Topic: Basic Research

Abstract
<div><h4>Urine excretion of C3dg and sC5b-9 coincide with proteinuria and development of preeclampsia in pregnant women with type-1 diabetes.</h4><i>Isaksson GL, Nielsen LH, Palarasah Y, Jensen DM, ... Ovesen PG, Jensen BL</i><br /><b>Objective</b><br />Pregnant women with type-1 diabetes have an increased risk of preeclampsia with kidney injury and cardiovascular complications. Urine excretion of plasmin and soluble membrane attack complex (sC5b-9) is elevated in severe preeclampsia. We hypothesized a coupling between these events and that active plasmin promotes intratubular complement activation and membrane deposition.<br /><b>Methods</b><br />Stored urine and plasma samples from pregnant women with type-1 diabetes (n = 88) collected at gestational weeks 12, 20, 28, 32, 36 and 38 were used. In the cohort, 14 women developed preeclampsia and were compared with 16 nonpreeclampsia controls.<br /><b>Results</b><br />Urine C3dg and sC5b-9-associated C9 neoantigen/creatinine ratios increased and were significantly higher in women who developed preeclampsia. Plasma concentrations did not change with gestation. Urine plasmin(ogen) correlated to urine C3dg (r = 0.51, P < 0.001) and C9 neoantigen (r = 0.68, P < 0.001); urine albumin correlated to C3dg (r = 0.44, P < 0.001) and C9 (r = 0.59, P < 0.001). Membrane-associated C3dg and C9 neoantigen was detected in urinary extracellular vesicles from patients but not controls at 36 weeks. Receiver operating characteristic curves showed that C3dg and C9 neoantigen were inferior to albumin as predictive biomarkers for preeclampsia.<br /><b>Conclusion</b><br />In preeclampsia, urinary excretion of activated complement relates significantly to albuminuria and to plasmin(ogen) but not to activation in plasma. Intratubular complement activation in preeclampsia is a postfiltration event tightly related to proteinuria/plasminogenuria and a possible mechanistic link to cellular damage and kidney injury.<br /><br />Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>J Hypertens: 01 Feb 2023; 41:223-232</small></div>
Isaksson GL, Nielsen LH, Palarasah Y, Jensen DM, ... Ovesen PG, Jensen BL
J Hypertens: 01 Feb 2023; 41:223-232 | PMID: 36583350
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Abstract
<div><h4>Adrenomedullin in paraventricular nucleus attenuates adipose afferent reflex and sympathoexcitation via receptors mediated nitric oxide-gamma-aminobutyric acid A type receptor pathway in rats with obesity-related hypertension.</h4><i>Wang FZ, Qian P, Liu MY, Ding L, ... Li RG, Zhou YB</i><br /><b>Background</b><br />Hypothalamic paraventricular nucleus (PVN) is an important central site for the control of the adipose afferent reflex (AAR) that increases sympathetic outflow and blood pressure in obesity-related hypertension (OH).<br /><b>Method</b><br />In this study, we investigated the effects of nitric oxide (NO) and cardiovascular bioactive polypeptide adrenomedullin (ADM) in the PVN on AAR and sympathetic nerve activity (SNA) in OH rats induced by a high-fat diet.<br /><b>Results</b><br />The results showed that ADM, total neuronal NO synthase (nNOS) and phosphorylated-nNOS protein expression levels in the PVN of the OH rats were down-regulated compared to the control rats. The enhanced AAR in OH rats was attenuated by PVN acute application of NO donor sodium nitroprusside (SNP), but was strengthened by the nNOS inhibitor nNOS-I, guanylyl cyclase inhibitor (1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and gamma-aminobutyric acid A type receptor (GABAA) antagonist Bicuculline. Moreover, PVN ADM microinjection not only decreased basal SNA but also attenuated the enhanced AAR in OH rats, which were effectively inhibited by ADM receptor antagonist ADM22-52, nNOS-I, ODQ or Bicuculline pretreatment. Bilateral PVN acute microinjection of ADM also caused greater increases in NO and cyclic guanosine monophosphate (cGMP) levels, and nNOS phosphorylation. Adeno-associated virus vectors encoding ADM (AAV-ADM) transfection in the PVN of OH rats not only decreased the elevated AAR, basal SNA and blood pressure (BP), but also increased the expression and activation of nNOS. Furthermore, AAV-ADM transfection improved vascular remodeling in OH rats.<br /><b>Conclusion</b><br />Taken together, our data highlight the roles of ADM in improving sympathetic overactivation, enhanced AAR and hypertension, and its related mechanisms associated with receptors mediated NO-cGMP-GABAA pathway in OH condition.<br /><br />Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>J Hypertens: 01 Feb 2023; 41:233-245</small></div>
Abstract
<div><h4>Lipidomics in gestational diabetes mellitus.</h4><i>Wang Y, Pan XF, Pan A</i><br /><b>Purpose of review</b><br />Epidemiological and mechanistic studies have reported relationships between blood lipids, mostly measured by traditional method in clinical settings, and gestational diabetes mellitus (GDM). Recent advances of high-throughput lipidomics techniques have made available more comprehensive lipid profiling in biological samples. This review aims to summarize evidence from prospective studies in assessing relations between blood lipids and GDM, and discuss potential underlying mechanisms.<br /><b>Recent findings</b><br />Mass spectrometry and nuclear magnetic resonance spectroscopy-based analytical platforms are extensively used in lipidomics research. Epidemiological studies have identified multiple novel lipidomic biomarkers that are associated with risk of GDM, such as certain types of fatty acids, glycerolipids, glycerophospholipids, sphingolipids, cholesterol, and lipoproteins. However, the findings are inconclusive mainly due to the heterogeneities in study populations, sample sizes, and analytical platforms. Mechanistic evidence indicates that abnormal lipid metabolism may be involved in the pathogenesis of GDM by impairing pancreatic β-cells and inducing insulin resistance through several etiologic pathways, such as inflammation and oxidative stress.<br /><b>Summary</b><br />Lipidomics is a powerful tool to study pathogenesis and biomarkers for GDM. Lipidomic biomarkers and pathways could help to identify women at high risk for GDM and could be potential targets for early prevention and intervention of GDM.<br /><br />Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>Curr Opin Lipidol: 01 Feb 2023; 34:1-11</small></div>
Wang Y, Pan XF, Pan A
Curr Opin Lipidol: 01 Feb 2023; 34:1-11 | PMID: 36637074
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<div><h4>Omega-3 fatty acids and cognitive function.</h4><i>Welty FK</i><br /><b>Purpose of review</b><br />The aim is to provide an update on omega-3 polyunsaturated fatty acids (n-3 PUFA) in preventing cognitive decline and dementia.<br /><b>Recent findings</b><br />Prospective studies and three new meta-analyses suggest that fish or n-3 PUFA intake are associated with a reduction in development of mild cognitive decline and Alzheimer\'s disease. Supplementation with docosahexaenoic acid (DHA) in randomized controlled trials (RCTs) in those with mild cognitive impairment showed benefit on cognitive decline, whereas there was no benefit in Alzheimer\'s disease. In cognitively healthy individuals with clinical coronary artery disease (CAD), 3.36 g EPA and DHA daily slowed cognitive ageing by 2.5 years. Of 15 RCTs in cognitively healthy individuals age more than 55 years, seven reported benefit, whereas eight did not. Potential mechanisms for differences in outcomes include dose, trial duration, apolipoproteinE genotype, sex, stage and rate of cognitive decline, cognitive testing employed and individual characteristics. The downstream product of DHA, neuroprotectin D1, may be involved in beneficial effects.<br /><b>Summary</b><br />Patients with early memory complaints or a family history of dementia and those with CAD should be counselled on the potential benefits of fish intake and supplementation with n-3 PUFA. ApolipoproteinE4 carriers may especially benefit from DHA supplementation prior to development of cognitive decline.<br /><br />Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>Curr Opin Lipidol: 01 Feb 2023; 34:12-21</small></div>
Welty FK
Curr Opin Lipidol: 01 Feb 2023; 34:12-21 | PMID: 36637075
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<div><h4>Inhibition of Intimal Thickening By PRH (Proline-Rich Homeodomain) in Mice.</h4><i>Reolizo LM, Williams H, Wadey K, Frankow A, ... Johnson J, George SJ</i><br /><b>Background</b><br />Late vein graft failure is caused by intimal thickening resulting from endothelial cell (EC) damage and inflammation which promotes vascular smooth muscle cell (VSMC) dedifferentiation, migration, and proliferation. Nonphosphorylatable PRH (proline-rich homeodomain) S163C:S177C offers enhanced stability and sustained antimitotic effect. Therefore, we investigated whether adenovirus-delivered PRH S163C:S177C protein attenuates intimal thickening via VSMC phenotype modification without detrimental effects on ECs.<br /><b>Methods</b><br />PRH S163C:S177C was expressed in vitro (human saphenous vein-VSMCs and human saphenous vein-ECs) and in vivo (ligated mouse carotid arteries) by adenoviruses. Proliferation, migration, and apoptosis were quantified and phenotype was assessed using Western blotting for contractile filament proteins and collagen gel contraction. EC inflammation was quantified using VCAM (vascular cell adhesion protein)-1, ICAM (intercellular adhesion molecule)-1, interleukin-6, and monocyte chemotactic factor-1 measurement and monocyte adhesion. Next Generation Sequencing was utilized to identify novel downstream mediators of PRH action and these and intimal thickening were investigated in vivo.<br /><b>Results</b><br />PRH S163C:S177C inhibited proliferation, migration, and apoptosis and promoted contractile phenotype (enhanced contractile filament proteins and collagen gel contraction) compared with virus control in human saphenous vein-VSMCs. PRH S163C:S177C expression in human saphenous vein-ECs significantly reduced apoptosis, without affecting cell proliferation and migration, while reducing TNF (tumor necrosis factor)-α-induced VCAM-1 and ICAM-1 and monocyte adhesion and suppressing interleukin-6 and monocyte chemotactic factor-1 protein levels. PRH S163C:S177C expression in ligated murine carotid arteries significantly impaired carotid artery ligation-induced neointimal proliferation and thickening without reducing endothelial coverage. Next Generation Sequencing revealed STAT-1 (signal transducer and activator of transcription 1) and HDAC-9 (histone deacetylase 9) as mediators of PRH action and was supported by in vitro and in vivo analyses.<br /><b>Conclusions</b><br />We observed PRH S163C:S177C attenuated VSMC proliferation, and migration and enhanced VSMC differentiation at least in part via STAT-1 and HDAC-9 signaling while promoting endothelial repair and anti-inflammatory properties. These findings highlight the potential for PRH S163C:S177C to preserve endothelial function whilst suppressing intimal thickening, and reducing late vein graft failure.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print</small></div>
Reolizo LM, Williams H, Wadey K, Frankow A, ... Johnson J, George SJ
Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print | PMID: 36700427
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<div><h4>Endothelial Damage Arising From High Salt Hypertension Is Elucidated by Vascular Bed Systematic Profiling.</h4><i>Vinaiphat A, Pazhanchamy K, JebaMercy G, Ngan SC, ... McCarthy NE, Sze SK</i><br /><b>Background</b><br />Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach.<br /><b>Methods</b><br />We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation.<br /><b>Results</b><br />Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart.<br /><b>Conclusions</b><br />These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.<br /><br /><br /><br /><small>Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print</small></div>
Vinaiphat A, Pazhanchamy K, JebaMercy G, Ngan SC, ... McCarthy NE, Sze SK
Arterioscler Thromb Vasc Biol: 26 Jan 2023; epub ahead of print | PMID: 36700429
