have provided a detailed account of the antiplatelet effects of targeting vital metabolic checkpoints such as pyruvate dehydrogenase kinases (PDKs) and pyruvate kinase M2 (PKM2) that preferentially drive the pyruvate flux to aerobic glycolysis. Furthermore, we discuss the role of fatty acids, and glutamine oxidation in mitochondria and their subsequent role in driving OXPHOS and platelet activation. While the approach of targeting metabolic regulatory mechanisms in platelets to prevent their activation is still in a nascent stage, accumulating evidence highlights its beneficial effects as a potentially novel antithrombotic strategy.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 14 Sep 2023; epub ahead of print</small></div>
Flora GD, Nayak MK, Ghatge M, Chauhan AK
Cardiovasc Res: 14 Sep 2023; epub ahead of print | PMID: 37706546
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<div><h4>Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload-Induced Hypertrophy.</h4><i>Adapala RK, Katari V, Kanugula AK, Ohanyan V, Paruchuri S, Thodeti CK</i><br /><b>Background</b><br />Left ventricular hypertrophy is a bipolar response, starting as an adaptive response to the hemodynamic challenge, but over time develops maladaptive pathology partly due to microvascular rarefaction and impaired coronary angiogenesis. Despite the profound influence on cardiac function, the mechanotransduction mechanisms that regulate coronary angiogenesis, leading to heart failure, are not well known.<br /><b>Methods</b><br />We subjected endothelial-specific knockout mice of mechanically activated ion channel, TRPV4 (transient receptor potential cation channel subfamily V member 4; TRPV4<sup>ECKO</sup>) to pressure overload via transverse aortic constriction and examined cardiac function, cardiomyocyte hypertrophy, cardiac fibrosis, and apoptosis. Further, we measured microvascular density and underlying TRPV4 mechanotransduction mechanisms using human microvascular endothelial cells, ECM gels of varying stiffness, unbiased RNA sequencing, siRNA, Western blot, qPCR, and confocal immunofluorescence techniques.<br /><b>Results</b><br />We demonstrate that endothelial-specific deletion of TRPV4 preserved cardiac function, cardiomyocyte structure, and reduced cardiac fibrosis compared with TRPV4<sup>lox/lox</sup> mice, 28 days post-transverse aortic constriction. Interestingly, comprehensive RNA sequencing analysis revealed an upregulation of proangiogenic factors (VEGFα NOS3, and FGF2) with concomitant increase in microvascular density in TRPV4<sup>ECKO</sup> hearts after transverse aortic constriction compared with TRPV4<sup>lox/lox</sup>. Further, an increased expression of VEGFR2 (vascular endothelial growth factor receptor 2) and activation of the YAP (yes-associated protein) pathway were observed in TRPV4<sup>ECKO</sup> hearts. Mechanistically, we found that downregulation of TRPV4 in endothelial cells induced matrix stiffness-dependent activation of YAP and VEGFR2 via the Rho/Rho kinase/LATS pathway.<br /><b>Conclusions</b><br />Our results suggest that endothelial TRPV4 acts as a mechanical break for coronary angiogenesis, and uncoupling endothelial TRPV4 mechanotransduction attenuates pathological cardiac hypertrophy by enhancing coronary angiogenesis.<br /><br /><br /><br /><small>Hypertension: 13 Sep 2023; epub ahead of print</small></div>
Adapala RK, Katari V, Kanugula AK, Ohanyan V, Paruchuri S, Thodeti CK
Hypertension: 13 Sep 2023; epub ahead of print | PMID: 37702061
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<div><h4>Lifestyle management of hypertension: International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension.</h4><i>Charchar FJ, Prestes PR, Mills C, Ching SM, ... Stergiou G, Tomaszewski M</i><br /><AbstractText>Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools.</AbstractText><br /><br />Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.<br /><br /><small>J Hypertens: 13 Sep 2023; epub ahead of print</small></div>
Charchar FJ, Prestes PR, Mills C, Ching SM, ... Stergiou G, Tomaszewski M
J Hypertens: 13 Sep 2023; epub ahead of print | PMID: 37712135
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<div><h4>A cardiac amino-terminal GRK2 peptide inhibits insulin resistance yet enhances maladaptive cardiovascular and brown adipose tissue remodeling in females during diet-induced obesity.</h4><i>Manaserh IH, Bledzka KM, Ampong I, Junker A, Grondolsky J, Schumacher SM</i><br /><AbstractText>Obesity and metabolic disorders are increasing in epidemic proportions, leading to poor outcomes including heart failure. With a growing recognition of the effect of adipose tissue dysfunction on heart disease, it is less well understood how the heart can influence systemic metabolic homeostasis. Even less well understood is sex differences in cardiometabolic responses. Previously, our lab investigated the role of the amino-terminus of GRK2 in cardiometabolic remodeling using transgenic mice with cardiac restricted expression of a short peptide, βARKnt. Male mice preserved insulin sensitivity, enhanced metabolic flexibility and adipose tissue health, elicited cardioprotection, and improved cardiac metabolic signaling. To examine the effect of cardiac βARKnt expression on cardiac and metabolic function in females in response to diet-induced obesity, we subjected female mice to high fat diet (HFD) to trigger cardiac and metabolic adaptive changes. Despite equivalent weight gain, βARKnt mice exhibited improved glucose tolerance and insulin sensitivity. However, βARKnt mice displayed a progressive reduction in energy expenditure during cold challenge after acute and chronic HFD stress. They also demonstrated reduced cardiac function and increased markers of maladaptive remodeling and tissue injury, and decreased or aberrant metabolic signaling. βARKnt mice exhibited reduced lipid deposition in the brown adipose tissue (BAT), but delayed or decreased markers of BAT activation and function suggested multiple mechanisms contributed to the decreased thermogenic capacity. These data suggest a non-canonical cardiac regulation of BAT lipolysis and function that highlights the need for studies elucidating the mechanisms of sex-specific responses to metabolic dysfunction.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 13 Sep 2023; epub ahead of print</small></div>
Manaserh IH, Bledzka KM, Ampong I, Junker A, Grondolsky J, Schumacher SM
J Mol Cell Cardiol: 13 Sep 2023; epub ahead of print | PMID: 37714510
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<div><h4>Platelets provide robustness of spatial blood coagulation to the variation of initial conditions.</h4><i>Balandina AN, Koltsova EM, Shibeko AM, Kuprash AD, ... Ataullakhanov FI, Panteleev MA</i><br /><AbstractText>Activated platelets provide phospholipid surface and secrete coagulation factors, enhancing blood clotting. We investigated the role of platelets in the regulation of blood coagulation spatial dynamics. We activated blood clotting with tissue factor-bearing (TF) surface in platelet-rich plasma (PRP) or platelet-free plasma (PFP). When blood coagulation was initiated by high TF density, clot growth rate (V) in PRP (2 × 10<sup>5</sup>/μL platelets) was only 15 % greater than in PFP. Spatial distribution of thrombin in PRP had a peak-like shape in the area of the fibrin clot edge, while in PFP thrombin was distributed in the shape of descending plateau. Platelet inhibition with prostaglandin E1 or cytochalasin D made spatial thrombin distribution look like in the case of PFP. Inhibition of blood coagulation by natural endogenous inhibitor heparin was diminished in PRP, while the effect of the exogenous or artificial inhibitors (rivaroxaban, nitrophorin, hirudin) remained undisturbed in the presence of platelets. Ten times decrease of the TF surface density greatly depressed blood coagulation in PFP. In PRP only clotting initiation phase was, while the propagation phase remained intact. Coagulation factor deficiency greatly reduced amount of thrombin and decreased V in PFP rather than in PPR. Thus, platelets were redundant for clotting in normal plasma under physiological conditions but provided robustness of the coagulation system to the changes in initial conditions.</AbstractText><br /><br />Copyright © 2023 Elsevier Ltd. All rights reserved.<br /><br /><small>Thromb Res: 13 Sep 2023; 230:133-143</small></div>
Balandina AN, Koltsova EM, Shibeko AM, Kuprash AD, ... Ataullakhanov FI, Panteleev MA
Thromb Res: 13 Sep 2023; 230:133-143 | PMID: 37717370
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<div><h4>Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension.</h4><i>Ranasinghe ADCU, Holohan M, Borger KM, Donahue DL, ... Castellino FJ, Schwarz MA</i><br /><b>Background</b><br />Epigenetic regulation of vascular remodeling in pulmonary hypertension (PH) is poorly understood. Transcription regulating, histone acetylation code alters chromatin accessibility to promote transcriptional activation. Our goal was to identify upstream mechanisms that disrupt epigenetic equilibrium in PH.<br /><b>Methods</b><br />Human pulmonary artery smooth muscle cells (PASMCs), human idiopathic pulmonary arterial hypertension (iPAH):human PASMCs, iPAH lung tissue, failed donor lung tissue, human pulmonary microvascular endothelial cells, iPAH:PASMC and non-iPAH:PASMC RNA-seq databases, NanoString nCounter, and cleavage under targets and release using nuclease were utilized to investigate histone acetylation, hyperacetylation targets, protein and gene expression, sphingolipid activation, cell proliferation, and gene target identification. SPHK2 (sphingosine kinase 2) knockout was compared with control C57BL/6NJ mice after 3 weeks of hypoxia and assessed for indices of PH.<br /><b>Results</b><br />We identified that Human PASMCs are vulnerable to the transcription-promoting epigenetic mediator histone acetylation resulting in alterations in transcription machinery and confirmed its pathological existence in PH:PASMC cells. We report that SPHK2 is elevated as much as 20-fold in iPAH lung tissue and is elevated in iPAH:PASMC cells. During PH pathogenesis, nuclear SPHK2 activates nuclear bioactive lipid S1P (sphingosine 1-phosphate) catalyzing enzyme and mediates transcription regulating histone H3K9 acetylation (acetyl histone H3 lysine 9 [Ac-H3K9]) through EMAP (endothelial monocyte activating polypeptide) II. In iPAH lungs, we identified a 4-fold elevation of the reversible epigenetic transcription modulator Ac-H3K9:H3 ratio. Loss of SPHK2 inhibited hypoxic-induced PH and Ac-H3K9 in mice. We discovered that pulmonary vascular endothelial cells are a priming factor of the EMAP II/SPHK2/S1P axis that alters the acetylome with a specificity for PASMC, through hyperacetylation of histone H3K9. Using cleavage under targets and release using nuclease, we further show that EMAP II-mediated SPHK2 has the potential to modify the local transcription machinery of pluripotency factor KLF4 (Krüppel-like factor 4) by hyperacetylating KLF4 Cis-regulatory elements while deletion and targeted inhibition of SPHK2 rescues transcription altering Ac-H3K9.<br /><b>Conclusions</b><br />SPHK2 expression and its activation of the reversible histone H3K9 acetylation in human pulmonary artery smooth muscle cell represent new therapeutic targets that could mitigate PH vascular remodeling.<br /><br /><br /><br /><small>Circ Res: 12 Sep 2023; epub ahead of print</small></div>
Ranasinghe ADCU, Holohan M, Borger KM, Donahue DL, ... Castellino FJ, Schwarz MA
Circ Res: 12 Sep 2023; epub ahead of print | PMID: 37698017
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<div><h4>BAK contributes critically to necrosis and infarct generation during reperfused myocardial infarction.</h4><i>Qin D, Jia XF, Hanna A, Lee J, ... Frangogiannis NG, Kitsis RN</i><br /><AbstractText>At least seven cell death programs are activated during myocardial infarction (MI), but which are most important in causing heart damage is not understood. Two of these programs are mitochondrial-dependent necrosis and apoptosis. The canonical function of the pro-cell death BCL-2 family proteins BAX and BAK is to mediate permeabilization of the outer mitochondrial membrane during apoptosis allowing apoptogen release. BAX has also been shown to sensitize cells to mitochondrial-dependent necrosis, although the underlying mechanisms remain ill-defined. Genetic deletion of Bax or both Bax and Bak in mice reduces infarct size following reperfused myocardial infarction (MI/R), but the contribution of BAK itself to cardiomyocyte apoptosis and necrosis and infarction has not been investigated. In this study, we use Bak-deficient mice and isolated adult cardiomyocytes to delineate the role of BAK in the pathogenesis of infarct generation and post-infarct remodeling during MI/R and non-reperfused MI. Generalized homozygous deletion of Bak reduced infarct size ~50% in MI/R in vivo, which was attributable primarily to decreases in necrosis. Protection from necrosis was also observed in BAK-deficient isolated cardiomyocytes suggesting that the cardioprotection from BAK loss in vivo is at least partially cardiomyocyte-autonomous. Interestingly, heterozygous Bak deletion, in which the heart still retains ~28% of wild type BAK levels, reduced infarct size to a similar extent as complete BAK absence. In contrast to MI/R, homozygous Bak deletion did not attenuate acute infarct size or long-term scar size, post-infarct remodeling, cardiac dysfunction, or mortality in non-reperfused MI. We conclude that BAK contributes significantly to cardiomyocyte necrosis and infarct generation during MI/R, while its absence does not appear to impact the pathogenesis of non-reperfused MI. These observations suggest BAK may be a therapeutic target for MI/R and that even partial pharmacological antagonism may provide benefit.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 12 Sep 2023; epub ahead of print</small></div>
Qin D, Jia XF, Hanna A, Lee J, ... Frangogiannis NG, Kitsis RN
J Mol Cell Cardiol: 12 Sep 2023; epub ahead of print | PMID: 37709008
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<div><h4>Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.</h4><i>Yoshimoto T, Ishiyama H, Hattori Y, Nishimura K, ... Koga M, Ihara M</i><br /><b>Background:</b><br/>and aims</b><br />RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease.<br /><b>Methods</b><br />From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers.<br /><b>Results</b><br />In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels.<br /><b>Conclusions</b><br />Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.<br /><br />Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.<br /><br /><small>Atherosclerosis: 12 Sep 2023; 382:117281</small></div>
Yoshimoto T, Ishiyama H, Hattori Y, Nishimura K, ... Koga M, Ihara M
Atherosclerosis: 12 Sep 2023; 382:117281 | PMID: 37722316
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<div><h4>Does the small conductance Ca-activated K current I flow under physiological conditions in rabbit and human atrial isolated cardiomyocytes?</h4><i>Giommi A, Gurgel ARB, Smith GL, Workman AJ</i><br /><b>Background</b><br />The small conductance Ca<sup>2+</sup>-activated K<sup>+</sup> current (I<sub>SK</sub>) is a potential therapeutic target for treating atrial fibrillation.<br /><b>Aim</b><br />To clarify, in rabbit and human atrial cardiomyocytes, the intracellular [Ca<sup>2+</sup>]-sensitivity of I<sub>SK</sub>, and its contribution to action potential (AP) repolarisation, under physiological conditions.<br /><b>Methods</b><br />Whole-cell-patch clamp, fluorescence microscopy: to record ion currents, APs and [Ca<sup>2+</sup>]<sub>i</sub>; 35-37°C.<br /><b>Results</b><br />In rabbit atrial myocytes, 0.5 mM Ba<sup>2+</sup> (positive control) significantly decreased whole-cell current, from -12.8 to -4.9 pA/pF (P < 0.05, n = 17 cells, 8 rabbits). By contrast, the I<sub>SK</sub> blocker apamin (100 nM) had no effect on whole-cell current, at any set [Ca<sup>2+</sup>]<sub>i</sub> (~100-450 nM). The I<sub>SK</sub> blocker ICAGEN (1 μM: ≥2 x IC<sub>50</sub>) also had no effect on current over this [Ca<sup>2+</sup>]<sub>i</sub> range. In human atrial myocytes, neither 1 μM ICAGEN (at [Ca<sup>2+</sup>]<sub>i</sub> ~ 100-450 nM), nor 100 nM apamin ([Ca<sup>2+</sup>]<sub>i</sub> ~ 250 nM) affected whole-cell current (5-10 cells, 3-5 patients/group). APs were significantly prolonged (at APD<sub>30</sub> and APD<sub>70</sub>) by 2 mM 4-aminopyridine (positive control) in rabbit atrial myocytes, but 1 μM ICAGEN had no effect on APDs, versus either pre-ICAGEN or time-matched controls. High concentration (10 μM) ICAGEN (potentially I<sub>SK</sub>-non-selective) moderately increased APD<sub>70</sub> and APD<sub>90</sub>, by 5 and 26 ms, respectively. In human atrial myocytes, 1 μM ICAGEN had no effect on APD<sub>30-90</sub>, whether stimulated at 1, 2 or 3 Hz (6-9 cells, 2-4 patients/rate).<br /><b>Conclusion</b><br />I<sub>SK</sub> does not flow in human or rabbit atrial cardiomyocytes with [Ca<sup>2+</sup>]<sub>i</sub> set within the global average diastolic-systolic range, nor during APs stimulated at physiological or supra-physiological (≤3 Hz) rates.<br /><br />Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 11 Sep 2023; epub ahead of print</small></div>
Giommi A, Gurgel ARB, Smith GL, Workman AJ
J Mol Cell Cardiol: 11 Sep 2023; epub ahead of print | PMID: 37704101
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<div><h4>In vitro effects of Gla-domainless factor Xa analog on procoagulant and fibrinolytic pathways in apixaban-treated plasma and whole blood.</h4><i>Terada R, Johnson PM, Butt AL, Mishima Y, ... Levy JH, Tanaka KA</i><br /><b>Background</b><br />Andexanet alfa is a Gla-domainless FXa (GDXa) analog used as an antidote to FXa inhibitors. Despite its clinical use, laboratory monitoring for anti-Xa reversal and the effect of andexanet on fibrinolysis has not been explored. We used a GDXa with a serine-to-alanine mutation at position 195 (chymotrypsin numbering) to model the interaction between andexanet and apixaban.<br /><b>Methods</b><br />Six batches of pooled plasma, and whole blood from healthy volunteers were treated with increasing concentrations of apixaban with/without GDXa. Thrombin generation and plasmin generation (TG and PG) were tested in plasma, and whole blood thrombus formation was tested using thromboelastometry or a flow-chamber system. FXa was also tested in isolation for its ability to support plasmin activation with/without apixaban and GDXa.<br /><b>Results</b><br />Apixaban (250-800 nM) concentration-dependently decreased the velocity and peak of TG in plasma. Apixaban prolonged the onset of thrombus formation in thromboelastometry and flow-chamber tests. GDXa normalized apixaban-induced delays in TG and whole blood thrombus formation. However, GDXa minimally affected the low PG velocity and peak caused by apixaban at higher concentrations (500-800 nM). FXa promoted plasmin generation independent of fibrin that was inhibited by apixaban at supratherapeutic concentrations.<br /><b>Conclusions</b><br />This study demonstrated the feasibility of assessing coagulation lag time recovery in plasma and whole blood following in vitro apixaban reversal using GDXa, a biosimilar to andexanet. In contrast, GDXa-induced changes in plasmin generation and fibrinolysis were limited in PG and tPA-added ROTEM assays, supporting the endogenous profibrinolytic activity of FXa and its inhibition at elevated apixaban concentrations.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>Thromb Res: 09 Sep 2023; 230:119-125</small></div>
Terada R, Johnson PM, Butt AL, Mishima Y, ... Levy JH, Tanaka KA
Thromb Res: 09 Sep 2023; 230:119-125 | PMID: 37713998
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<div><h4>Cardiac Aging Is Promoted by Pseudohypoxia Increasing p300-Induced Glycolysis.</h4><i>Serio S, Pagiatakis C, Musolino E, Felicetta A, ... Condorelli G, Papait R</i><br /><b>Rationale</b><br />Heart failure is typical in the elderly. Metabolic remodeling of cardiomyocytes underlies inexorable deterioration of cardiac function with aging: glycolysis increases at the expense of oxidative phosphorylation, causing an energy deficit contributing to impaired contractility. Better understanding of the mechanisms of this metabolic switching could be critical for reversing the condition.<br /><b>Objective</b><br />To investigate the role of 3 histone modifications (H3K27ac, H3K27me3, and H3K4me1) in the metabolic remodeling occurring in the aging heart.<br /><b>Results</b><br />We report a set of species-conserved enhancers associated with transcriptional changes underlying age-related metabolic remodeling in cardiomyocytes. Activation of the enhancer region of <i>Hk2</i>-a key glycolysis pathway gene-was fostered in old age-onset mouse heart by pseudohypoxia, wherein hypoxia-related genes are expressed under normal O<sub>2</sub> levels, via increased activity of the transcriptional coactivator p300 (E1A-associated binding protein p300)/CBP (CREB-binding protein). Pharmacological inhibition of p300/CBP before the onset of cardiac aging led to a more aerobic, less glycolytic, metabolic state, improved heart contractility, and overall blunting of cardiac decline.<br /><b>Conclusions</b><br />Taken together, our results suggest how epigenetic dysregulation of glycolysis pathway enhancers could potentially be targeted to treat heart failure in the elderly.<br /><br /><br /><br /><small>Circ Res: 08 Sep 2023; epub ahead of print</small></div>
Serio S, Pagiatakis C, Musolino E, Felicetta A, ... Condorelli G, Papait R
Circ Res: 08 Sep 2023; epub ahead of print | PMID: 37681309