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<div><h4>Circulating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney Disease.</h4><i>Koide T, Mandai S, Kitaoka R, Matsuki H, ... Yokota T, Uchida S</i><br /><b>Background</b><br />Chronic kidney disease (CKD) accelerates vascular calcification via phenotypic switching of vascular smooth muscle cells (VSMCs). We investigated the roles of circulating small extracellular vesicles (sEVs) between the kidneys and VSMCs and uncovered relevant sEV-propagated microRNAs (miRNAs) and their biological signaling pathways.<br /><b>Methods and results</b><br />We established CKD models in rats and mice by adenine-induced tubulointerstitial fibrosis. Cultures of A10 embryonic rat VSMCs showed increased calcification and transcription of osterix (<i>Sp7</i>), osteocalcin (<i>Bglap</i>), and osteopontin (<i>Spp1</i>) when treated with rat CKD serum. sEVs, but not sEV-depleted serum, accelerated calcification in VSMCs. Intraperitoneal administration of a neutral sphingomyelinase and biogenesis/release inhibitor of sEVs, GW4869 (2.5 mg/kg per 2 days), inhibited thoracic aortic calcification in CKD mice under a high-phosphorus diet. GW4869 induced a nearly full recovery of calcification and transcription of osteogenic marker genes. In CKD, the miRNA transcriptome of sEVs revealed a depletion of 4 miRNAs, <i>miR-16-5p</i>, <i>miR-17~92</i> cluster-originated <i>miR-17-5p</i>/<i>miR-20a-5p</i>, and <i>miR-106b-5p</i>. Their expression decreased in sEVs from CKD patients as kidney function deteriorated. Transfection of VSMCs with each miRNA-mimic mitigated calcification. In silico analyses revealed VEGFA (vascular endothelial growth factor A) as a convergent target of these miRNAs. We found a 16-fold increase in <i>VEGFA</i> transcription in the thoracic aorta of CKD mice under a high-phosphorus diet, which GW4869 reversed. Inhibition of VEGFA-VEGFR2 signaling with sorafenib, fruquintinib, sunitinib, or <i>VEGFR2</i>-targeted siRNA mitigated calcification in VSMCs. Orally administered fruquintinib (2.5 mg/kg per day) for 4 weeks suppressed the transcription of osteogenic marker genes in the mouse aorta. The area under the curve of <i>miR-16-5p</i>, <i>miR-17-5p</i>, <i>20a-5p</i>, and <i>miR-106b-5p</i> for the prediction of abdominal aortic calcification was 0.7630, 0.7704, 0.7407, and 0.7704, respectively.<br /><b>Conclusions</b><br />The miRNA transcriptomic signature of circulating sEVs uncovered their pathologic role, devoid of the calcification-protective miRNAs that target VEGFA signaling in CKD-driven vascular calcification. These sEV-propagated miRNAs are potential biomarkers and therapeutic targets for vascular calcification.<br /><br /><br /><br /><small>Circ Res: 26 Jan 2023; epub ahead of print</small></div>
Koide T, Mandai S, Kitaoka R, Matsuki H, ... Yokota T, Uchida S
Circ Res: 26 Jan 2023; epub ahead of print | PMID: 36700539
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<div><h4>Aircraft noise exposure induces pro-inflammatory vascular conditioning and amplifies vascular dysfunction and impairment of cardiac function after myocardial infarction.</h4><i>Molitor M, Jimenez MTB, Hahad O, Witzler C, ... Münzel T, Wenzel P</i><br /><b>Aims</b><br />Traffic noise may play an important role in the development and deterioration of ischemic heart disease. Thus, we sought to determine the mechanisms of cardiovascular dysfunction and inflammation induced by aircraft noise in a mouse model of myocardial infarction (MI) and in humans with incident MI.<br /><b>Methods and results</b><br />C57BL/6J mice were exposed to noise alone (average sound pressure level 72 dB; peak level 85 dB) up to 4d, resulting in pro-inflammatory aortic gene expression in the myeloid cell adhesion/diapedesis pathways. Noise alone promoted adhesion and infiltration of inflammatory myeloid cells in vascular/cardiac tissue, paralleled by an increased percentage of leukocytes with a pro-inflammatory, reactive oxygen species (ROS)-producing phenotype and augmented expression of Nox-2/phospho-NFκB in peripheral blood. Ligation of the LAD resulted in worsening of cardiac function, pronounced cardiac infiltration of CD11b+ myeloid cells and Ly6Chigh monocytes and induction of interleukin (IL) 6, IL-1β, CCL-2 and Nox-2, being aggravated by noise exposure prior to MI. MI induced stronger endothelial dysfunction and more pronounced increases in vascular ROS in animals preconditioned with noise. Participants of the population-based Gutenberg Health Cohort Study (median follow-up:11.4y) with incident MI revealed elevated CRP at baseline and worse LVEF after MI in case of a history of noise exposure and subsequent annoyance development.<br /><b>Conclusion</b><br />Aircraft noise exposure before MI substantially amplifies subsequent cardiovascular inflammation and aggravates ischemic heart failure, facilitated by a pro-inflammatory vascular conditioning. Our translational results suggest, that measures to reduce environmental noise exposure will be helpful in improving clinical outcome of subjects with MI.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 26 Jan 2023; epub ahead of print</small></div>
Molitor M, Jimenez MTB, Hahad O, Witzler C, ... Münzel T, Wenzel P
Cardiovasc Res: 26 Jan 2023; epub ahead of print | PMID: 36702626
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<div><h4>Interleukin-33 Mediates Cardiomyopathy After Acute Kidney Injury by Signaling to Cardiomyocytes.</h4><i>Florens N, Kasam RK, Rudman-Melnick V, Lin SC, Prasad V, Molkentin JD</i><br /><b>Background</b><br />Acute kidney injury (AKI) is a short-term life-threatening condition that, if survived, can lead to renal insufficiency and development of chronic kidney disease. The pathogenesis of AKI and chronic kidney disease involves direct effects on the heart and the development of hypertrophy and cardiomyopathy.<br /><b>Methods</b><br />We used mouse models of ischemia/reperfusion AKI and unilateral ureteral obstruction to investigate the role of IL-33 (interleukin-33) and its receptor-encoding gene <i>Il1rl1</i> (also called ST2L [suppression of tumorigenicity 2]) in cardiac remodeling after AKI. Mice with cell type-specific genetic disruption of the IL-33/ST2L axis were used, and IL-33 monoclonal antibody, adeno-associated virus encoding IL-33 or ST2L, and recombinant IL-33, as well.<br /><b>Results</b><br />Mice deficient in <i>Il33</i> were refractory to cardiomyopathy associated with 2 models of kidney injury. Treatment of mice with monoclonal IL-33 antibody also protected the heart after AKI. Moreover, overexpression of IL-33 or injection of recombinant IL-33 induced cardiac hypertrophy or cardiomyopathy, or both, but not in mice lacking <i>Il1rl1</i>. AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte-specific deletion of <i>Il1rl1</i> but not in endothelial cell- or fibroblast-specific deletion of <i>Il1rl1</i>. Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy.<br /><b>Conclusions</b><br />These results indicate that IL-33 released from the kidney during AKI underlies cardiorenal syndrome by directly signaling to cardiac myocytes, suggesting that antagonism of IL-33/ST2 axis would be cardioprotective in patients with kidney disease.<br /><br /><br /><br /><small>Circulation: 25 Jan 2023; epub ahead of print</small></div>
Florens N, Kasam RK, Rudman-Melnick V, Lin SC, Prasad V, Molkentin JD
Circulation: 25 Jan 2023; epub ahead of print | PMID: 36695175
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<div><h4>Homeostatic, Non-Canonical Role of Macrophage Elastase in Vascular Integrity.</h4><i>Salarian M, Ghim M, Toczek J, Han J, ... Humphrey JD, Sadeghi MM</i><br /><b>Background</b><br />Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm.<br /><b>Methods</b><br /><i>Apoe</i><sup>-/-</sup> and <i>Mmp12</i><sup>-/-</sup>/<i>Apoe</i><sup>-/-</sup> mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH<sub>1-5</sub> (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined.<br /><b>Results</b><br />Unexpectedly, death from aortic rupture was significantly higher in <i>Mmp12</i><sup>-/-</sup>/<i>Apoe</i><sup>-/-</sup> mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in <i>Mmp12</i><sup><i>-/</i>-</sup> aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in <i>Mmp12</i><sup>-/-</sup> mice pointed to complement overactivation. Treatment with IgG-FH<sub>1-5</sub> decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused <i>Mmp12</i><sup>-/-</sup> mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice.<br /><b>Conclusions</b><br />An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.<br /><br /><br /><br /><small>Circ Res: 24 Jan 2023; epub ahead of print</small></div>
Salarian M, Ghim M, Toczek J, Han J, ... Humphrey JD, Sadeghi MM
Circ Res: 24 Jan 2023; epub ahead of print | PMID: 36691905
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<div><h4>ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm.</h4><i>Cai D, Sun C, Murashita T, Que X, Chen SY</i><br /><b>Background</b><br />Macrophage activation plays a critical role in abdominal aortic aneurysm (AAA) development. However, molecular mechanisms controlling macrophage activation and vascular inflammation in AAA remain largely unknown. The objective of the study was to identify novel mechanisms underlying adenosine deaminase acting on RNA (ADAR1) function in macrophage activation and AAA formation.<br /><b>Methods</b><br />Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development/dissection. Ang II (Angiotensin II) infusion of ApoE-/- mouse model combined with macrophage-specific knockout of ADAR1 was used to study ADAR1 macrophage-specific role in AAA formation/dissection. The relevance of macrophage ADAR1 to human AAA was examined using human aneurysm specimens. Moreover, a novel humanized AAA model was established to test the role of human macrophages in aneurysm formation in human arteries.<br /><b>Results</b><br />Allograft transplantation of wild-type abdominal aortas to ADAR1+/- recipient mice significantly attenuated AAA formation, suggesting that nonvascular ADAR1 is essential for AAA development. ADAR1 deficiency in hematopoietic cells decreased the prevalence and severity of AAA while inhibited macrophage infiltration and aorta wall inflammation. ADAR1 deletion blocked the classic macrophage activation, diminished NF-κB (nuclear factor kappa B) signaling, and enhanced the expression of a number of anti-inflammatory microRNAs. Mechanistically, ADAR1 interacted with Drosha to promote its degradation, which attenuated Drosha-DGCR8 (DiGeorge syndrome critical region 8) interaction, and consequently inhibited pri- to pre-microRNA processing of microRNAs targeting IKKβ, resulting in an increased IKKβ (inhibitor of nuclear factor kappa-B) expression and enhanced NF-κB signaling. Significantly, ADAR1 was induced in macrophages and interacted with Drosha in human AAA lesions. Reconstitution of ADAR1-deficient, but not the wild type, human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries.<br /><b>Conclusions</b><br />Macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism, that is, Drosha protein degradation, which inhibits the processing of microRNAs targeting NF-kB signaling and thus elicits macrophage-mediated vascular inflammation in AAA.<br /><br /><br /><br /><small>Circ Res: 23 Jan 2023; epub ahead of print</small></div>
Cai D, Sun C, Murashita T, Que X, Chen SY
Circ Res: 23 Jan 2023; epub ahead of print | PMID: 36688311
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<div><h4>miR-448 regulates potassium voltage-gated channel subfamily A member 4 (KCNA4) in ischemia and heart failure.</h4><i>Kang GJ, Xie A, Kim E, Dudley SC</i><br /><b>Background</b><br />MicroRNA ,miR-448, mediates some of the effects of ischemia on arrhythmic risk. Potassium Voltage-gated Channel Subfamily A Member 4 (KCNA4) encodes a K<sub>v</sub>1.4 current that opens in response to membrane depolarization and is essential for regulating action potential duration in heart. KCNA4 has a miR-448 binding site.<br /><b>Objective</b><br />Therefore, we investigated whether miR-448 was involved in the regulation of KCNA4 mRNA expression in ischemia.<br /><b>Methods</b><br />Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of KCNA4 and miR-448. Pull-down assays were used to examine the interaction between miR-448 and KCNA4. A miR-448 decoy and binding site mutation were used to examine specificity of the effect for KCNA4.<br /><b>Results</b><br />The expression of KCNA4 is diminished in ischemia and human HF tissues with ventricular tachycardia. Previously, we have shown miR-448 is upregulated in ischemia, and inhibition can prevent arrhythmic risk after myocardial infarction. The 3\'-UTR of KCNA4 has a conserved miR-448 binding site. MiR-448 bound to this site directly and reduced KCNA4 expression and the transient outward potassium current (Ito). Inhibition of miR-448 restored KCNA4.<br /><b>Conclusion</b><br />These findings showed a link between K<sub>v</sub>1.4 downregulation and miR-448-mediated upregulation in ischemia, suggesting a new mechanism for the antiarrhythmic effect of miR-448 inhibition.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 21 Jan 2023; epub ahead of print</small></div>