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<div><h4>Extracellular Perinexal Separation Is a Principal Determinant of Cardiac Conduction.</h4><i>Adams WP, Raisch TB, Zhao Y, Davalos R, ... Gourdie RG, Poelzing S</i><br /><b>Background</b><br />Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via gap junctions predicts a direct relationship between conduction velocity (CV) and bulk extracellular resistance. By contrast, ephaptic theory is premised on the existence of a biphasic relationship between CV and the volume of specialized extracellular clefts within intercalated discs such as the perinexus. Our objective was to determine the relationship between ventricular CV and structural changes to micro- and nanoscale extracellular spaces.<br /><b>Methods</b><br />Conduction and Cx43 (connexin43) protein expression were quantified from optically mapped guinea pig whole-heart preparations perfused with the osmotic agents albumin, mannitol, dextran 70 kDa, or dextran 2 MDa. Peak sodium current was quantified in isolated guinea pig ventricular myocytes. Extracellular resistance was quantified by impedance spectroscopy. Intercellular communication was assessed in a heterologous expression system with fluorescence recovery after photobleaching. Perinexal width was quantified from transmission electron micrographs.<br /><b>Results</b><br />CV primarily in the transverse direction of propagation was significantly reduced by mannitol and increased by albumin and both dextrans. The combination of albumin and dextran 70 kDa decreased CV relative to albumin alone. Extracellular resistance was reduced by mannitol, unchanged by albumin, and increased by both dextrans. Cx43 expression and conductance and peak sodium currents were not significantly altered by the osmotic agents. In response to osmotic agents, perinexal width, in order of narrowest to widest, was albumin with dextran, 70 kDa; albumin or dextran, 2 MDa; dextran, 70 kDa or no osmotic agent, and mannitol. When compared in the same order, CV was biphasically related to perinexal width.<br /><b>Conclusions</b><br />Cardiac conduction does not correlate with extracellular resistance but is biphasically related to perinexal separation, providing evidence that the relationship between CV and extracellular volume is determined by ephaptic mechanisms under conditions of normal gap junctional coupling.<br /><br /><br /><br /><small>Circ Res: 08 Sep 2023; epub ahead of print</small></div>
Adams WP, Raisch TB, Zhao Y, Davalos R, ... Gourdie RG, Poelzing S
Circ Res: 08 Sep 2023; epub ahead of print | PMID: 37681314
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<div><h4>Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via IFN-I Signaling.</h4><i>Zhou Z, Zhang M, Zhao C, Gao X, ... Hu J, Wang DW</i><br /><AbstractText>Myocarditis is a challenging inflammatory disease of the heart, and better understanding of its pathogenesis is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by CYP (cytochrome P450) enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by sEH (soluble epoxide hydrolase), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and in the murine heart and correlated with the increased expression and activity of sEH after coxsackie B3 virus infection. Administration of a sEH inhibitor prevented coxsackie B3 virus-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated viral infection or improved viral resistance by activating type I IFN (interferon) signaling. At the molecular level, EETs enhanced the interaction between GSK3β (glycogen synthase kinase-3 beta) and TBK1 (TANK-binding kinase 1) to promote IFN-β production. Our findings revealed that EETs and sEH inhibitors prevent the progress of coxsackie B3 virus-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.</AbstractText><br /><br /><br /><br /><small>Circ Res: 08 Sep 2023; epub ahead of print</small></div>
Zhou Z, Zhang M, Zhao C, Gao X, ... Hu J, Wang DW
Circ Res: 08 Sep 2023; epub ahead of print | PMID: 37681352
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<div><h4>Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction.</h4><i>Pandey AK, Bhatt DL, Pandey A, Marx N, ... Pandey A, Verma S</i><br /><AbstractText>For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 07 Sep 2023; epub ahead of print</small></div>
Pandey AK, Bhatt DL, Pandey A, Marx N, ... Pandey A, Verma S
Eur Heart J: 07 Sep 2023; epub ahead of print | PMID: 37674356
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<div><h4>ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1.</h4><i>Amin Sharifi M, Wierer M, An Dang T, Milic J, ... Schunkert H, Kessler T</i><br /><b>Background</b><br />The <i>ADAMTS7</i> locus was genome-wide and significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis.<br /><b>Methods</b><br />Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe<sup>-/-</sup> and Apoe<sup>-/-</sup>Adamts7<sup>-/-</sup> mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. <i>ADAMTS7</i> expression was measured in fibrous caps of human carotid artery plaques.<br /><b>Results</b><br />In humans, <i>ADAMTS7</i> expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe<sup>-/-</sup> mice, atherosclerotic aortas of Apoe<sup>-/-</sup> mice lacking Adamts-7 (Apoe<sup>-/-</sup>Adamts7<sup>-/-</sup>) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe<sup>-/-</sup> and Apoe<sup>-/-</sup>Adamts7<sup>-/-</sup> mice after the Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe<sup>-/-</sup> as compared to Apoe<sup>-/-</sup> Adamts7<sup>-/-</sup> mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site.<br /><b>Conclusions</b><br />ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events.<br /><br /><br /><br /><small>Circ Res: 07 Sep 2023; epub ahead of print</small></div>
Amin Sharifi M, Wierer M, An Dang T, Milic J, ... Schunkert H, Kessler T
Circ Res: 07 Sep 2023; epub ahead of print | PMID: 37675562
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<div><h4>Sodium as an Important Regulator of Immunometabolism.</h4><i>Miyauchi H, Geisberger S, Luft FC, Wilck N, ... Kempa S, Müller DN</i><br /><AbstractText>Salt sensitivity concerns blood pressure alterations after a change in salt intake (sodium chloride). The heart is a pump, and vessels are tubes; sodium can affect both. A high salt intake increases cardiac output, promotes vascular dysfunction and capillary rarefaction, and chronically leads to increased systemic vascular resistance. More recent findings suggest that sodium also acts as an important second messenger regulating energy metabolism and cellular functions. Besides endothelial cells and fibroblasts, sodium also affects innate and adaptive immunometabolism, immune cell function, and influences certain microbes and microbiota-derived metabolites. We propose the idea that the definition of salt sensitivity should be expanded beyond high blood pressure to cellular and molecular salt sensitivity.</AbstractText><br /><br /><br /><br /><small>Hypertension: 07 Sep 2023; epub ahead of print</small></div>
Miyauchi H, Geisberger S, Luft FC, Wilck N, ... Kempa S, Müller DN
Hypertension: 07 Sep 2023; epub ahead of print | PMID: 37675565
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<div><h4>Undiagnosed Pediatric Elevated Blood Pressure Is Characterized by Induction of Proinflammatory and Cytotoxic Mediators.</h4><i>Thürmann L, Bauer M, Ferland M, Messingschlager M, ... Standl M, Trump S</i><br /><b>Background</b><br />Inflammatory processes have been suggested as a culprit of vascular damage in pediatric hypertension. We aimed to investigate transcriptional changes of immune modulators and determine their association with office blood pressure in adolescents who were not diagnosed with hypertension at the time of the study visit.<br /><b>Methods</b><br />Office blood pressure measurements and blood samples were taken from adolescents of 2 German birth cohorts, GINIplus (The German Infant Study on the Influence of Nutrition Intervention Plus Air Pollution and Genetics on Allergy Development; discovery cohort, n=1219) and LISA (Influences of Lifestyle-related factors on the Immune System and the Development of Allergies in Childhood; validation cohort, n=809), during the 15-year follow-up visit and categorized based on the European Society of Hypertension Guideline. Hs-CRP (high-sensitivity C-reactive protein) and expression of 51 genes encoding cytokines/receptors and transcription factors were analyzed.<br /><b>Results</b><br />The prevalence of elevated systolic blood pressure (overweight/obese) was 14.0% (5.1%) and 16.4% (5.2%) in the discovery and validation cohorts, respectively. An enhanced cytotoxic (<i>GZMB, PRF1, IL2RB</i>) and proinflammatory (<i>FOS, IL1B</i>, hs-CRP) immune profile was observed in association with the hypertension class in both cohorts. Expression of hs-CRP and <i>IL1B</i> was driven by overweight with <i>IL1B</i> being identified as a mediator between body mass index and elevated systolic blood pressure (adj.β/95% CI, 0.01/0.0002-0.02). The association of <i>GZMB</i> (adjusted odds ratio/95% CI, 1.67/1.26-2.21; <i>P</i>=0.0004) and <i>PRF1</i> (adjusted odds ratio/95% CI, 1.70/1.26-2.29; <i>P</i>=0.0005) in the hypertension class remained significant in normal-weight individuals without parental predisposition. These effects were confirmed in LISA.<br /><b>Conclusions</b><br />Adolescent hypertension is not limited to known risk groups. As adolescents in the hypertension class show an inflammatory profile similar to that of established hypertension in adults, blood pressure monitoring at a young age is critical to ensure early intervention and prevention of adverse sequelae.<br /><br /><br /><br /><small>Hypertension: 07 Sep 2023; epub ahead of print</small></div>
Thürmann L, Bauer M, Ferland M, Messingschlager M, ... Standl M, Trump S
Hypertension: 07 Sep 2023; epub ahead of print | PMID: 37675573
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<div><h4>Oxidized Phospholipid oxPAPC Alters Regulatory T-Cell Differentiation and Decreases Their Protective Function in Atherosclerosis.</h4><i>Appleton BD, Palmer SA, Smith HP, Stephens LE, Major AS</i><br /><b>Background</b><br />Regulatory T cells (T<sub>regs</sub>) are protective in atherosclerosis but reduced during disease progression due to cell death and loss of stability. However, the mechanisms of T<sub>reg</sub> dysfunction remain unknown. Oxidized phospholipids are abundant in atherosclerosis and can activate innate immune cells, but little is known regarding their impact on T cells. Given T<sub>reg</sub> loss during atherosclerosis progression and oxidized phospholipid levels in the plaque microenvironment, we investigated whether oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), an oxidized phospholipid associated with atherosclerotic plaques, alters T<sub>reg</sub> differentiation and function.<br /><b>Methods</b><br />CD4<sup>+</sup> T cells were polarized to T<sub>reg,</sub> T helper (Th) 1, and Th17 cells with or without oxPAPC and assessed by flow cytometry. Gene expression in oxPAPC-treated T<sub>regs</sub> was analyzed by bulk RNA sequencing. Functional studies of oxPAPC-induced T<sub>regs</sub> were performed by coculturing T<sub>regs</sub> with CellTrace Violet-labeled cells in vitro, and by adoptively transferring T<sub>regs</sub> to hyperlipidemic <i>Ldlr</i><sup><i>-/-</i></sup> mice to measure atherosclerosis progression.<br /><b>Results</b><br />Compared with controls, oxPAPC-treated T<sub>regs</sub> were less viable, but surviving cells expressed higher levels of the Th1-associated markers T-bet, CXCR3, and IFN (interferon)-γ. Th1 and Th17 skewing cultures were unaltered by oxPAPC. IFN-γ is linked to T<sub>reg</sub> instability, thus T<sub>reg</sub> polarization experiments were repeated using <i>Ifngr1</i><sup><i>-/-</i></sup> CD4<sup>+</sup> T cells. IFNγR1 (INF gamma receptor 1) deficiency did not improve cell viability in oxPAPC-treated T<sub>regs</sub>; however, T-bet and IFN-γ expression was not increased in surviving cells suggesting a role for IFN-γsignaling. OxPAPC-treated T<sub>regs</sub> were less suppressive in vitro, and adoptive transfer studies in hyperlipidemic <i>Ldlr</i><sup><i>-/-</i></sup> mice showed that oxPAPC-induced T<sub>regs</sub> possessed altered tissue homing and were insufficient to inhibit atherosclerosis progression.<br /><b>Conclusions</b><br />OxPAPC elicits T<sub>reg</sub>-specific changes altering T<sub>reg</sub> differentiation and inducing a Th1-like phenotype in surviving cells partially through IFN-γ signaling. This is biologically relevant as oxPAPC-treated T<sub>regs</sub> do not reduce atherosclerosis progression in <i>Ldlr</i><sup><i>-/-</i></sup> mice. This study supports the role of oxidized phospholipids in negatively impacting T<sub>reg</sub> differentiation and atheroprotective function.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print</small></div>