Kang GJ, Xie A, Kim E, Dudley SC
Heart Rhythm: 21 Jan 2023; epub ahead of print | PMID: 36693615
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<div><h4>Interdependent Nuclear Co-Trafficking of ASPP1 and p53 Aggravates Cardiac Ischemia/Reperfusion Injury.</h4><i>Yang Y, Zhang Y, Yang J, Zhang M, ... Yang B, Pan Z</i><br /><b>Objective</b><br />ASPP1 (apoptosis stimulating of p53 protein 1) is critical in regulating cell apoptosis as a cofactor of p53 to promote its transcriptional activity in the nucleus. However, whether cytoplasmic ASPP1 affects p53 nuclear trafficking and its role in cardiac diseases remains unknown. This study aims to explore the mechanism by which ASPP1 modulates p53 nuclear trafficking and the subsequent contribution to cardiac ischemia/reperfusion (I/R) injury.<br /><b>Methods and results</b><br />The immunofluorescent staining showed that under normal condition ASPP1 and p53 colocalized in the cytoplasm of neonatal mouse ventricular cardiomyocytes, while they were both upregulated and translocated to the nuclei upon hypoxia/reoxygenation treatment. The nuclear translocation of ASPP1 and p53 was interdependent, as knockdown of either ASPP1 or p53 attenuated nuclear translocation of the other one. Inhibition of importin-β1 resulted in the cytoplasmic sequestration of both p53 and ASPP1 in neonatal mouse ventricular cardiomyocytes with hypoxia/reoxygenation stimulation. Overexpression of ASPP1 potentiated, whereas knockdown of ASPP1 inhibited the expression of Bax (Bcl2-associated X), PUMA (p53 upregulated modulator of apoptosis), and Noxa, direct apoptosis-associated targets of p53. ASPP1 was also increased in the I/R myocardium. Cardiomyocyte-specific transgenic overexpression of ASPP1 aggravated I/R injury as indicated by increased infarct size and impaired cardiac function. Conversely, knockout of ASPP1 mitigated cardiac I/R injury. The same qualitative data were observed in neonatal mouse ventricular cardiomyocytes exposed to hypoxia/reoxygenation injury. Furthermore, inhibition of p53 significantly blunted the proapoptotic activity and detrimental effects of ASPP1 both in vitro and in vivo.<br /><b>Conclusions</b><br />Binding of ASPP1 to p53 triggers their nuclear cotranslocation via importin-β1 that eventually exacerbates cardiac I/R injury. The findings imply that interfering the expression of ASPP1 or the interaction between ASPP1 and p53 to block their nuclear trafficking represents an important therapeutic strategy for cardiac I/R injury.<br /><br /><br /><br /><small>Circ Res: 20 Jan 2023; 132:208-222</small></div>
Yang Y, Zhang Y, Yang J, Zhang M, ... Yang B, Pan Z
Circ Res: 20 Jan 2023; 132:208-222 | PMID: 36656967
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<div><h4>Immunology of Giant Cell Arteritis.</h4><i>Weyand CM, Goronzy JJ</i><br /><AbstractText>Giant cell arteritis is an autoimmune disease of medium and large arteries, characterized by granulomatous inflammation of the three-layered vessel wall that results in vaso-occlusion, wall dissection, and aneurysm formation. The immunopathogenesis of giant cell arteritis is an accumulative process in which a prolonged asymptomatic period is followed by uncontrolled innate immunity, a breakdown in self-tolerance, the transition of autoimmunity from the periphery into the vessel wall and, eventually, the progressive evolution of vessel wall inflammation. Each of the steps in pathogenesis corresponds to specific immuno-phenotypes that provide mechanistic insights into how the immune system attacks and damages blood vessels. Clinically evident disease begins with inappropriate activation of myeloid cells triggering the release of hepatic acute phase proteins and inducing extravascular manifestations, such as muscle pains and stiffness diagnosed as polymyalgia rheumatica. Loss of self-tolerance in the adaptive immune system is linked to aberrant signaling in the NOTCH pathway, leading to expansion of NOTCH1<sup>+</sup>CD4<sup>+</sup> T cells and the functional decline of NOTCH4<sup>+</sup> T regulatory cells (Checkpoint 1). A defect in the endothelial cell barrier of adventitial vasa vasorum networks marks Checkpoint 2; the invasion of monocytes, macrophages and T cells into the arterial wall. Due to the failure of the immuno-inhibitory PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death ligand 1) pathway, wall-infiltrating immune cells arrive in a permissive tissues microenvironment, where multiple T cell effector lineages thrive, shift toward high glycolytic activity, and support the development of tissue-damaging macrophages, including multinucleated giant cells (Checkpoint 3). Eventually, the vascular lesions are occupied by self-renewing T cells that provide autonomy to the disease process and limit the therapeutic effectiveness of currently used immunosuppressants. The multi-step process deviating protective to pathogenic immunity offers an array of interception points that provide opportunities for the prevention and therapeutic management of this devastating autoimmune disease.</AbstractText><br /><br /><br /><br /><small>Circ Res: 20 Jan 2023; 132:238-250</small></div>
Weyand CM, Goronzy JJ
Circ Res: 20 Jan 2023; 132:238-250 | PMID: 36656970
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<div><h4>Mechanistic Insights of the LEMD2 p.L13R Mutation and Its Role in Cardiomyopathy.</h4><i>Chen R, Buchmann S, Kroth A, Arias-Loza AP, ... Frantz S, Gerull B</i><br /><b>Background</b><br />Nuclear envelope proteins play an important role in the pathogenesis of hereditary cardiomyopathies. Recently, a new form of arrhythmic cardiomyopathy caused by a homozygous mutation (p.L13R) in the inner nuclear membrane protein LEMD2 was discovered. The aim was to unravel the molecular mechanisms of mutant LEMD2 in the pathogenesis of cardiomyopathy.<br /><b>Methods</b><br />We generated a Lemd2 p.L13R knock-in mouse model and a corresponding cell model via CRISPR/Cas9 technology and investigated the cardiac phenotype as well as cellular and subcellular mechanisms of nuclear membrane rupture and repair.<br /><b>Results</b><br />Knock-in mice developed a cardiomyopathy with predominantly endocardial fibrosis, left ventricular dilatation, and systolic dysfunction. Electrocardiograms displayed pronounced ventricular arrhythmias and conduction disease. A key finding of knock-in cardiomyocytes on ultrastructural level was a significant increase in nuclear membrane invaginations and decreased nuclear circularity. Furthermore, increased DNA damage and premature senescence were detected as the underlying cause of fibrotic and inflammatory remodeling. As the p.L13R mutation is located in the Lap2/Emerin/Man1 (LEM)-domain, we observed a disrupted interaction between mutant LEMD2 and BAF (barrier-to-autointegration factor), which is required to initiate the nuclear envelope rupture repair process. To mimic increased mechanical stress with subsequent nuclear envelope ruptures, we investigated mutant HeLa-cells upon electrical stimulation and increased stiffness. Here, we demonstrated impaired nuclear envelope rupture repair capacity, subsequent cytoplasmic leakage of the DNA repair factor KU80 along with increased DNA damage, and recruitment of the cGAS (cyclic GMP-AMP synthase) to the nuclear membrane and micronuclei.<br /><b>Conclusions</b><br />We show for the first time that the Lemd2 p.L13R mutation in mice recapitulates human dilated cardiomyopathy with fibrosis and severe ventricular arrhythmias. Impaired nuclear envelope rupture repair capacity resulted in increased DNA damage and activation of the cGAS/STING/IFN pathway, promoting premature senescence. Hence, LEMD2 is a new player inthe disease group of laminopathies.<br /><br /><br /><br /><small>Circ Res: 20 Jan 2023; 132:e43-e58</small></div>
Chen R, Buchmann S, Kroth A, Arias-Loza AP, ... Frantz S, Gerull B
Circ Res: 20 Jan 2023; 132:e43-e58 | PMID: 36656972
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<div><h4>Alternative polyadenylation regulation in cardiac development and cardiovascular disease.</h4><i>Cao J, Kuyumcu-Martinez MN</i><br /><AbstractText>Cleavage and polyadenylation of pre-mRNAs is a necessary step for gene expression and function. Majority of human genes exhibit multiple polyadenylation sites, which can be alternatively used to generate different mRNA isoforms from a single gene. Alternative polyadenylation (APA) of pre-mRNAs is important for proteome and transcriptome landscape. APA is tightly regulated during development and contributes to tissue-specific gene regulation. Mis-regulation of APA is linked to a wide range of pathological conditions. APA-mediated gene regulation in the heart is emerging as new area of research. Here, we will discuss the impact of APA on gene regulation during heart development and in cardiovascular diseases. First, we will briefly review how APA impacts gene regulation and discuss molecular mechanisms that control APA. Then, we will address APA regulation during heart development and its dysregulation in cardiovascular diseases. Finally, we will discuss pre-mRNA targeting strategies to correct aberrant APA patterns of essential genes for the treatment or prevention of cardiovascular diseases. The RNA field is blooming due to the advancements in RNA-based technologies. RNA-based vaccines and therapies are becoming the new line of effective and safe approaches for the treatment and prevention of human diseases. Overall, this review will be influential for understanding gene regulation at the RNA level via APA in the heart and will help design RNA-based tools for the treatment of cardiovascular diseases in the future.</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: 20 Jan 2023; epub ahead of print</small></div>
Cao J, Kuyumcu-Martinez MN
Cardiovasc Res: 20 Jan 2023; epub ahead of print | PMID: 36657944
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<div><h4>Sortilin enhances fibrosis and calcification in aortic valve disease by inducing interstitial cell heterogeneity.</h4><i>Iqbal F, Schlotter F, Becker-Greene D, Lupieri A, ... Sonawane AR, Aikawa E</i><br /><b>Aims</b><br />Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored.<br /><b>Methods and results</b><br />An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype.<br /><b>Conclusion</b><br />Sortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.<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: 20 Jan 2023; epub ahead of print</small></div>
Iqbal F, Schlotter F, Becker-Greene D, Lupieri A, ... Sonawane AR, Aikawa E
Eur Heart J: 20 Jan 2023; epub ahead of print | PMID: 36660854
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<div><h4>Procoagulant phenotype induced by oxidized high-density lipoprotein associates with acute kidney injury and death.</h4><i>Prado Y, Pérez L, Eltit F, Echeverría C, ... Cabello-Verrugio C, Simon F</i><br /><b>Background</b><br />Oxidative stress derived from severe systemic inflammation promotes conversion from high-density lipoprotein HDL to oxidized HDL (oxHDL), which interacts with vascular endothelial cells (ECs). OxHDL acquires procoagulant features playing a role in modulating coagulation, which has been linked with organ failure in ICU patients. However, whether oxHDL elicits a ECs-mediated procoagulant phenotype generating organ failure and death, and the underlying molecular mechanism is not known. Therefore, we studied whether oxHDL-treated rats and high-oxHDL ICU patients exhibit a procoagulant phenotype and its association with kidney injury and mortality and the endothelial underlying molecular mechanism.<br /><b>Methods</b><br />Human ECs, oxHDL-treated rats and ICU patients were subjected to several cellular and molecular studies, coagulation analyses, kidney injury assessment and mortality determination.<br /><b>Results</b><br />OxHDL-treated ECs showed a procoagulant protein expression reprograming characterized by increased E-/P-selectin and vWF mRNA expression through specific signaling pathways. OxHDL-treated rats exhibited a procoagulant phenotype and modified E-/P-selectin, vWF, TF and t-PA mRNA expression correlating with plasma TF, t-PA and D-dimer. Also, showed increased death events and the relative risk of death, and increased creatinine, urea, BUN/creatinine ratio, KIM-1, NGAL, β2M, and decreased eGFR, all concordant with kidney injury, correlated with plasma TF, t-PA and D-dimer. ICU patients showed correlation between plasma oxHDL and increased creatinine, cystatin, BUN, BUN/creatinine ratio, KIM-1, NGAL, β2M, and decreased GFR. Notably, ICU high-oxHDL patients showed decreased survival. Interestingly, altered coagulation factors TF, t-PA and D-dimer correlated with both increased oxHDL levels and kidney injury markers, indicating a connection between these factors.<br /><b>Conclusion</b><br />Increased circulating oxHDL generates an endothelial-dependent procoagulant phenotype that associates with acute kidney injury and increased risk of death.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>Thromb Res: 20 Jan 2023; 223:7-23</small></div>