Appleton BD, Palmer SA, Smith HP, Stephens LE, Major AS
Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print | PMID: 37675632
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<div><h4>Unanticipated Enhancement of Intestinal TG Output by Apoc3 ASO Inhibition.</h4><i>Mufaqam Syed-Abdul M, Tian L, Lewis GF</i><br /><b>Background</b><br />The objective of this study was to investigate whether apoC3 (apolipoprotein C3) inhibition with an antisense oligonucleotide (ASO) modulates intestinal triglyceride secretion.<br /><b>Methods</b><br />Sprague-Dawley rats were treated with subcutaneous injections of apoC3 ASO 25 mg/kg twice weekly or inactive ASO for 4 weeks before the assessment of lymph flow, triglyceride and apoB48 appearance in the lymph. Rats were surgically implanted with catheters in the mesenteric lymph duct and duodenum. Following an overnight fast, an intraduodenal lipid bolus (1.5-mL intralipid) was administered. Lymph fluid was collected for the following 4 hours to compare effects on lymph flow, lymph triglyceride and apoB48 concentration, and secretion. To assess suppression of apoC3 expression and protein abundance by apoC3 ASO compared with inactive ASO (placebo), intestinal and hepatic tissues were collected from a subset of animals before (fasting) and after an enteral lipid bolus (post-lipid).<br /><b>Results</b><br />ApoC3 ASO significantly reduced apoC3 mRNA expression in the liver compared with inactive ASO (fasting: 42%, <i>P</i>=0.0048; post-lipid: 66%, <i>P</i><0.001) and in the duodenum (fasting: 29%, <i>P</i>=0.0424; post-lipid: 53%, <i>P</i>=0.0120). As expected, plasma triglyceride also decreased significantly (fasting: 74%, <i>P</i><0.001; post-lipid: 33%, <i>P</i>=0.0276). Lymph flow and cumulative lymph volume remained unchanged following apoC3 ASO therapy; however, lymph triglyceride, but not apoB48 output, increased by 38% (ANOVA, <i>P</i><0.001). Last, no changes were observed in stool triglyceride, intestinal fat (quantified via oil red O staining), and expression of mRNAs involved in triglyceride synthesis, lipid droplet formation, and chylomicron transport and secretion.<br /><b>Conclusions</b><br />Despite the marked reduction in plasma triglyceride concentration that occurs with apoC3 ASO inhibition, intestinal triglyceride output surprisingly increased rather than decreased. These data demonstrate that the reduction of intestinal triglyceride output does not contribute to the potent plasma triglyceride-lowering observed with this novel therapy for hypertriglyceridemia. Further studies are required to explore the mechanism of this intestinal effect.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print</small></div>
Mufaqam Syed-Abdul M, Tian L, Lewis GF
Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print | PMID: 37675633
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<div><h4>Diversity of Megakaryocytes.</h4><i>Puhm F, Laroche A, Boilard E</i><br /><AbstractText>Megakaryocytes are commonly known as large, polyploid, bone marrow resident cells that contribute to hemostasis through the production of platelets. Soon after their discovery in the 19th century, megakaryocytes were described in tissue locations other than the bone marrow, specifically in the lungs and the blood circulation. However, the localization of megakaryocytes in the lungs and the contribution of lung megakaryocytes to the general platelet pool has only recently been appreciated. Moreover, the conception of megakaryocytes as uniform cells with the sole purpose of platelet production has been challenged. Here, we review the literature on megakaryocyte cell identity and location with a special focus on recent observations of megakaryocyte subpopulations identified by transcriptomic analyses.</AbstractText><br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print</small></div>
Puhm F, Laroche A, Boilard E
Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print | PMID: 37675634
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<div><h4>Transcriptomic Profiling Identifies Ferroptosis-Related Gene Signatures in Ischemic Muscle Satellite Cells Affected by Peripheral Artery Disease.</h4><i>Tran L, Xie B, Assaf E, Ferrari R, ... Watkins S, Sachdev U</i><br /><b>Background</b><br />We hypothesized that transcriptomic profiling of muscle satellite cells in peripheral artery disease (PAD) would identify damage-related pathways contributing to skeletal muscle myopathy. We identified a potential role for ferroptosis-a form of programmed lytic cell death by iron-mediated lipid peroxidation-as one such pathway. Ferroptosis promotes myopathy in ischemic cardiac muscle but has an unknown role in PAD.<br /><b>Methods</b><br />Muscle satellite cells from donors with PAD were obtained during surgery. cDNA libraries were processed for single-cell RNA sequencing using the 10X Genomics platform. Protein expression was confirmed based on pathways inferred by transcriptomic analysis.<br /><b>Results</b><br />Unsupervised cluster analysis of over 25 000 cells aggregated from 8 donor samples yielded distinct cell populations grouped by a shared unique transcriptional fingerprint. Quiescent cells were diminished in ischemic muscle while myofibroblasts and apoptotic cells were prominent. Differential gene expression demonstrated a surprising increase in genes associated with iron transport and oxidative stress and a decrease in GPX4 (glutathione peroxidase 4) in ischemic PAD-derived cells. Release of the danger signal HMGB1 (high mobility group box-1) correlated with ferroptotic markers including surface transferrin receptor and were higher in ischemia. Furthermore, lipid peroxidation in muscle satellite cells was modulated by ferrostatin, a ferroptosis inhibitor. Histology confirmed iron deposition and lipofuscin, an inducer of ferroptosis in PAD-affected muscle.<br /><b>Conclusions</b><br />This is the first report documenting that genes known to be involved in ferroptosis are differentially expressed in human skeletal muscle affected by PAD. Targeting ferroptosis may be a novel therapeutic strategy to reduce PAD myopathy.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print</small></div>
Tran L, Xie B, Assaf E, Ferrari R, ... Watkins S, Sachdev U
Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print | PMID: 37675635
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<div><h4>PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice.</h4><i>Lee SK, Malik R, Zhou J, Wang W, ... Ramachandran R, Trigatti BL</i><br /><b>Background</b><br />SR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested.<br /><b>Methods</b><br />We tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days.<br /><b>Results</b><br />Platelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide-mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice.<br /><b>Conclusions</b><br />The PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print</small></div>
Lee SK, Malik R, Zhou J, Wang W, ... Ramachandran R, Trigatti BL
Arterioscler Thromb Vasc Biol: 07 Sep 2023; epub ahead of print | PMID: 37675637
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<div><h4>Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation.</h4><i>Xiao Z, Wei X, Li M, Yang K, ... Liang Y, Ge J</i><br /><b>Background</b><br />Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI.<br /><b>Methods</b><br />MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury.<br /><b>Results</b><br />Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury.<br /><b>Conclusion</b><br />This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 07 Sep 2023; 183:54-66</small></div>
Xiao Z, Wei X, Li M, Yang K, ... Liang Y, Ge J
J Mol Cell Cardiol: 07 Sep 2023; 183:54-66 | PMID: 37689005
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<div><h4>Possibilities of dapagliflozin-induced cardioprotection on doxorubicin + cyclophosphamide mode of chemotherapy-induced cardiomyopathy.</h4><i>Avagimyan A, Sheibani M, Nana P, Mkrtchyan L, ... Shafie D, Sarrafzadegan N</i><br /><b>Rationale</b><br />The global burden of cardiovascular (CV) and oncological diseases continues to increase. In this regard, the prevention of CV diseases (CVD) before and after cancer treatment is an urgent and unsolved problem in medicine. For this reason, our research group aimed to investigate the possibility of dapagliflozin-related cardioprotection, using an experimental model of chronic Doxorubicin (Adriamycin) + Cyclophosphamide (AC)-mode of chemotherapy-induced cardiomyopathy.<br /><b>Objective</b><br />The redox balance, lipid metabolism, endothelial dysfunction, and myocardial damage parameters were measured to evaluate the pathways of dapagliflozin-induced stabilization of CV homeostasis.<br /><b>Methods</b><br />For this study, 80 inbred Wistar rats were randomly assigned to four equally sized groups. A model of chronic cardiotoxicity was attained by using doxorubicin and cyclophosphamide co-administration. In the case, the markers of redox-balance, cholesterol metabolism, endothelial dysfunction, myocardial alteration, and morphological examination were assessed.<br /><b>Results</b><br />For all parameters, statistically significant deviations were obtained, emphasizing the sequel of AC-mode chemotherapy-related detergent effect on CV system (group 2). Moreover, the data obtained from dapagliflozin-treated groups (group 3) showed that this strategy provide limitation of lipid peroxidation, cholesterol metabolism and endothelial function normalization, with subsequent morphological preservation of myocardium.<br /><b>Conclusion</b><br />Dapagliflozin has a broad spectrum of pleiotropic influences, namely cholesterol-lowering, anti-inflammatory, and endothelium-stabilizing properties. These properties provide a favorable environment for the prevention of chemotherapy-related cardiomyopathy.<br /><br />Copyright © 2023. Published by Elsevier B.V.<br /><br /><small>Int J Cardiol: 02 Sep 2023:131331; epub ahead of print</small></div>
Avagimyan A, Sheibani M, Nana P, Mkrtchyan L, ... Shafie D, Sarrafzadegan N
Int J Cardiol: 02 Sep 2023:131331; epub ahead of print | PMID: 37666280
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<div><h4>Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke.</h4><i>Huang Y, Gu S, Han Z, Yang Z, ... Borlongan C, Lu J</i><br /><AbstractText><br /><b>Background:</b><br/>Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant tissue plasminogen activator) based on arterial thrombectomy could improve the prognosis of patients with acute ischemic stroke, but it could not reduce the incidence of recanalization-related adverse effects. Recently, selective brain hypothermia has been shown to offer neuroprotection against stroke. To enhance the recanalization rate of ischemic stroke and reduce the adverse effects such as tiny thrombosis, brain edema, and hemorrhage, we described for the first time a combined approach of hypothermia and thrombolysis via intraarterial hypothermic rtPA. Methods and Results We initially established the optimal regimen of hypothermic rtPA in adult rats subjected to middle cerebral artery occlusion. Subsequently, we explored the mechanism of action mediating hypothermic rtPA by probing reduction of brain tissue temperature, attenuation of blood-brain barrier damage, and sequestration of inflammation coupled with untargeted metabolomics. Hypothermic rtPA improved neurological scores and reduced infarct volume, while limiting hemorrhagic transformation in middle cerebral artery occlusion rats. These therapeutic outcomes of hypothermic rtPA were accompanied by reduced brain temperature, glucose metabolism, and blood-brain barrier damage. A unique metabolomic profile emerged in hypothermic rtPA-treated middle cerebral artery occlusion rats characterized by downregulated markers for energy metabolism and inflammation. <br /><b>Conclusions:</b><br/>The innovative use of hypothermic rtPA enhances their combined, as opposed to stand-alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke.</AbstractText><br /><br /><br /><br /><small>J Am Heart Assoc: 01 Sep 2023:e029817; epub ahead of print</small></div>
Huang Y, Gu S, Han Z, Yang Z, ... Borlongan C, Lu J
J Am Heart Assoc: 01 Sep 2023:e029817; epub ahead of print | PMID: 37655472
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<div><h4>Fetoplacental vascular effects of maternal adrenergic antihypertensive and cardioprotective medications in pregnancy.</h4><i>Tropea T, Mavichak W, Evangelinos A, Brennan-Richardson C, ... Johnstone ED, Brownbill P</i><br /><AbstractText>Maternal cardiovascular diseases, including hypertension and cardiac conditions, are associated with poor fetal outcomes. A range of adrenergic antihypertensive and cardioprotective medications are often prescribed to pregnant women to reduce major maternal complications during pregnancy. Although these treatments are not considered teratogenic, they may have detrimental effects on fetal growth and development, as they cross the fetoplacental barrier, and may contribute to placental vascular dysregulation. Medication risk assessment sheets do not include specific advice to clinicians and women regarding the safety of these therapies for use in pregnancy and the potential off-target effects of adrenergic medications on fetal growth have not been rigorously conducted. Little is known of their effects on the fetoplacental vasculature. There is also a dearth of knowledge on adrenergic receptor activation and signalling within the endothelium and vascular smooth muscle cells of the human placenta, a vital organ in the maintenance of adequate blood flow to satisfy fetal growth and development. The fetoplacental circulation, absent of sympathetic innervation, and unique in its reliance on endocrine, paracrine and autocrine influence in the regulation of vascular tone, appears vulnerable to dysregulation by adrenergic antihypertensive and cardioprotective medications compared with the adult peripheral circulation. This semi-systematic review focuses on fetoplacental vascular expression of adrenergic receptors, associated cell signalling mechanisms and predictive consequences of receptor activation/deactivation by antihypertensive and cardioprotective medications.</AbstractText><br /><br />Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.<br /><br /><small>J Hypertens: 01 Sep 2023; epub ahead of print</small></div>
Tropea T, Mavichak W, Evangelinos A, Brennan-Richardson C, ... Johnstone ED, Brownbill P
J Hypertens: 01 Sep 2023; epub ahead of print | PMID: 37694528
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<div><h4>Loss of 12-Lipoxygenase Improves the Post-Transfusion Function of Stored Platelets.</h4><i>Larsen HJ, Byrne D, Özpolat T, Chauhan A, ... Fu X, Stolla M</i><br /><b>Background</b><br />Platelets for transfusion are stored for 5 to 7 days. Previous studies have shown that HETE levels in the storage bag negatively correlate with platelet performance in vivo, suggesting that the dysregulation of bioactive lipid mediators may contribute to the storage lesion. In the current study, we sought to understand how genetic deletion and pharmacological inhibition of 12-LOX (12-lipoxygenase) affects platelets during storage and after transfusion.<br /><b>Methods</b><br />Platelets from 12-LOX<sup>+/+</sup> (wild-type [WT]) and 12-LOX<sup>-/-</sup> mice were stored for 24 and 48 hours and profiled using liquid chromatography-tandem mass spectrometry-multiple reaction monitoring or transfused into thrombocytopenic hIL4R-transgenic mice. Platelet function was assessed by flow cytometry and in vivo thrombosis and hemostasis models. To test the role of the COX-1 (cyclooxygenase-1) pathway, donor mice were treated with acetylsalicylic acid. Human platelets were treated with the 12-LOX inhibitor, VLX-1005, or vehicle, stored, and transfused to NOD/SCID mice.<br /><b>Results</b><br />Polyunsaturated fatty acids increased significantly in stored platelets from 12-LOX<sup>-/-</sup> mice, whereas oxylipin concentrations were significantly higher in WT platelets. After transfusion to thrombocytopenic mice, we observed significantly more baseline αIIbβ3 integrin activation in 12-LOX<sup>-/-</sup> platelets than in WT platelets. Stored platelets from 12-LOX<sup>-/-</sup> mice occluded vessels significantly faster than stored WT platelets. In hemostasis models, significantly more stored 12-LOX<sup>-/-</sup> than WT platelets accumulated at the site of venous injury leading to reduced blood loss. Inhibition of COX-1 abrogated both increased integrin activation and thromboxane generation in stored 12-LOX<sup>-/-</sup> platelets, highlighting the critical role of this pathway for improved post-transfusion function. Consistent with our mouse studies, human platelets stored with VLX-1005, showed increased integrin activation compared with vehicle-treated platelets after transfusion.<br /><b>Conclusions</b><br />Deleting 12-LOX improves the post-transfusion function of stored murine platelets by increasing thromboxane generation through COX-1-dependent arachidonic acid metabolism. Future studies should determine the feasibility and safety of 12-LOX-inhibited platelets transfused to humans.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print</small></div>
Larsen HJ, Byrne D, Özpolat T, Chauhan A, ... Fu X, Stolla M
Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print | PMID: 37650322
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<div><h4>Conditional, Tissue-Specific CRISPR/Cas9 Vector System in Zebrafish Reveals the Role of Nrp1b in Heart Regeneration.</h4><i>Singh Angom R, Wang Y, Wang E, Dutta S, Mukhopadhyay D</i><br /><b>Background</b><br />CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) technology-mediated genome editing has significantly improved the targeted inactivation of genes in vitro and in vivo in many organisms. Neuropilins play crucial roles in zebrafish heart regeneration, heart failure in mice, and electrical remodeling after myocardial infarction in rats. But the cell-specific functions of nrp1 have not been described before. In this study, we have investigated the role of nrp1 isoforms, including nrp1a and nrp1b, in cardiomyocytes during cardiac injury and regeneration in adult zebrafish hearts.<br /><b>Methods</b><br />In this study, we have reported a novel CRISPR-based vector system for conditional tissue-specific gene ablation in zebrafish. Specifically, the cardiac-specific <i>cmlc2</i> promoter drives Cas9 expression to silence the <i>nrp1</i> gene in cardiomyocytes in a heat-shock inducible manner. This vector system establishes a unique tool to regulate the gene knockout in both the developmental and adult stages and hence widens the possibility of loss-of-function studies in zebrafish at different stages of development and adulthood. Using this approach, we investigated the role of neuropilin isoforms <i>nrp1a</i> and <i>nrp1b</i> in response to cardiac injury and regeneration in adult zebrafish hearts.<br /><b>Results</b><br />We observed that both the isoforms (<i>nrp1a</i> and <i>nrp1b</i>) are upregulated after the cryoinjury. Interestingly, the <i>nrp1b</i> knockout significantly delayed heart regeneration and impaired cardiac function in the adult zebrafish after cryoinjury, demonstrated by reduced heart rate, ejection fractions, and fractional shortening. In addition, we show that the knockdown of <i>nrp1b</i> but not <i>nrp1a</i> induces activation of the cardiac remodeling genes in response to cryoinjury.<br /><b>Conclusions</b><br />To our knowledge, this is the first study where we have reported a heat-shock-mediated conditional knockdown of <i>nrp1a</i> and <i>nrp1b</i> isoforms using CRISPR/Cas9 technology in the cardiomyocyte in zebrafish and furthermore have identified a crucial role for the <i>nrp1b</i> isoform in zebrafish cardiac remodeling and eventually heart function in response to injury.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print</small></div>
Singh Angom R, Wang Y, Wang E, Dutta S, Mukhopadhyay D
Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print | PMID: 37650323