Prado Y, Pérez L, Eltit F, Echeverría C, ... Cabello-Verrugio C, Simon F
Thromb Res: 20 Jan 2023; 223:7-23 | PMID: 36689805
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<div><h4>Bone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities.</h4><i>Mitroulis I, Hajishengallis G, Chavakis T</i><br /><AbstractText>Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of differentiated myeloid cells with elevated pro-inflammatory potential, as a result of maladaptively trained myelopoiesis may be a crucial factor for the perpetuation of inflammation. Several cardiovascular risk factors, including sedentary lifestyle, unhealthy diet, hypercholesterolemia and hyperglycemia, may modulate bone marrow hematopoietic progenitors, causing sustained functional changes that favor chronic metabolic and vascular inflammation. In the present review, we summarize recent studies that support the function of long-term inflammatory memory in progenitors of the bone marrow for development and progression of cardiometabolic disease and related inflammatory comorbidities, including periodontitis and arthritis. We also discuss how maladaptive myelopoiesis associated with the presence of mutated hematopoietic clones, as present in clonal hematopoiesis, may accelerate atherosclerosis via increased inflammation.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 19 Jan 2023; epub ahead of print</small></div>
Mitroulis I, Hajishengallis G, Chavakis T
Cardiovasc Res: 19 Jan 2023; epub ahead of print | PMID: 36655373
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<div><h4>Smooth muscle mineralocorticoid receptor as an epigenetic regulator of vascular ageing.</h4><i>Ibarrola J, Kim SK, Lu Q, DuPont JJ, ... Jaffe JD, Jaffe IZ</i><br /><b>Aims</b><br />Vascular stiffness increases with age and independently predicts cardiovascular disease risk. Epigenetic changes, including histone modifications, accumulate with age but the global pattern has not been elucidated nor are the regulators known. Smooth muscle cell-mineralocorticoid receptor (SMC-MR) contributes to vascular stiffness in ageing mice. Thus, we investigated the regulatory role of SMC-MR in vascular epigenetics and stiffness.<br /><b>Methods and results</b><br />Mass spectrometry-based proteomic profiling of all histone modifications completely distinguished 3 from 12-month-old mouse aortas. Histone-H3 lysine-27 (H3K27) methylation (me) significantly decreased in ageing vessels and this was attenuated in SMC-MR-KO littermates. Immunoblotting revealed less H3K27-specific methyltransferase EZH2 with age in MR-intact but not SMC-MR-KO vessels. These ageing changes were examined in primary human aortic (HA)SMC from adult vs. aged donors. MR, H3K27 acetylation (ac), and stiffness gene (connective tissue growth factor, integrin-α5) expression significantly increased, while H3K27me and EZH2 decreased, with age. MR inhibition reversed these ageing changes in HASMC and the decline in stiffness genes was prevented by EZH2 blockade. Atomic force microscopy revealed that MR antagonism decreased intrinsic stiffness and the probability of fibronectin adhesion of aged HASMC. Conversely, ageing induction in young HASMC with H2O2; increased MR, decreased EZH2, enriched H3K27ac and MR at stiffness gene promoters by chromatin immunoprecipitation, and increased stiffness gene expression. In 12-month-old mice, MR antagonism increased aortic EZH2 and H3K27 methylation, increased EZH2 recruitment and decreased H3K27ac at stiffness genes promoters, and prevented ageing-induced vascular stiffness and fibrosis. Finally, in human aortic tissue, age positively correlated with MR and stiffness gene expression and negatively correlated with H3K27me3 while MR and EZH2 are negatively correlated.<br /><b>Conclusion</b><br />These data support a novel vascular ageing model with rising MR in human SMC suppressing EZH2 expression thereby decreasing H3K27me, promoting MR recruitment and H3K27ac at stiffness gene promoters to induce vascular stiffness and suggests new targets for ameliorating ageing-associated vascular disease.<br /><br />Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.<br /><br /><small>Cardiovasc Res: 18 Jan 2023; 118:3386-3400</small></div>
Ibarrola J, Kim SK, Lu Q, DuPont JJ, ... Jaffe JD, Jaffe IZ
Cardiovasc Res: 18 Jan 2023; 118:3386-3400 | PMID: 35020830
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<div><h4>Circ_0001326 suppresses trophoblast cell proliferation, invasion, migration and epithelial-mesenchymal transition progression in preeclampsia by miR-188-3p/HtrA serine peptidase 1 axis.</h4><i>Gao X, Qu H, Zhang Y</i><br /><b>Background</b><br />It has been reported that the alteration of circular RNAs (circRNAs) during preeclampsia (PE) can be associated with the pathogenesis of this disease. Herein, this work investigated the potential functions and mechanism of circ_0001326 in PE process.<br /><b>Methods</b><br />The levels of genes and proteins were evaluated by quantitative real-time PCR (qRT-PCR) and western blotting. The functional experiments were conducted using cell counting kit-8 (CCK-8), 5-ethynyl-2\'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays, respectively. The binding between miR-188-3p and circ_0001326 or HtrA serine peptidase 1 (HTRA1) was verified by bioinformatics analysis and dual-luciferase reporter assays.<br /><b>Results</b><br />Circ_0001326 and HTRA1 expression was increased, while miR-188-3p expression was decreased in the placental tissues of preeclamptic singleton pregnant women compared with the normal pregnant women. Functionally, up-regulation of circ_0001326 or HTRA1, or down-regulation of miR-188-3p led to the arrest of cell growth, invasion, migration and epithelial-mesenchymal transition (EMT) process in trophoblast cells. Mechanistically, circ_0001326 acted as a sponge for miR-188-3p, which directly targeted HTRA1. Moreover, circ_0001326 could regulate HTRA1 through sequestering miR-188-3p. A series of rescue experiments showed that miR-188-3p reversed the inhibitory effects of circ_0001326 knockdown on above behaviors of trophoblast cells. Besides that, HTRA1 silencing attenuated the action of miR-188-3p inhibitor on trophoblast cell phenotype alteration.<br /><b>Conclusion</b><br />Our study demonstrated that circ_0001326 could promote trophoblast cell proliferation, invasion, migration and EMT in PE by miR-188-3p/HTRA1 axis, indicating a novel insight into the pathogenesis of PE.<br /><br />Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>J Hypertens: 18 Jan 2023; epub ahead of print</small></div>
Abstract
<div><h4>PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications.</h4><i>Xu Z, Gao Z, Fu H, Zeng Y, ... He Q, Luo P</i><br /><b>Aims</b><br />Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity.<br /><b>Methods and results</b><br />We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homeostasis in cardiomyocytes, which led to defective contractile properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3.<br /><b>Conclusions</b><br />We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer-therapy.<br /><b>Translational perspective</b><br />We identified PTX3 as a potential biomarker and target for the treatment of trastuzumab-induced cardiac complications and demonstrated that lapatinib can prevent cardiac dysfunction caused by trastuzumab by blocking EFGR/STAT3-mediated PTX3 release from VECs, which provided a mechanistic rationale for the combined application of lapatinib and trastuzumab in cancer.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 18 Jan 2023; epub ahead of print</small></div>
Xu Z, Gao Z, Fu H, Zeng Y, ... He Q, Luo P
Cardiovasc Res: 18 Jan 2023; epub ahead of print | PMID: 36651911
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<div><h4>Circular RNAs at the intersection of cancer and heart disease: potential therapeutic targets in cardio-oncology.</h4><i>Neufeldt D, Cushman S, Bär C, Thum T</i><br /><AbstractText>Considerable progress has been made for managing cancer, however, with these advancements, comes the discovery of previously unknown adverse events. In particular, the prolonged lifespan of patients has uncovered severe cardiotoxic side effects of widely used anticancer therapies, which restrict their administration and thus compromise the success of the seemingly most suitable treatments in large cancer patient cohorts. Vice versa, cardiovascular diseases can also promote both the onset and progression of different cancers, highlighting that both conditions are deeply interlinked. Recognizing these close interactions, the novel interdisciplinary field of cardio-oncology has emerged to closely study these uniquely correlating diseases. In this regard, non-coding RNAs are gaining increasing attention since they constitute crucial regulators in many physiological but also pathological signaling pathways, including those of cancer and cardiac dysfunction. In this review, we focus on the new subtype of non-coding RNA, circular RNAs, in their distinct exchange within cardio-oncology and discuss their suitability as potent targets for the simultaneous treatment of cardiac dysfunction and cancer.</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: 18 Jan 2023; epub ahead of print</small></div>
Neufeldt D, Cushman S, Bär C, Thum T
Cardiovasc Res: 18 Jan 2023; epub ahead of print | PMID: 36651915
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<div><h4>Metabolism-based cardiomyocytes production for regenerative therapy.</h4><i>Umei TC, Tohyama S, Fukuda K</i><br /><AbstractText>Human pluripotent stem cells (hPSCs) are currently used in clinical applications such as cardiac regenerative therapy, studying disease models, and drug screening for heart failure. Transplantation of hPSC-derived cardiomyocytes (hPSC-CMs) can be used as an alternative therapy for heart transplantation. In contrast to differentiated somatic cells, hPSCs possess unique metabolic programs to maintain pluripotency, and understanding their metabolic features can contribute to the development of technologies that can be useful for their clinical applications. The production of hPSC-CMs requires stepwise specification during embryonic development and metabolic regulation is crucial for proper embryonic development. These metabolic features have been applied to hPSC-CM production methods, such as mesoderm induction, specifications for cardiac progenitors, and their maturation. This review describes the metabolic programs in hPSCs and the metabolic regulation in hPSC-CM production for cardiac regenerative therapy.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print</small></div>
Umei TC, Tohyama S, Fukuda K
J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print | PMID: 36681267