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<div><h4>Obesity Duration and Cardiometabolic Disease.</h4><i>Sidhu SK, Aleman JO, Heffron SP</i><br /><AbstractText>Cardiovascular disease risk is known to be influenced by both the severity of a risk factor and the duration of exposure (eg, LDL [low-density lipoprotein] cholesterol, tobacco smoke). However, this concept has been largely neglected within the obesity literature. While obesity severity has been closely linked with cardiometabolic diseases, the risk of developing these conditions among those with obesity may be augmented by greater obesity duration over the life span. Few longitudinal or contemporary studies have investigated the influence of both factors in combination-cumulative obesity exposure-instead generally focusing on obesity severity, often at a single time point, given ease of use and lack of established methods to encapsulate duration. Our review focuses on what is known about the influence of the duration of exposure to excess adiposity within the obesity-associated cardiometabolic disease risk equation by means of summarizing the hypothesized mechanisms for and evidence surrounding the relationships of obesity duration with diverse cardiovascular and metabolic disease. Through the synthesis of the currently available data, we aim to highlight the importance of a better understanding of the influence of obesity duration in cardiovascular and metabolic disease pathogenesis. We underscore the clinical importance of aggressive early attention to obesity identification and intervention to prevent the development of chronic diseases that arise from exposure to excess body weight.</AbstractText><br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print</small></div>
Sidhu SK, Aleman JO, Heffron SP
Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print | PMID: 37650325
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<div><h4>New Therapeutic Targets for the Prevention and Treatment of Venous Thromboembolism With a Focus on Factor XI Inhibitors.</h4><i>Chan NC, Weitz JI</i><br /><AbstractText>FXI (factor XI) and FXII (factor XII) have emerged as targets for new anticoagulants that have the potential to be both more efficacious and safer than the currently available direct oral anticoagulants for the prevention and treatment of venous thromboembolism. In this review, we discuss the role of FXI and FXII in the pathogenesis of venous thromboembolism, explain why FXI is a better target, and explain why FXI inhibitors have potential advantages over currently available anticoagulants. Finally, we describe the FXI inhibitors under development and discuss their potential to address unmet needs in venous thromboembolism management.</AbstractText><br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print</small></div>
Chan NC, Weitz JI
Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print | PMID: 37650326
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<div><h4>RNA-Binding Proteins Regulate Post-Transcriptional Responses to TGF-β to Coordinate Function and Mesenchymal Activation of Murine Endothelial Cells.</h4><i>Wardman R, Keles M, Pachkiv I, Hemanna S, ... Hentze MW, Heineke J</i><br /><b>Background</b><br />Endothelial cells (ECs) are primed to respond to various signaling cues. For example, TGF (transforming growth factor)-β has major effects on EC function and phenotype by driving ECs towards a more mesenchymal state (ie, triggering endothelial to mesenchymal activation), a dynamic process associated with cardiovascular diseases. Although transcriptional regulation triggered by TGF-β in ECs is well characterized, post-transcriptional regulatory mechanisms induced by TGF-β remain largely unknown.<br /><b>Methods</b><br />Using RNA interactome capture, we identified global TGF-β driven changes in RNA-binding proteins in ECs. We investigated specific changes in the RNA-binding patterns of hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) and Csde1 (cold shock domain containing E1) using RNA immunoprecipitation and overlapped this with RNA-sequencing data after knockdown of either protein for functional insight. Using a modified proximity ligation assay, we visualized the specific interactions between hnRNP H1 and Csde1 and target RNAs in situ both in vitro and in mouse heart sections.<br /><b>Results</b><br />Characterization of TGF-β-regulated RBPs (RNA-binding proteins) revealed hnRNP H1 and Csde1 as key regulators of the cellular response to TGF-β at the post-transcriptional level, with loss of either protein-promoting mesenchymal activation in ECs. We found that TGF-β drives an increase in binding of hnRNP H1 to its target RNAs, offsetting mesenchymal activation, but a decrease in Csde1 RNA-binding, facilitating this process. Both, hnRNP H1 and Csde1, dynamically bind and regulate specific subsets of mRNAs related to mesenchymal activation and endothelial function.<br /><b>Conclusions</b><br />Together, we show that RBPs play a key role in the endothelial response to TGF-β stimulation at the post-transcriptional level and that the RBPs hnRNP H1 and Csde1 serve to maintain EC function and counteract mesenchymal activation. We propose that TGF-β profoundly modifies RNA-protein interaction entailing feedback and feed-forward control at the post-transcriptional level, to fine-tune mesenchymal activation in ECs.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print</small></div>
Wardman R, Keles M, Pachkiv I, Hemanna S, ... Hentze MW, Heineke J
Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print | PMID: 37650327
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<div><h4>Endothelial Cell Regulates Neurovascular, Neuronal, and Behavioral Function.</h4><i>Marottoli FM, Zhang H, Flores-Barrera E, de la Villarmois EA, ... Tseng KY, Tai LM</i><br /><b>Background</b><br />Specialized brain endothelial cells and human <i>APOE3</i> are independently important for neurovascular function, yet whether <i>APOE3</i> expression by endothelial cells contributes to brain function is currently unknown. In the present study, we determined whether the loss of endothelial cell <i>APOE3</i> impacts brain vascular and neural function.<br /><b>Methods</b><br />We developed <i>APOE3</i><sup>fl/fl</sup>/Cdh5(PAC)-CreERT2<sup>+/-</sup> (<i>APOE3</i><sup>Cre+/-</sup>) and <i>APOE3</i><sup>fl/fl</sup>/Cdh5(PAC)-CreERT2<sup>-/-</sup> (<i>APOE3</i><sup>Cre</sup><sup>-/-</sup>, control) mice and induced endothelial cell <i>APOE3</i> knockdown with tamoxifen at ≈4 to 5 weeks of age. Neurovascular and neuronal function were evaluated by biochemistry, immunohistochemistry, behavioral testing, and electrophysiology at 9 months of age.<br /><b>Results</b><br />We found that the loss of endothelial <i>APOE3</i> expression was sufficient to cause neurovascular dysfunction including higher permeability and lower vessel coverage in tandem with deficits in spatial memory and fear memory extinction and a disruption of cortical excitatory/inhibitory balance.<br /><b>Conclusions</b><br />Our data collectively support the novel concept that endothelial <i>APOE3</i> plays a critical role in the regulation of the neurovasculature, neural circuit function, and behavior.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print</small></div>
Marottoli FM, Zhang H, Flores-Barrera E, de la Villarmois EA, ... Tseng KY, Tai LM
Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print | PMID: 37650329
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<div><h4>Extracellular Matrix Stiffness Regulates Microvascular Stability by Controlling Endothelial Paracrine Signaling to Determine Pericyte Fate.</h4><i>Yu Y, Leng Y, Song X, Mu J, ... Li J, Wang D</i><br /><b>Background</b><br />The differentiation of pericytes into myofibroblasts causes microvascular degeneration, ECM (extracellular matrix) accumulation, and tissue stiffening, characteristics of fibrotic diseases. It is unclear how pericyte-myofibroblast differentiation is regulated in the microvascular environment. Our previous study established a novel 2-dimensional platform for coculturing microvascular endothelial cells (ECs) and pericytes derived from the same tissue. This study investigated how ECM stiffness regulated microvascular ECs, pericytes, and their interactions.<br /><b>Methods</b><br />Primary microvessels were cultured in the tubular microvascular growth medium on 2-dimensional stiff substrates. Stiff ECM was prepared by incubating ECM solution in regular culture dishes for 1 hour followed by PBS wash. Soft ECM with Young modulus of ≈6 kPa was used unless otherwise noted. Bone grafts were prepared from the rat skull. Immunostaining, RNA sequencing, qRT-PCR, Western blotting, and knockdown experiments were performed on the cells.<br /><b>Results</b><br />Primary microvascular pericytes differentiated into myofibroblasts (NG2<sup>+</sup>αSMA<sup>+</sup>) on stiff ECM, even with the TGFβ (transforming growth factor beta) signaling inhibitor A83-01. Soft ECM and A83-01 cooperatively maintained microvascular stability while inhibiting pericyte-myofibroblast differentiation (NG2<sup>+</sup>αSMA<sup>-/low</sup>). We thus defined 2 pericyte subpopulations: primary (NG2<sup>+</sup>αSMA<sup>-/low</sup>) and activated (NG2<sup>+</sup>αSMA<sup>+</sup>) pericytes. Soft ECM promoted microvascular regeneration and inhibited fibrosis in bone graft transplantation in vivo. As integrins are the major mechanosensor, we performed qRT-PCR screening of integrin family members and found Itgb1 (integrin β1) was the major subunit downregulated by soft ECM and A83-01 treatment. Knocking down <i>Itgb1</i> suppressed myofibroblast differentiation on stiff ECM. Interestingly, ITGB1 phosphorylation (Y783) was mainly located on microvascular ECs on stiff ECM, which promoted EC secretion of paracrine factors, including CTGF (connective tissue growth factor), to induce pericyte-myofibroblast differentiation. CTGF knockdown or monoclonal antibody treatment partially reduced myofibroblast differentiation, implying the participation of multiple pathways in fibrosis formation.<br /><b>Conclusions</b><br />ECM stiffness and TGFβ signaling cooperatively regulate microvascular stability and pericyte-myofibroblast differentiation. Stiff ECM promotes EC ITGB1 phosphorylation (Y783) and CTGF secretion, which induces pericyte-myofibroblast differentiation.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print</small></div>
Yu Y, Leng Y, Song X, Mu J, ... Li J, Wang D
Arterioscler Thromb Vasc Biol: 31 Aug 2023; epub ahead of print | PMID: 37650330
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Abstract
<div><h4>Posttranslational ISGylation of NLRP3 by HERCs enzymes facilitates inflammasome activation in models of inflammation.</h4><i>Qin Y, Meng X, Wang M, Liang W, ... Zhao C, Zhao W</i><br /><AbstractText>The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system that initiates inflammatory responses. Post-translational modifications (PTMs) of NLRP3, including ubiquitination and phosphorylation, control inflammasome activation and determine the intensity of inflammation. However, the role of other PTMs in controlling NLRP3 inflammasome activation remains unclear. This study founded that toll-like receptor (TLR) priming induced NLRP3 ISGylation (a type of PTM in which ISG15 covalently binds to the target protein) to stabilise the NLRP3 protein. Viral infection, represented by SARS-COV-2 infection, and type I IFNs induced the expression of ISG15 and the predominant E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice). HERCs promoted NLRP3 ISGylation and inhibited K48-linked ubiquitination and proteasomal degradation, resulting in the enhancement of NLRP3 inflammasome activation. Concordantly, Herc6 deficiency ameliorated NLRP3-dependent inflammation, and hyperinflammation caused by viral infection. These results illustrate the mechanism by which type I IFNs responses control inflammasome activation and viral infection-induced aberrant NLRP3 activation. This work identifies ISGylation as a PTM of NLRP3 and provides a priming target for modulating NLRP3-dependent immunopathology.</AbstractText><br /><br /><br /><br /><small>J Clin Invest: 31 Aug 2023; epub ahead of print</small></div>
Qin Y, Meng X, Wang M, Liang W, ... Zhao C, Zhao W
J Clin Invest: 31 Aug 2023; epub ahead of print | PMID: 37651190
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Abstract
<div><h4>SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin.</h4><i>Gao J, Huang C, Kong L, Zhou W, ... Wei T, Shen W</i><br /><b>Background</b><br />Efferocytosis is an activity of macrophages that is pivotal for the resolution of inflammation in hypertension. The precise mechanism by which macrophages coordinate efferocytosis and internalize apoptotic cardiomyocytes remains unknown. The aim of this study was to determine whether SIRT3 (sirtuin-3) is required for both apoptotic cardiomyocyte engulfment and anti-inflammatory responses during efferocytosis.<br /><b>Methods</b><br />We generated myeloid SIRT3 knockout mice and knock-in mice carrying an acetylation-defective lysine to arginine K189R mutation (FXN<sup>K189R</sup>). The mice were given Ang II (angiotensin II) infusion for 7 days. We analyzed cardiac macrophages\' mitochondrial iron levels, efferocytosis activity, and phenotype both in vivo and in vitro.<br /><b>Results</b><br />We showed that SIRT3 deficiency exacerbated Ang II-induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN (frataxin) at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXN K189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXN<sup>K189R</sup> mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis.<br /><b>Conclusions</b><br />The SIRT3-FXN axis has the potential to resolve cardiac inflammation by increasing macrophage efferocytosis and anti-inflammatory activities.<br /><br /><br /><br /><small>Circ Res: 30 Aug 2023; epub ahead of print</small></div>
Gao J, Huang C, Kong L, Zhou W, ... Wei T, Shen W
Circ Res: 30 Aug 2023; epub ahead of print | PMID: 37646156
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<div><h4>Single-nuclear transcriptome profiling identifies persistent fibroblast activation in hypertrophic and failing human hearts of patients with longstanding disease.</h4><i>Kattih B, Boeckling F, Shumliakivska M, Tombor L, ... Zeiher AM, Dimmeler S</i><br /><b>Aims</b><br />Cardiac fibrosis drives the progression of heart failure in ischemic and hypertrophic cardiomyopathy. Therefore, the development of specific antifibrotic treatment regimens to counteract cardiac fibrosis is of high clinical relevance. Hence, this study examined the presence of persistent fibroblast activation during longstanding human heart disease at a single-cell resolution to identify putative therapeutic targets to counteract pathological cardiac fibrosis in patients.<br /><b>Methods and results</b><br />We used single nuclei RNA sequencing with human tissues from 2 samples of one healthy donor, 5 hypertrophic and 2 failing hearts. Unsupervised sub-clustering of 7,110 nuclei led to the identification of 7 distinct fibroblast clusters.Deconvolution of cardiac fibroblast heterogeneity revealed a distinct population of human cardiac fibroblasts with a molecular signature of persistent fibroblast activation and a transcriptional switch towards a profibrotic extracellular matrix composition in patients with established cardiac hypertrophy and heart failure. This subcluster was characterized by high expression of POSTN, RUNX1, CILP and a target gene AEBP1 (all p < 0.001). Strikingly, elevated circulating AEBP1 blood level were also detected in a validation cohort of patients with confirmed cardiac fibrosis and hypertrophic cardiomyopathy by cardiac magnetic resonance imaging (p < 0.01). Since endogenous AEBP1 expression was increased in patients with established cardiac hypertrophy and heart failure, we assessed the functional consequence of siRNA mediated AEBP1 silencing in human cardiac fibroblasts. Indeed, AEBP1 silencing reduced proliferation, migration, as well as fibroblast contractile capacity and α-SMA gene expression, which is a hallmark of fibroblast activation (all p < 0.05). Mechanistically, the antifibrotic effects of AEBP1 silencing were linked to TGFβ pathway modulation.<br /><b>Conclusion</b><br />Together, this study identifies persistent fibroblast activation in patients with longstanding heart disease, which might be detected by circulating AEBP1 and therapeutically modulated by its targeted silencing in human cardiac fibroblasts.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 30 Aug 2023; epub ahead of print</small></div>
Kattih B, Boeckling F, Shumliakivska M, Tombor L, ... Zeiher AM, Dimmeler S
Cardiovasc Res: 30 Aug 2023; epub ahead of print | PMID: 37648651
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<div><h4>Apolipoprotein E isoforms differentially affect LCAT-dependent cholesterol esterification.</h4><i>Vitali C, Pavanello C, Turri M, Lund-Katz S, ... Veglia F, Calabresi L</i><br /><b>Background:</b><br/>and aims</b><br />LCAT esterifies cholesterol in both HDL (α-activity) and apoB-containing lipoproteins (β-activity). The main activator of LCAT β-activity is apoE, which in humans exists in 3 main different isoforms (E2, E3 and E4). Here, to gather insights into the potential role of LCAT in apoB-containing lipoprotein metabolism, we investigated the ability of apoE isoforms to promote LCAT-mediated cholesterol esterification.<br /><b>Methods</b><br />We evaluated the plasma cholesterol esterification rate (CER) in 311 individuals who express functional LCAT and either apoE2, apoE3, or apoE4 and in 28 individuals who also carried LCAT mutations causing selective loss of LCAT α-activity (Fish-Eye Disease (FED)-causing mutations). The association of carrier status with CER was determined using an adjusted linear regression model. The kinetic of LCAT activity towards reconstituted HDLs (rHDLs) containing each apoE isoform was determined using the Michaelis-Menten model.<br /><b>Results</b><br />Plasma CER was ∼20% higher in apoE2 carriers compared to apoE3 carriers, and ∼30% higher in apoE2 carriers compared to apoE4 carriers. After adjusting for age, sex, total cholesterol, HDL-C, apoA-I, apoB, chronic kidney disease diagnosis, zygosity, and LCAT concentration, CER remained significantly different among carriers of the three apoE isoforms. The same trend was observed in carriers of FED-causing mutations. rHDLs containing apoE2 were associated with a lower affinity but higher maximal esterification rate, compared to particles containing apoE3 or apoE4.<br /><b>Conclusion</b><br />The present results suggest that the apoE2 isoform is associated with a higher LCAT-mediated cholesterol esterification. This observation may contribute to the characterization of the peculiar functional properties of apoE2.<br /><br />Copyright © 2023 Elsevier B.V. All rights reserved.<br /><br /><small>Atherosclerosis: 30 Aug 2023; 382:117266</small></div>
Vitali C, Pavanello C, Turri M, Lund-Katz S, ... Veglia F, Calabresi L
Atherosclerosis: 30 Aug 2023; 382:117266 | PMID: 37725860
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Abstract
<div><h4>TRAF Family Member 4 Promotes Cardiac Hypertrophy Through the Activation of the AKT Pathway.</h4><i>Li J, Wang CQ, Xiao WC, Chen Y, ... Deng KQ, Li HP</i><br /><AbstractText><br /><b>Background:</b><br/>Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis of cardiac hypertrophy has led to a lack of development and application of therapeutic methods. Methods and Results Our study provides the first evidence that TRAF4, a member of the tumor necrosis factor receptor-associated factor (TRAF) family, acts as a promoter of cardiac hypertrophy. Here, Western blotting assays demonstrated that TRAF4 is upregulated in cardiac hypertrophy. Additionally, TRAF4 deletion inhibits the development of cardiac hypertrophy in a mouse model after transverse aortic constriction surgery, whereas its overexpression promotes phenylephrine stimulation-induced cardiomyocyte hypertrophy in primary neonatal rat cardiomyocytes. Mechanistically, RNA-seq analysis revealed that TRAF4 promoted the activation of the protein kinase B pathway during cardiac hypertrophy. Moreover, we found that inhibition of protein kinase B phosphorylation rescued the aggravated cardiomyocyte hypertrophic phenotypes caused by TRAF4 overexpression in phenylephrine-treated neonatal rat cardiomyocytes, suggesting that TRAF4 may regulate cardiac hypertrophy in a protein kinase B-dependent manner. <br /><b>Conclusions:</b><br/>Our results revealed the regulatory function of TRAF4 in cardiac hypertrophy, which may provide new insights into developing therapeutic and preventive targets for this disease.</AbstractText><br /><br /><br /><br /><small>J Am Heart Assoc: 29 Aug 2023:e028185; epub ahead of print</small></div>
Li J, Wang CQ, Xiao WC, Chen Y, ... Deng KQ, Li HP
J Am Heart Assoc: 29 Aug 2023:e028185; epub ahead of print | PMID: 37642020
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<div><h4>Neutrophils for Revascularization Require Activation of CCR6 and CCL20 by TNFα.</h4><i>Lörchner H, Cañes Esteve L, Góes ME, Harzenetter R, ... Pöling J, Braun T</i><br /><b>Background</b><br />Activation of immune-inflammatory pathways involving TNFα (tumor necrosis factor alpha) signaling is critical for revascularization and peripheral muscle tissue repair after ischemic injury. However, mechanisms of TNFα-driven inflammatory cascades directing recruitment of proangiogenic immune cells to sites of ischemia are unknown.<br /><b>Methods</b><br />Muscle tissue revascularization after permanent femoral artery ligation was monitored in mutant mice by laser Doppler imaging and light sheet fluorescence microscopy. TNFα-mediated signaling and the role of the CCL20 (C-C motif chemokine ligand 20)-CCR6 (C-C chemokine receptor 6) axis for formation of new vessels was studied in vitro and in vivo using bone marrow transplantation, flow cytometry, as well as biochemical and molecular biological techniques.<br /><b>Results</b><br />TNFα-mediated activation of tumor necrosis factor receptor TNFR (tumor necrosis factor receptor) 1 but not TNFR2 was found to be required for postischemic muscle tissue revascularization. Bone marrow-derived CCR6<sup>+</sup> neutrophil granulocytes were identified as a previously undescribed TNFα-induced population of proangiogenic neutrophils, characterized by increased expression of VEGFA (vascular endothelial growth factor A). Mechanistically, postischemic activation of TNFR1 induced expression of the CCL20 in vascular cells and promoted translocation of the CCL20 receptor CCR6 to the cell surface of neutrophils, essentially conditioning VEGFA-expressing proangiogenic neutrophils for CCL20-dependent recruitment to sites of ischemia. Moreover, impaired revascularization of ischemic peripheral muscle tissue in diabetic mice was associated with reduced numbers of proangiogenic neutrophils and diminished CCL20 expression. Administration of recombinant CCL20 enhanced recruitment of proangiogenic neutrophils and improved revascularization of diabetic ischemic skeletal muscles, which was sustained by sequential treatment with fluvastatin.<br /><b>Conclusions</b><br />We demonstrate that site-specific activation of the CCL20-CCR6 axis via TNFα recruits proangiogenic VEGFA-expressing neutrophils to sites of ischemic injury for initiation of muscle tissue revascularization. The findings provide an attractive option for tissue revascularization, particularly under diabetic conditions.<br /><br /><br /><br /><small>Circ Res: 29 Aug 2023; epub ahead of print</small></div>