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<div><h4>Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age.</h4><i>Pecha S, Ismaili D, Geelhoed B, Knaut M, ... Christ T, Ravens U</i><br /><b>Aims</b><br />The incidence of atrial fibrillation (AF) increases with age. Women have a lower risk. Little is known on the impact of age, sex and clinical variables on action potentials (AP) recorded in right atrial tissue obtained during open heart surgery from patients in sinus rhythm (SR) and in longstanding AF. We here investigated whether age or sex have an impact on the shape of AP recorded in vitro from right atrial tissue.<br /><b>Methods</b><br />We performed multivariable analysis of individual AP data from trabeculae obtained during heart surgery of patients in SR (n = 320) or in longstanding AF (n = 201). AP were recorded by sharp microelectrodes at 37 °C at 1 Hz. Impact of clinical variables were modeled using a multivariable mixed model regression.<br /><b>Results</b><br />In SR, AP duration at 90% repolarization (APD<sub>90</sub>) increased with age. Lower ejection fraction and higher body mass index were associated with smaller action potential amplitude (APA) and maximum upstroke velocity (V<sub>max</sub>). The use of beta-blockers was associated with larger APD<sub>90</sub>. In tissues from women, resting membrane potential was less negative and APA as well as V<sub>max</sub> were smaller. Besides shorter APD<sub>20</sub> in elderly patients, effects of age and sex on atrial AP were lost in AF.<br /><b>Conclusion</b><br />The higher probability to develop AF at advanced age cannot be explained by a shortening in APD<sub>90</sub>. Less negative RMP and lower upstroke velocity might contribute to lower incidence of AF in women, which may be of clinical relevance.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print</small></div>
Pecha S, Ismaili D, Geelhoed B, Knaut M, ... Christ T, Ravens U
J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print | PMID: 36681268
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<div><h4>Cardiac muscle patches containing four types of cardiac cells derived from human pluripotent stem cells improve recovery from cardiac injury in mice.</h4><i>Lou X, Tang Y, Ye L, Pretorius D, ... Thomson JA, Zhang J</i><br /><b>Aims</b><br />We have shown that human cardiac muscle patches (hCMPs) containing three different types of cardiac cells-cardiomyocytes (CMs), smooth-muscle cells (SMCs), and endothelial cells (ECs), all of which were differentiated from human pluripotent stem cells (hPSCs)-significantly improved cardiac function, infarct size, and hypertrophy in a pig model of myocardial infarction (MI). However, hPSC-CMs are phenotypically immature, which may lead to arrythymogenic concerns; thus, since hPSC-derived cardiac fibroblasts (hPSC-CFs) appear to enhance the maturity of hPSC-CMs, we compared hCMPs containing hPSC-CMs, -SMCs, -ECs, and -CFs (4TCC-hCMPs) with a second hCMP construct that lacked hPSC-CFs but was otherwise identical (3TCC-hCMPs).<br /><b>Methods</b><br />hCMPs were generated in a fibrin scaffold. MI was induced in SCID mice through permanent coronary artery (LAD) ligation, followed by treatment with cardiac muscle patches. Animal groups included: MI heart treated with 3TCC-hCMP; with 4TCC-hCMP; MI heart treated with no patch (MI group) and sham group. Cardiac function was evaluated via echocardiography, and cell engraftment rate while infarct size was evaluated histologically at four weeks after patch transplantation.<br /><b>Results</b><br />The results from experiments in cultured hCMPs demonstrate that the inclusion of CF in 4TCC-hCMPs had: 1) better organized sarcomeres; 2) abundant structural, metabolic, and ion- channel markers of CM maturation; and 3) greater conduction velocities (31 ± 3.23 cm/s, p<0.005) and action-potential durations (APD50 = 365 ms ± 2.649, P<0.0001; APD = 408 ms ± 2.757, P<0.0001) than those (velocity and AP duration time) in 3TCC-hCMPs. Furthermore, when 4TCC- hCMPs transplantation resulted in better cardiac function (EF = 49.18% ± 0.86, p<0.05), reduced infarct size (22.72% ± 0.98, p<0.05), and better engraftment (15.99% ± 1.56, p<0.05) as compared with 3TCC-hCMPs (EF = 41.55 ± 0.92%, infarct size = 39.23 ± 4.28%, and engraftment = 8.56 ± 1.79%, respectively).<br /><b>Conclusion</b><br />Collectively, these observations suggest that the inclusion of hPSC-CFs during hCMP manufacture promotes hPSC-CM maturation and increases the potency of implanted hCMPs for improving cardiac recovery in mice model of MI.<br /><b>Translational perspective</b><br />Heart transplantation surgery remains the only established treatment for end-stage heart disease, and the supply of donated hearts is far lower than the number of patients in need of treatment. Thus, the goal of cardiac tissue engineering is to replace the scarred region of an injured heart with functional cardiac muscle. The results presented in this report suggest that engineered human cardiac-muscle patches may be more effective for the treatment of heart disease when they are constructed with cardiomyocytes, smooth-muscle cells, endothelial cells, and cardiac fibroblasts than when the cardiac fibroblasts are omitted.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 17 Jan 2023; epub ahead of print</small></div>
Lou X, Tang Y, Ye L, Pretorius D, ... Thomson JA, Zhang J
Cardiovasc Res: 17 Jan 2023; epub ahead of print | PMID: 36647784
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<div><h4>VGLL4-TEAD1 promotes vascular smooth muscle cell differentiation from human pluripotent stem cells via TET2.</h4><i>Wang Z, Quan Y, Hu M, Xu Y, ... Li M, Wang Y</i><br /><AbstractText>The Hippo signaling pathway plays a critical role in cardiovascular development and stem cell differentiation. Using microarray profiling, we found that the Hippo pathway components vestigial-like family member 4 (VGLL4) and TEA domain transcription factor 1 (TEAD1) were upregulated during vascular smooth muscle cell (VSMC) differentiation from H1 ESCs (.H1 embryonic stem cells) To further explore the role and molecular mechanisms of VGLL4 in regulating VSMC differentiation, we generated a VGLL4-knockdown H1 ESC line (heterozygous knockout) using the CRISPR/Cas9 system and found that VGLL4 knockdown inhibited VSMC specification. In contrast, overexpression of VGLL4 using the PiggyBac transposon system facilitated VSMC differentiation. We confirmed that this effect was mediated via TEAD1 and VGLL4 interaction. In addition, bioinformatics analysis revealed that Ten-eleven-translocation 2 (TET2), a DNA demethylase, is a target of TEAD1, and a luciferase assay further verified that TET2 is the target of the VGLL4-TEAD1 complex. Indeed, TET2 overexpression promoted VSMC marker gene expression and countered the VGLL4 knockdown-mediated inhibitory effects on VSMC differentiation. In summary, we revealed a novel role of VGLL4 in promoting VSMC differentiation from hESCs and identified TET2 as a new target of the VGLL4-TEAD1 complex, which may demethylate VSMC marker genes and facilitate VSMC differentiation. This study provides new insights into the VGLL4-TEAD1-TET2 axis in VSMC differentiation and vascular development.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print</small></div>
Wang Z, Quan Y, Hu M, Xu Y, ... Li M, Wang Y
J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print | PMID: 36657637
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<div><h4>Integrated proteomics reveals alterations in sarcomere composition and developmental processes during postnatal swine heart development.</h4><i>Aballo TJ, Roberts DS, Bayne EF, Zhu W, ... Zhang J, Ge Y</i><br /><AbstractText>The neonatal swine heart possesses an endogenous ability to regenerate injured myocardium through the proliferation of pre-existing cardiomyocyte (CM) populations. However, this regenerative capacity is lost shortly after birth. Normal postnatal developmental processes and the regenerative capacity of mammalian hearts are tightly linked, but not much is known about how the swine cardiac proteome changes throughout postnatal development. Herein, we integrated robust and quantitative targeted \"top-down\" and global \"bottom-up\" proteomic workflows to comprehensively define the dynamic landscape of the swine cardiac proteome throughout postnatal maturation. Using targeted top-down proteomics, we were able to identify significant alterations in sarcomere composition, providing new insight into the proteoform landscape of sarcomeres that can disassemble, a process necessary for productive CM proliferation. Furthermore, we quantified global changes in protein abundance using bottom-up proteomics, identified over 700 differentially expressed proteins throughout postnatal development, and mapped these proteins to changes in developmental and metabolic processes. We envision these results will help guide future investigations to comprehensively understand endogenous cardiac regeneration toward the development of novel therapeutic strategies for heart failure.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print</small></div>
Aballo TJ, Roberts DS, Bayne EF, Zhu W, ... Zhang J, Ge Y
J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print | PMID: 36657638
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<div><h4>The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy.</h4><i>Cattaneo M, Beltrami AP, Thomas AC, Spinetti G, ... Puca AA, Madeddu P</i><br /><b>Aims</b><br />The aging heart naturally incurs a progressive decline in function and perfusion that available treatments cannot halt. However, some exceptional individuals maintain good health until the very late stage of their life due to favourable gene-environment interaction. We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications. Moreover, supplementation of LAV-BPIFB4 via an adeno-associated viral vector improves cardiovascular performance in limb ischemia, atherosclerosis, and diabetes models. Here, we asked if the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart\'s spontaneous aging.<br /><b>Methods and results</b><br />Immunohistological studies showed a remarkable reduction in vessel coverage by pericytes in failing hearts explanted from elderly patients. This defect was attenuated in patients carrying the homozygous LAV-BPIFB4 genotype. Moreover, pericytes isolated from older hearts showed low levels of BPIFB4, depressed pro-angiogenic activity, and loss of ribosome biogenesis. LAV-BPIFB4 supplementation restored pericyte function and pericyte-endothelial cell interactions through a mechanism involving the nucleolar protein nucleolin. Conversely, BPIFB4 silencing in normal pericytes mimed the heart failure pericytes. Finally, gene therapy with LAV-BPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage.<br /><b>Conclusions</b><br />We report the success of the LAV-BPIFB4 gene/protein in improving homeostatic processes in the heart\'s aging. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 13 Jan 2023; epub ahead of print</small></div>
Cattaneo M, Beltrami AP, Thomas AC, Spinetti G, ... Puca AA, Madeddu P
Cardiovasc Res: 13 Jan 2023; epub ahead of print | PMID: 36635236
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<div><h4>STRA6 is essential for induction of vascular smooth muscle lineages in human embryonic cardiac outflow tract development.</h4><i>Zhou C, Häneke T, Rohner E, Sohlmér J, ... Adameyko I, Sahara M</i><br /><b>Aims</b><br />Retinoic acid (RA) signaling is essential for heart development, and dysregulation of the RA signaling can cause several types of cardiac outflow tract (OFT) defects, the most frequent congenital heart disease (CHD) in humans. Matthew-Wood syndrome is caused by inactivating mutations of a transmembrane protein gene STRA6 that transports vitamin A (retinol) from extracellular into intracellular spaces. This syndrome shows a broad spectrum of malformations including CHD, although murine Stra6-null neonates did not exhibit overt heart defects. Thus, the detailed mechanisms by which STRA6 mutations could lead to cardiac malformations in humans remain unclear. Here, we investigated the role of STRA6 in the context of human cardiogenesis and CHD.<br /><b>Methods and results</b><br />To gain molecular signatures in species-specific cardiac development, we first compared single-cell RNA sequencing (RNA-seq) datasets, uniquely obtained from human and murine embryonic hearts. We found that while STRA6 mRNA was much less frequently expressed in murine embryonic heart cells derived from the Mesp1+ lineage tracing mice (Mesp1Cre/+; Rosa26tdTomato), it was expressed predominantly in the OFT region-specific heart progenitors in human developing hearts. Next, we revealed that STRA6-knockout human embryonic stem cells (hESCs) could differentiate into cardiomyocytes similarly to wild-type hESCs, but could not differentiate properly into mesodermal nor neural crest cell-derived smooth muscle cells (SMCs) in vitro. This is supported by the population RNA-seq data showing downregulation of the SMC-related genes in the STRA6-knockout hESC-derived cells. Further, through machinery assays, we identified the previously unrecognized interaction between RA nuclear receptors RARα/RXRα and TBX1, an OFT-specific cardiogenic transcription factor, which would likely act downstream to STRA6-mediated RA signaling in human cardiogenesis.<br /><b>Conclusion</b><br />Our study highlights a critical role of human-specific STRA6 progenitors for proper induction of vascular SMCs that is essential for normal OFT formation. Thus, these results shed light on novel and human-specific CHD mechanisms, driven by STRA6 mutations.<br /><b>Translational perspectives</b><br />Dysregulation of the RA signaling can cause cardiac OFT defects, however, the detailed mechanisms by which STRA6 mutations lead to cardiac malformations have remained unclear. Our study highlights a critical role of human-specific STRA6 progenitors for proper induction of vascular SMCs that is essential for normal OFT formation. These results shed light on novel and human-specific CHD programs, driven by STRA6 mutations. Thus, our study paves the way for further studies of deciphering the origins and the disease mechanisms of a rare genetic disorder Matthew-Wood syndrome, which would help us develop diagnosis, prevention, and novel treatment for the disease.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 13 Jan 2023; epub ahead of print</small></div>