Lörchner H, Cañes Esteve L, Góes ME, Harzenetter R, ... Pöling J, Braun T
Circ Res: 29 Aug 2023; epub ahead of print | PMID: 37641931
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<div><h4>S14-Phosphorylated RPN6 Mediates Proteasome Activation by PKA and Alleviates Proteinopathy.</h4><i>Yang L, Parajuli N, Wu P, Liu J, Wang X</i><br /><b>Background</b><br />A better understanding of the regulation of proteasome activities can facilitate the search for new therapeutic strategies. A cell culture study shows that cAMP-dependent PKA (protein kinase A) activates the 26S proteasome by pS14-Rpn6 (serine14-phosphorylated Rpn6), but this discovery and its physiological significance remain to be established in vivo.<br /><b>Methods</b><br />Male and female mice with Ser14 of Rpn6 mutated to Ala (S14A [Rpn6/Psmd11<sup>S14A</sup>]) or Asp (S14D) to respectively block or mimic pS14-Rpn6 were created and used along with cells derived from them. cAMP/PKA were manipulated pharmacologically. Ubiquitin-proteasome system functioning was evaluated with the GFPdgn reporter mouse and proteasomal activity assays. Impact of S14A and S14D on proteotoxicity was tested in mice and cardiomyocytes overexpressing the misfolded protein R120G-CryAB (R120G).<br /><b>Results</b><br />PKA activation increased pS14-Rpn6 and 26S proteasome activities in wild-type but not S14A embryonic fibroblasts (mouse embryonic fibroblasts), adult cardiomyocytes, and mouse hearts. Basal 26S proteasome activities were significantly greater in S14D myocardium and adult mouse cardiomyocytes than in wild-type counterparts. S14D::GFPdgn mice displayed significantly lower myocardial GFPdgn protein but not mRNA levels than GFPdgn mice. In R120G mice, a classic model of cardiac proteotoxicity, basal myocardial pS14-Rpn6 was significantly lower compared with nontransgenic littermates, which was not always associated with reduction of other phosphorylated PKA substrates. Cultured S14D neonatal cardiomyocytes displayed significantly faster proteasomal degradation of R120G than wild-type neonatal cardiomyocytes. Compared with R120G mice, S14D/S14D::R120G mice showed significantly greater myocardial proteasome activities, lower levels of total and K48-linked ubiquitin conjugates, and of aberrant CryAB protein aggregates, less fetal gene reactivation, and cardiac hypertrophy, and delays in cardiac malfunction.<br /><b>Conclusions</b><br />This study establishes in animals that pS14-Rpn6 mediates the activation of 26S proteasomes by PKA and that the reduced pS14-Rpn6 is a key pathogenic factor in cardiac proteinopathy, thereby identifying a new therapeutic target to reduce cardiac proteotoxicity.<br /><br /><br /><br /><small>Circ Res: 29 Aug 2023; epub ahead of print</small></div>
Yang L, Parajuli N, Wu P, Liu J, Wang X
Circ Res: 29 Aug 2023; epub ahead of print | PMID: 37641975
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<div><h4>PDE4D mediates impaired β-adrenergic receptor signaling in the sinoatrial node in mice with hypertensive heart disease.</h4><i>Dorey TW, McRae MD, Belke DD, Rose RA</i><br /><b>Aims</b><br />The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII) induced hypertensive heart disease.<br /><b>Methods and results</b><br />C57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. Heart rate (HR) and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization activated current (If), and L-type Ca2+ current (ICa, L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice.<br /><b>Conclusions</b><br />AngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to upregulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 29 Aug 2023; epub ahead of print</small></div>
Dorey TW, McRae MD, Belke DD, Rose RA
Cardiovasc Res: 29 Aug 2023; epub ahead of print | PMID: 37643895
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<div><h4>Blockade of CXCR4 promotes macrophage autophagy through the PI3K/AKT/mTOR pathway to alleviate coronary heart disease.</h4><i>Li F, Peng J, Lu Y, Zhou M, ... Luo P, Xia B</i><br /><b>Objective</b><br />Autophagy is important in regulating inflammation and cholesterol efflux, suggesting that targeting autophagy may slow down atherosclerosis (AS). Since the pathological basis of coronary artery disease (CAD) is atherosclerosis, it is crucial to investigate the role of autophagy in atherosclerosis. This study aimed to investigate the role of the chemokine CXC chemokine receptor 4 (CXCR4) in promoting macrophage autophagy through the phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway to alleviate coronary artery disease.<br /><b>Methods</b><br />The human left coronary artery and myocardium were collected to detect CXCR4, MAP1LC3(LC3) and SQSTM1(p62) expression. ApoE-/- mice were used to establish an atherosclerosis mice model, while human monocytes (THP-1) were used to establish a foam cell model and co-cultured with foam cells using siRNACXCR4. Western blotting was conducted to quantify CXCR4, PI3K/AKT/mTOR pathway protein, LC3, Beclin1 and p62 protein levels. The left coronary artery from humans and mouse aorta and myocardium were stained with Hematoxylin and Eosin (H&E), macrophages with Oil Red O staining and foam cells were assessed by Movat\'s staining. CXCR4 levels, PI3K/AKT/mTOR pathway protein, LC3 and p62 were detected by immunohistochemistry (IHC) and immunofluorescence assays. Detection of autophagosomes in macrophages using transmission electron microscopy. We further assessed whether the effect of CXCR4-mediated macrophage autophagy on the formation of atherosclerosis and structural changes in the myocardium was mediated via the PI3K/AKT/mTOR signaling pathway.<br /><b>Results</b><br />CXCR4 and p62 proteins were upregulated in human coronary lesions, mouse aorta, myocardial tissue, and foam cells, while LC3II/LC3I was downregulated. p85 (P-PI3K), Ser473 (P-AKT), and Ser2448 (P-mTOR) phosphorylated proteins associated with the PI3K/AKT/mTOR pathway were detected in AS and foam cell models. Upregulated CXCR4 inhibited autophagy of macrophages and increased the severity of atherosclerotic lesions. After specific knockdown of CXCR4 by adeno-associated virus (AAV9-CXCR4-RNAi) and siRNACXCR4, the above indicators were reversed, macrophage autophagy was promoted, the severity of atherosclerotic lesions was reduced, and the disorganized arrangement of myocardial architecture was improved.<br /><b>Conclusion</b><br />Knockdown of CXCR4 reduces the extent of coronary artery disease by promoting macrophage autophagy through the PI3K/AKT/mTOR pathway to attenuate atherosclerosis.<br /><br />Copyright © 2023. Published by Elsevier B.V.<br /><br /><small>Int J Cardiol: 29 Aug 2023:131303; epub ahead of print</small></div>
Li F, Peng J, Lu Y, Zhou M, ... Luo P, Xia B
Int J Cardiol: 29 Aug 2023:131303; epub ahead of print | PMID: 37652272
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<div><h4>Significance of lipids, lipoproteins, and apolipoproteins during the first 14-16 months of life.</h4><i>Nielsen ST, Lytsen RM, Strandkjær N, Rasmussen IJ, ... Tybjærg-Hansen A, Frikke-Schmidt R</i><br /><b>Background:</b><br/>and aims</b><br />The aims of this study were to investigate lipid parameters during the first 14-16 months of life, to identify influential factors, and to test whether high concentrations at birth predict high concentrations at 2- and 14-16 months.<br /><b>Methods</b><br />The Copenhagen Baby Heart Study, including 13,354 umbilical cord blood samples and parallel venous blood samples from children and parents at birth (n = 444), 2 months (n = 364), and 14-16 months (n = 168), was used.<br /><b>Results</b><br />Concentrations of lipids, lipoproteins, and apolipoproteins in umbilical cord blood samples correlated highly with venous blood samples from newborns. Concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and lipoprotein(a) increased stepwise from birth to 2 months to 14-16 months. Linear mixed models showed that concentrations of LDL cholesterol, non-HDL cholesterol, and lipoprotein(a) above the 80th percentile at birth were associated with significantly higher concentrations at 2 and 14-16 months. Finally, lipid concentrations differed according to sex, gestational age, birth weight, breastfeeding, and parental lipid concentrations.<br /><b>Conclusions</b><br />Lipid parameters changed during the first 14-16 months of life, and sex, gestational age, birth weight, breastfeeding, and high parental concentrations influenced concentrations. Children with high concentrations of atherogenic lipid traits at birth had higher concentrations at 2 and 14-16 months. These findings increase our knowledge of how lipid traits develop over the first 14-16 months of life and may help in deciding the optimal child age for universal familial hypercholesterolaemia screening.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 26 Aug 2023; epub ahead of print</small></div>
Nielsen ST, Lytsen RM, Strandkjær N, Rasmussen IJ, ... Tybjærg-Hansen A, Frikke-Schmidt R
Eur Heart J: 26 Aug 2023; epub ahead of print | PMID: 37632410
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<div><h4>Acute activation of adipocyte lipolysis reveals dynamic lipid remodeling of the hepatic lipidome.</h4><i>Zhang S, Williams KJ, Verlande-Ferrero A, Chan AP, ... Masri S, Villanueva CJ</i><br /><AbstractText>Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte secreted lipidome and show that there is inter-organ crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome, showed that free fatty acids increase within 30 minutes of β3-adrenergic receptor activation, and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of ATGL exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together these data highlight critical role of adipocyte lipolysis in inter-organ crosstalk between adipocytes and liver.</AbstractText><br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 26 Aug 2023:100434; epub ahead of print</small></div>
Zhang S, Williams KJ, Verlande-Ferrero A, Chan AP, ... Masri S, Villanueva CJ
J Lipid Res: 26 Aug 2023:100434; epub ahead of print | PMID: 37640283
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This program is still in alpha version.