Zhou C, Häneke T, Rohner E, Sohlmér J, ... Adameyko I, Sahara M
Cardiovasc Res: 13 Jan 2023; epub ahead of print | PMID: 36635482
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<div><h4>Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection.</h4><i>Carnevale R, Cammisotto V, Bartimoccia S, Nocella C, ... Pignatelli P, Violi F</i><br /><b>Background</b><br />SARS-CoV-2 is associated with an increased risk of venous and arterial thrombosis, but the underlying mechanism is still unclear.<br /><b>Methods</b><br />We performed a cross-sectional analysis of platelet function in 25 SARS-CoV-2 and 10 healthy subjects by measuring Nox2 (NADPH oxidase 2)-derived oxidative stress and thromboxane B<sub>2</sub>, and investigated if administration of monoclonal antibodies against the S protein (Spike protein) of SARS-CoV-2 affects platelet activation. Furthermore, we investigated in vitro if the S protein of SARS-CoV-2 or plasma from SARS-CoV-2 enhanced platelet activation.<br /><b>Results</b><br />Ex vivo studies showed enhanced platelet Nox2-derived oxidative stress and thromboxane B<sub>2</sub> biosynthesis and under laminar flow platelet-dependent thrombus growth in SARS-CoV-2 compared with controls; both effects were lowered by Nox2 and TLR4 (Toll-like receptor 4) inhibitors. Two hours after administration of monoclonal antibodies, a significant inhibition of platelet activation was observed in patients with SARS-CoV-2 compared with untreated ones. In vitro study showed that S protein per se did not elicit platelet activation but amplified the platelet response to subthreshold concentrations of agonists and functionally interacted with platelet TLR4. A docking simulation analysis suggested that TLR4 binds to S protein via three receptor-binding domains; furthermore, immunoprecipitation and immunofluorescence showed S protein-TLR4 colocalization in platelets from SARS-CoV-2. Plasma from patients with SARS-CoV-2 enhanced platelet activation and Nox2-related oxidative stress, an effect blunted by TNF (tumor necrosis factor) α inhibitor; this effect was recapitulated by an in vitro study documenting that TNFα alone promoted platelet activation and amplified the platelet response to S protein via p47phox upregulation.<br /><b>Conclusions</b><br />The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.<br /><br /><br /><br /><small>Circ Res: 13 Jan 2023; epub ahead of print</small></div>
Carnevale R, Cammisotto V, Bartimoccia S, Nocella C, ... Pignatelli P, Violi F
Circ Res: 13 Jan 2023; epub ahead of print | PMID: 36636919
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<div><h4>In vitro validation of chromogenic substrate assay for evaluation of surrogate FVIII-activity of emicizumab.</h4><i>Yamaguchi T, Shinozawa K, Nagatoishi S, Mitsuhashi A, ... Tsumoto K, Kinai E</i><br /><AbstractText>[Introduction] Emicizumab, a bispecific antibody mimicking activated factor VIII (FVIII), is increasingly used in prophylaxis against bleeding in hemophilia A. Human factor-based chromogenic substrate assay (hCSA) shows concentration-dependency between emicizumab and reported FVIII activity. However, the assay measurement settings have not been optimized for emicizumab, and the reported FVIII activity cannot be directly referred as surrogate FVIII activity. [Materials and Methods] For in vitro validation of hCSA-reported surrogate FVIII activity, we compared the equation curves for emicizumab concentration with surrogate FVIII activity using spiked plasma in the thrombin generation assay (TGA), hCSA, and clot waveform analysis (CWA). Then, we generated conversion equations for hCSA-reported surrogate FVIII value to that of TGA. We also assessed the additive effect of rFVIII onto 340 nM (i.e., 50 μg/mL) emicizumab using the same assays. [Results] With 1:20 diluted plasma, halving hCSA-reported surrogate FVIII activity can be approximated to that in TGA triggered by the extrinsic pathway reagent (27.3 IU/dL vs. 13.9 IU/dL) under therapeutic emicizumab concentration. Both in TGA and hCSA, the additive effect of added FVIII on therapeutic emicizumab concentration (340 nM) was maintained at low levels of FVIII but gradually decreased at higher levels. [Conclusions] Surrogate FVIII activity can be estimated simply by halving hCSA-reported FVIII value, and the additive effect of FVIII on emicizumab diminishes at high concentrations. Based on our in vitro study, a clinical study is currently being conducted to compare individual variation of surrogate FVIII activity in hCSA and TGA.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>Thromb Res: 13 Jan 2023; 222:131-139</small></div>
Yamaguchi T, Shinozawa K, Nagatoishi S, Mitsuhashi A, ... Tsumoto K, Kinai E
Thromb Res: 13 Jan 2023; 222:131-139 | PMID: 36657269
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<div><h4>Inhibition of P21-activated kinase 1 promotes vascular smooth muscle cells apoptosis through reduction of phosphorylation of Bad.</h4><i>Jiao L, Yi W, Chang YR, Cheng WL, ... Zhao F, Lu Z</i><br /><b>Background</b><br />P21-activated kinase 1 (Pak1) has an effect on cell apoptosis and recently been reported to play an important role in various cardiovascular diseases, in which vascular smooth muscle cell (VSMC) apoptosis is a key process. Thus, we hypothesized that Pak1 may be a novel target to regulate vascular smooth muscle cell (VSMC) behaviors.<br /><b>Methods and results</b><br />In the present study, we found that the expression of Pak1 was dramatically upregulated in VSMCs upon H2O2 administration and were dependent on stimulation time. Through a loss-of-function approach, Pak1 knockdown increased apoptosis of VSMCs, as tested by TUNEL immunofluorescence staining, whereas it inhibited the proliferation of VSMCs examined by EdU staining. Moreover, we also noticed that Pak1 silencing promoted the mRNA and protein levels of pro-apoptosis genes but decreased anti-apoptosis marker expression. Importantly, we showed that Pak1 knockdown reduced the phosphorylation of Bad. Moreover, increased Pak1 expression was also noticed in carotid arteries upon wire-jury.<br /><b>Conclusion</b><br />Our study identified that Pak1 acted as a novel regulator of apoptosis of VSMCs partially through phosphorylation of Bad.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Am J Hypertens: 12 Jan 2023; epub ahead of print</small></div>
Jiao L, Yi W, Chang YR, Cheng WL, ... Zhao F, Lu Z
Am J Hypertens: 12 Jan 2023; epub ahead of print | PMID: 36634025
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<div><h4>The RNA-binding protein QKI governs a muscle-specific alternative splicing program that shapes the contractile function of cardiomyocytes.</h4><i>Montañés-Agudo P, Aufiero S, Schepers EN, van der Made I, ... Pinto YM, Creemers EE</i><br /><b>Aims</b><br />In the heart, splicing factors orchestrate the functional properties of cardiomyocytes by regulating the alternative splicing of multiple genes. Work in embryonic stem cells has shown that the splicing factor Quaking (QKI) regulates alternative splicing during cardiomyocyte differentiation. However, the relevance and function of QKI in adult cardiomyocytes remains unknown. In this study we aim to identify the in vivo function of QKI in the adult mouse heart.<br /><b>Methods and results</b><br />We generated mice with conditional deletion of QKI in cardiomyocytes by the Cre-Lox system. Mice with cardiomyocyte-specific deletion of QKI died during the fetal period (E14.5), without obvious anatomical abnormalities of the heart. Adult mice with tamoxifen-inducible QKI deletion rapidly developed heart failure associated with severe disruption of sarcomeres, already 7 days after knocking out QKI. RNA sequencing revealed that QKI regulates the alternative splicing of more than 1000 genes, including sarcomere and cytoskeletal components, calcium handling genes and (post)transcriptional regulators. Many of these splicing changes corresponded to the loss of muscle-specific isoforms in the heart. Forced overexpression of QKI in cultured neonatal rat ventricular myocytes directed these splicing events in the opposite direction, and enhanced contractility of cardiomyocytes.<br /><b>Conclusion</b><br />Altogether, our findings show that QKI is an important regulator of the muscle-specific alternative splicing program that builds the contractile apparatus of cardiomyocytes.<br /><b>Translational perspective</b><br />Alternative splicing generates protein isoforms to maintain mechanical, structural, and metabolic properties of cardiomyocytes. We are the first to show that QKI is one of the essential splicing factors in the adult heart. During heart failure, alternative splicing of numerous genes is altered, thereby affecting cardiac function. Recent observations that QKI expression is downregulated in hearts of heart failure patients indicates that loss of QKI-mediated processes contributes to decreased sarcomere organization in these patients. Modulation of QKI activity may serve as a future therapeutic strategy to adapt cardiac isoform expression and improve cardiac function in heart failure patients.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 11 Jan 2023; epub ahead of print</small></div>
Montañés-Agudo P, Aufiero S, Schepers EN, van der Made I, ... Pinto YM, Creemers EE
Cardiovasc Res: 11 Jan 2023; epub ahead of print | PMID: 36627242
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<div><h4>Empagliflozin inhibits excessive autophagy through the AMPK/GSK3β signaling pathway in diabetic cardiomyopathy.</h4><i>Madonna R, Moscato S, Cufaro MC, Pieragostino D, ... Zucchi R, De Caterina R</i><br /><b>Background:</b><br/>and aims</b><br />Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on heart failure and cardiovascular mortality in diabetic and nondiabetic patients, with unclear mechanisms. Autophagy is a cardioprotective mechanism under acute stress conditions, but excessive autophagy accelerates myocardial cell death leading to autosis. We evaluated the protective role of empagliflozin (EMPA) against cardiac injury in murine diabetic cardiomyopathy.<br /><b>Methods and results</b><br />Male mice, rendered diabetics by one single intraperitoneal injection of streptozotocin and treated with EMPA (30 mg/kg/day) had fewer apoptotic cells (4.9 ± 2.1 vs 1 ± 0.5 TUNEL-positive cells %, p < 0.05), less senescence (10.1 ± 2 vs 7.9 ± 1.2 β-gal positivity/tissue area, p < 0.05), fibrosis (0.2 ± 0.05 vs 0.15 ± 0.06, p < 0.05 fibrotic area/tissue area), autophagy (7.9 ± 0.05 vs 2.3 ± 0.6 fluorescence intensity/total area, p < 0.01), and connexin (Cx)-43 lateralization compared with diabetic mice. Proteomic analysis showed a downregulation of the 5\' adenosine monophosphate-activated protein kinase (AMPK) pathway and upstream activation of sirtuins in the heart of diabetic mice treated with EMPA compared with diabetic mice. Because sirtuin activation leads to modulation of cardiomyogenic transcription factors, we analyzed the DNA binding activity to serum response elements (SRE) of serum response factor (SRF) by electromobility shift assay. Compared with diabetic mice (0.5 ± 0.01 densitometric units, DU), nondiabetic mice treated with EMPA (2.2 ± 0.01 DU, p < 0.01) and diabetic mice treated with EMPA (2.0 ± 0.1 DU, p < 0.01) significantly increased SRF binding activity to SRE, paralleled by increased cardiac actin expression (4.1 ± 0.1 vs 2.2 ± 0.01 target protein/β-actin ratio, p < 0.01). EMPA significantly reversed cardiac dysfunction on echocardiography in diabetic mice and inhibited excessive autophagy in high-glucose-treated cardiomyocytes by inhibiting the autophagy inducer GSK3β, leading to reactivation of cardiomyogenic transcription factors.<br /><b>Conclusions</b><br />Taken together, our results describe a novel paradigm in which EMPA inhibits hyperactivation of autophagy through the AMPK/GSK3β signaling pathway in the context of diabetes.<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: 11 Jan 2023; epub ahead of print</small></div>
Madonna R, Moscato S, Cufaro MC, Pieragostino D, ... Zucchi R, De Caterina R
Cardiovasc Res: 11 Jan 2023; epub ahead of print | PMID: 36627733
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<div><h4>Angiotensin II Type 1A Receptor Expressed in Smooth Muscle Cells is Required for Hypertensive Vascular Remodeling in Mice Infused With Angiotensin II.</h4><i>Okuno K, Torimoto K, Cicalese SM, Preston K, ... Sparks MA, Eguchi S</i><br /><b>Background</b><br />Ang II (angiotensin II) type 1 (AT<sub>1</sub>) receptors play a critical role in cardiovascular diseases such as hypertension. Rodents have 2 types of AT<sub>1</sub> receptor (AT<sub>1A</sub> and AT<sub>1B</sub>) of which knock-in <i>Tagln</i>-mediated smooth muscle AT<sub>1A</sub> silencing attenuated Ang II-induced hypertension. Although vascular remodeling, a significant contributor to organ damage, occurs concurrently with hypertension in Ang II-infused mice, the contribution of smooth muscle AT<sub>1A</sub> in this process remains unexplored. Accordingly, it is hypothesized that smooth muscle AT<sub>1A</sub> receptors exclusively contribute to both medial thickening and adventitial fibrosis regardless of the presence of hypertension.<br /><b>Methods</b><br />About 1 µg/kg per minute Ang II was infused for 2 weeks in 2 distinct AT<sub>1A</sub> receptor silenced mice, knock-in <i>Tagln</i>-mediated constitutive smooth muscle AT<sub>1A</sub> receptor silenced mice, and <i>Myh11</i>-mediated inducible smooth muscle AT<sub>1A</sub> together with global AT<sub>1B</sub> silenced mice for evaluation of hypertensive cardiovascular remodeling.<br /><b>Results</b><br />Medial thickness, adventitial collagen deposition, and immune cell infiltration in aorta were increased in control mice but not in both smooth muscle AT<sub>1A</sub> receptor silenced mice. Coronary arterial perivascular fibrosis in response to Ang II infusion was also attenuated in both AT<sub>1A</sub> receptor silenced mice. Ang II-induced cardiac hypertrophy was attenuated in constitutive smooth muscle AT<sub>1A</sub> receptor silenced mice. However, Ang II-induced cardiac hypertrophy and hypertension were not altered in inducible smooth muscle AT<sub>1A</sub> receptor silenced mice.<br /><b>Conclusions</b><br />Smooth muscle AT<sub>1A</sub> receptors mediate Ang II-induced vascular remodeling including medial hypertrophy and inflammatory perivascular fibrosis regardless of the presence of hypertension. Our data suggest an independent etiology of blood pressure elevation and hypertensive vascular remodeling in response to Ang II.<br /><br /><br /><br /><small>Hypertension: 11 Jan 2023; epub ahead of print</small></div>
Okuno K, Torimoto K, Cicalese SM, Preston K, ... Sparks MA, Eguchi S
Hypertension: 11 Jan 2023; epub ahead of print | PMID: 36628961
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<div><h4>A systematic review of global autopsy rates in all-cause mortality and young sudden death.</h4><i>Paratz ED, Rowe SJ, Stub D, Pflaumer A, La Gerche A</i><br /><AbstractText>Autopsy is the gold-standard method for determining cause of death. Young sudden death (SD) is a prototype condition in which autopsy is universally recommended. The aim of this review was to quantify real-world global rates of autopsy in either all-cause death or young SD. A systematic review was conducted. Rates of autopsy in all-cause death and in young SD were determined in each country using scientific and commercial search engines. 59/195 countries (30.3%) reported autopsy rates in all-cause death, with rates varying from 0.01-83.9%. Almost all of these figures derived from academic publications rather than governmental statistics. Only 16/195 countries (8.2%) reported autopsy rates in the context of young SD, with reported rates ranging from 5-100%. The definition of \'young\' was heterogeneous. No governmental statistics reported autopsy rates in young SD. Risks of bias included inability to verify reported figures, heterogeneity in reporting of clinical vs medicolegal autopsies, and the small number of studies identified overall, resulting in the consistent exclusion of low and middle-income countries. In conclusion, most countries globally do not report autopsy rates in either all-cause death (69.7%) or in sudden death (92.8%). Without transparent reporting of autopsy rates, global burdens of disease and rates of sudden cardiac death cannot be reliably calculated.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 11 Jan 2023; epub ahead of print</small></div>
Paratz ED, Rowe SJ, Stub D, Pflaumer A, La Gerche A
Heart Rhythm: 11 Jan 2023; epub ahead of print | PMID: 36640854
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<div><h4>Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.</h4><i>Tousif S, Singh AP, Umbarkar P, Galindo C, ... Prabhu SD, Lal H</i><br /><b>Background</b><br />The tyrosine kinase inhibitor ponatinib is the only treatment option for chronic myelogenous leukemia patients with T315I (gatekeeper) mutation. Pharmacovigilance analysis of Food and Drug Administration and World Health Organization datasets has revealed that ponatinib is the most cardiotoxic agent among all Food and Drug Administration-approved tyrosine kinase inhibitors in a real-world scenario. However, the mechanism of ponatinib-induced cardiotoxicity is unknown.<br /><b>Methods</b><br />The lack of well-optimized mouse models has hampered the in vivo cardio-oncology studies. Here, we show that cardiovascular comorbidity mouse models evidence a robust cardiac pathological phenotype upon ponatinib treatment. A combination of multiple in vitro and in vivo models was employed to delineate the underlying molecular mechanisms.<br /><b>Results</b><br />An unbiased RNA sequencing analysis identified the enrichment of dysregulated inflammatory genes, including a multifold upregulation of alarmins S100A8/A9, as a top hit in ponatinib-treated hearts. Mechanistically, we demonstrate that ponatinib activates the S100A8/9-TLR4 (Toll-like receptor 4)-NLRP3 (NLR family pyrin domain-containing 3)-IL (interleukin)-1β signaling pathway in cardiac and systemic myeloid cells, in vitro and in vivo, thereby leading to excessive myocardial and systemic inflammation. Excessive inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive glucocorticoid dexamethasone or specific inhibitors of NLRP3 (CY-09) or S100A9 (paquinimod) nearly abolished the ponatinib-induced cardiac dysfunction.<br /><b>Conclusions</b><br />Taken together, these findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. From a translational perspective, our results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing ponatinib-induced cardiotoxicity.<br /><br /><br /><br /><small>Circ Res: 10 Jan 2023; epub ahead of print</small></div>
Tousif S, Singh AP, Umbarkar P, Galindo C, ... Prabhu SD, Lal H
Circ Res: 10 Jan 2023; epub ahead of print | PMID: 36625265
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<div><h4>Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction.</h4><i>Ragni M, Greco CM, Felicetta A, Ren SV, ... Condorelli G, Nisoli E</i><br /><b>Aims</b><br />Heart failure with reduced ejection fraction (HFrEF) is a leading cause of mortality worldwide, requiring novel therapeutic and lifestyle interventions. Metabolic alterations and energy production deficit are hallmarks and thereby promising therapeutic targets for this complex clinical syndrome. We aim to study the molecular mechanisms and effects on cardiac function in rodents with HFrEF of a designer diet in which free essential amino acids - in specifically designed percentages - substituted for protein.<br /><b>Methods and results</b><br />Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricle (LV) pressure overload or sham surgery. Whole body glucose homeostasis was studied with glucose tolerance test, while myocardial dysfunction and fibrosis were measured with echocardiogram and histological analysis. Mitochondrial bioenergetics and morphology were investigated with oxygen consumption rate measurement and electron microscopy evaluation. Circulating and cardiac non-targeted metabolite profiles were analyzed by ultrahigh performance liquid chromatography-tandem mass spectroscopy, while RNA sequencing was used to identify signalling pathways mainly affected. The amino acid-substituted diet shows remarkable preventive and therapeutic effects. This dietary approach corrects the whole-body glucose metabolism and restores the unbalanced metabolic substrate usage - by improving mitochondrial fuel oxidation - in the failing heart. In particular, biochemical, molecular, and genetic approaches suggest that renormalization of branched-chain amino acid oxidation in cardiac tissue, which is suppressed in HFrEF, plays a relevant role. Beyond the changes of systemic metabolism, cell-autonomous processes may explain at least in part the diet\'s cardioprotective impact.<br /><b>Conclusion</b><br />Collectively, these results suggest that manipulation of dietary amino acids, and especially essential amino acids, is a potential adjuvant therapeutic strategy to treat systolic dysfunction and HFrEF in humans.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Cardiovasc Res: 10 Jan 2023; epub ahead of print</small></div>
Ragni M, Greco CM, Felicetta A, Ren SV, ... Condorelli G, Nisoli E
Cardiovasc Res: 10 Jan 2023; epub ahead of print | PMID: 36626303
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<div><h4>New insights in AV nodal anatomy, physiology and immunochemistry: a comprehensive review and a proposed model of the slow-fast AVNRT circuit in agreement with direct potential recordings in the Koch\'s triangle area.</h4><i>Pandozi C, Matteucci A, Galeazzi M, Russo M, ... Malacrida M, Colivicchi F</i><br /><AbstractText>Atrioventricular nodal re-entrant tachycardia (AVNRT) is humans\' most frequent regular tachycardia. In this review, we describe the most recent discoveries regarding the anatomical, physiological and molecular biological features of the AV junction that could underlie the typical slow-fast AVNRT mechanisms, as these insights could lead to the proposal of a new theory concerning the circuit of this arrhythmia. Despite several models have been proposed over the years, the precise anatomical site of the re-entrant circuit and the pathway involved in the slow-fast AVNRT have not been conclusively defined. One possible way to evaluate all the hypotheses regarding the nodal tachycardia circuit in humans is to map this circuit. Thus, we tried to identify the slow potential of nodal and inferior extension structures by using automated mapping of atrial activation during both sinus rhythm and typical slow-fast AVNRT. This constitutes a first step towards the definition of nodal area activation in sinus rhythm and during slow-fast AVNRT. Further studies and technical improvements in recording the potentials of the AVN structures are necessary to confirm our initial results.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 09 Jan 2023; epub ahead of print</small></div>
Pandozi C, Matteucci A, Galeazzi M, Russo M, ... Malacrida M, Colivicchi F
Heart Rhythm: 09 Jan 2023; epub ahead of print | PMID: 36634901
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<div><h4> Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension.</h4><i>Cuthbertson I, Morrell NW, Caruso P</i><br /><AbstractText>Pulmonary arterial hypertension forms the first and most severe of the 5 categories of pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling of peripheral pulmonary arteries, caused by the excessive proliferation of vascular wall cells, including endothelial cells, smooth muscle cells and fibroblasts, and perivascular inflammation. Compelling evidence from animal models suggests endothelial cell dysfunction is a key initial trigger of pulmonary vascular remodeling, which is characterised by hyperproliferation and early apoptosis followed by enrichment of apoptosis-resistant populations. Dysfunctional pulmonary arterial endothelial cells lose their ability to produce vasodilatory mediators, together leading to augmented pulmonary arterial smooth muscle cell responses, increased pulmonary vascular pressures and right ventricular afterload, and progressive right ventricular hypertrophy and heart failure. It is recognized that a range of abnormal cellular molecular signatures underpin the pathophysiology of pulmonary arterial hypertension and are enhanced by loss-of-function mutations in the <i>BMPR2</i> gene, the most common genetic cause of pulmonary arterial hypertension and associated with worse disease prognosis. Widespread metabolic abnormalities are observed in the heart, pulmonary vasculature, and systemic tissues, and may underpin heterogeneity in responsivity to treatment. Metabolic abnormalities include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine and sphingosine metabolism, reduced insulin sensitivity, and defective iron handling. This review critically discusses published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies.</AbstractText><br /><br /><br /><br /><small>Circ Res: 06 Jan 2023; 132:109-126</small></div>
Cuthbertson I, Morrell NW, Caruso P
Circ Res: 06 Jan 2023; 132:109-126 | PMID: 36603064
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<div><h4>Microcirculation and Physical Exercise In Hypertension.</h4><i>De Ciuceis C, Rizzoni D, Palatini P</i><br /><AbstractText>Hypertension is associated with important alterations in the morphology of small arteries and arterioles. Vascular-specific manifestations are changes in the structure and function of vascular smooth muscle cells, extracellular matrix, perivascular tissues, and endothelial cells. Arteriole and capillary remodeling and capillary rarefaction have been observed in hypertensive animals and human beings which contribute to increased vascular resistance. An impairment of different angiogenetic factors, such as VEGF (vascular endothelial growth factor), VEGFR (vascular endothelial growth factor receptor)-2, TIMP (tissue inhibitor matrix metalloproteinases)-1, and TSP (thrombospondin)-1, seems to be responsible for the reduction of the microvascular network. Exercise training has been shown to improve vascular structure and function in hypertension not only in the large arteries but also in the peripheral circulation. Exercise training may regress microvascular remodeling and normalize capillary density, leading to capillary growth possibly by increasing proangiogenic stimuli such as VEGF. Exercise enhances endothelium-dependent vascular relaxation through NO release increase and oxidative stress reduction. Other mechanisms include improved balance between prostacyclin and thromboxane levels, lower circulating levels of endothelin-1, attenuation of infiltration of immune cells into perivascular adipose tissue, and increase of local adiponectin secretion. In addition, exercise training favorably modulates the expression of several microRNAs leading to a positive modification in muscle fiber composition. Identifying the bioactive molecules and biological mechanisms that mediate exercise benefits through pathways that differ from those used by antihypertensive drugs may help to improve our knowledge of hypertension pathophysiology and facilitate the development of new therapeutic strategies.</AbstractText><br /><br /><br /><br /><small>Hypertension: 05 Jan 2023; epub ahead of print</small></div>
De Ciuceis C, Rizzoni D, Palatini P
Hypertension: 05 Jan 2023; epub ahead of print | PMID: 36601920
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<div><h4>Genetic Regulation of Gene Expression and Splicing Predict Causal Genes.</h4><i>Aherrahrou R, Lue D, Perry RN, Aberra YT, ... Kaikkonen MU, Civelek M</i><br /><b>Background</b><br />Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses of genome-wide association studies have identified over 175 loci associated with CAD. The majority of these loci are in noncoding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we aimed to identify the subset of the CAD genome-wide association studies risk loci associated with the regulation of transcription in distinct SMC phenotypes.<br /><b>Methods</b><br />Here, we measured gene expression in SMCs isolated from the ascending aortas of 151 heart transplant donors of various genetic ancestries in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single-nucleotide polymorphism markers across the genome.<br /><b>Results</b><br />We identified 4910 expression and 4412 splice quantitative trait loci representing regions of the genome associated with transcript abundance and splicing. A total of 3660 expression quantitative trait locus (eQTLs) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 eQTLs were SMC- and sex-specific, respectively. We made these results available for public query on a user-friendly website. To identify the effector transcript(s) regulated by CAD genome-wide association studies loci, we used 4 distinct colocalization approaches. We identified 84 eQTL and 164 splice quantitative trait loci that colocalized with CAD loci, highlighting the importance of genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. Notably, 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. One CAD locus colocalized with an SMC sex-specific eQTL (<i>TERF2IP</i>), and another locus colocalized with SMC-specific eQTL (<i>ALKBH8</i>). The most significantly associated CAD locus, 9p21, was an splice quantitative trait loci for the long noncoding RNA <i>CDKN2B-AS1</i>, also known as <i>ANRIL</i>, in proliferative SMCs.<br /><b>Conclusions</b><br />Collectively, our results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in distinct SMC phenotypes.<br /><br /><br /><br /><small>Circ Res: 04 Jan 2023; epub ahead of print</small></div>
Aherrahrou R, Lue D, Perry RN, Aberra YT, ... Kaikkonen MU, Civelek M
Circ Res: 04 Jan 2023; epub ahead of print | PMID: 36597873
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<div><h4>SGK1 Inhibition Attenuates the Action Potential Duration in Re-Engineered Heart Cell Models of Drug-Induced QT Prolongation.</h4><i>Kim M, Sager PT, Tester DJ, Pradhananga S, ... Das S, Ackerman MJ</i><br /><b>Background</b><br />Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a HERG/I<sub>Kr</sub> blocker such as dofetilide prolongs the cardiac action potential duration (APD) and the QT interval on the electrocardiogram. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD90 in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) derived from patients with congenital long QT syndrome.<br /><b>Objective</b><br />Here, we test the efficacy of 2 novel SGK1 inhibitors in iPSC-CM models of dofetilide-induced APD prolongation.<br /><b>Methods</b><br />Normal iPSC-CMs were treated with dofetilide to produce a DI-QTP iPSC-CM model. SGK1-I1\'s and SGK1-I2\'s therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using FluoVolt.<br /><b>Results</b><br />The APD90 was prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms vs 436 ± 4 ms, p<0.0001). While 10 μM mexiletine shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 4 ms to 563 ± 8 ms (46% attenuation, p<0.0001), 30 nM of SGK1-I1 shortened the APD90 from 673 ± 8 ms to 502 ± 7 ms (72% attenuation, p<0.0001). Additionally, 300 nM SGK1-I2 shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 8 ms to 460 ± 7 ms (90% attenuation, p<0.0001).<br /><b>Conclusions</b><br />These novel SGK1 inhibitors substantially attenuated the pathological APD prolongation in a human heart cell model of DI-QTP. This pre-clinical data supports development of this therapeutic strategy to counter and neutralize DI-QTP thereby increasing the safety profile for patients receiving drugs with a torsadogenic potential.<br /><br />Copyright © 2023. Published by Elsevier Inc.<br /><br /><small>Heart Rhythm: 04 Jan 2023; epub ahead of print</small></div>
Kim M, Sager PT, Tester DJ, Pradhananga S, ... Das S, Ackerman MJ
Heart Rhythm: 04 Jan 2023; epub ahead of print | PMID: 36610526
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<div><h4>Targeting Epsins to Inhibit Fibroblast Growth Factor Signaling While Potentiating Transforming Growth Factor-β Signaling Constrains Endothelial-to-Mesenchymal Transition in Atherosclerosis.</h4><i>Dong Y, Wang B, Du M, Zhu B, ... Linton MF, Chen H</i><br /><b>Background</b><br />Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, the underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) in atherosclerosis and assessed the efficacy of a therapeutic peptide in a preclinical model of this disease.<br /><b>Methods</b><br />Using single-cell RNA sequencing combined with molecular, cellular, and biochemical analyses, we investigated the role of epsins in stimulating EndoMT using knockout in <i>Apoe</i><sup><i>-/-</i></sup> and lineage tracing/proprotein convertase subtilisin/kexin type 9 serine protease mutant viral-induced atherosclerotic mouse models. The therapeutic efficacy of a synthetic peptide targeting atherosclerotic plaques was then assessed in <i>Apoe</i><sup><i>-/-</i></sup> mice.<br /><b>Results</b><br />Single-cell RNA sequencing and lineage tracing revealed that epsins 1 and 2 promote EndoMT and that the loss of endothelial epsins inhibits EndoMT marker expression and transforming growth factor-β signaling in vitro and in atherosclerotic mice, which is associated with smaller lesions in the <i>Apoe</i><sup><i>-/-</i></sup> mouse model. Mechanistically, the loss of endothelial cell epsins results in increased fibroblast growth factor receptor-1 expression, which inhibits transforming growth factor-β signaling and EndoMT. Epsins directly bind ubiquitinated fibroblast growth factor receptor-1 through their ubiquitin-interacting motif, which results in endocytosis and degradation of this receptor complex. Consequently, administration of a synthetic ubiquitin-interacting motif-containing peptide atheroma ubiquitin-interacting motif peptide inhibitor significantly attenuates EndoMT and progression of atherosclerosis.<br /><b>Conclusions</b><br />We conclude that epsins potentiate EndoMT during atherogenesis by increasing transforming growth factor-β signaling through fibroblast growth factor receptor-1 internalization and degradation. Inhibition of EndoMT by reducing epsin-fibroblast growth factor receptor-1 interaction with a therapeutic peptide may represent a novel treatment strategy for atherosclerosis.<br /><br /><br /><br /><small>Circulation: 02 Jan 2023; epub ahead of print</small></div>
Abstract
<div><h4>Ulinastatin ameliorates preeclampsia induced by N(gamma)-nitro-l-arginine methyl ester in a rat model via inhibition of the systemic and placental inflammatory response.</h4><i>Yu Z, Liu Y, Zhang Y, Cui J, ... Xu Y, Wang J</i><br /><b>Background</b><br />The pathogenesis of preeclampsia (PE) is associated with inflammation and endothelial damage. Ulinastatin (UTI) mainly inhibits proteolytic activity and significantly reduces the release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) from macrophages. It also ameliorates vascular endothelial damage in pathological conditions. Hence, we investigated the effects of UTI in a rat model of PE induced using N(gamma)-nitro-l-arginine methyl ester (L-NAME).<br /><b>Methods</b><br />Although inducing PE in a rat model, 5000 U/kg of UTI were injected daily. Systolic blood pressure (SBP) and protein levels in the urine were measured. Renal function, and serum concentrations of TNF-α, IL-6, placental growth factor (PLGF), and von Willebrand factor (vWF) were evaluated. The number and weight of live fetuses as well as the weight of placentas were measured. Placentas were collected for western blot and pathological analysis.<br /><b>Results</b><br />UTI slightly ameliorated proteinuria and the increases in SBP, blood urea nitrogen (BUN), and serum creatinine. Furthermore, UTI improved serum and placental protein expression levels of TNF-α, IL-6, vWF, and PLGF. Pathological analysis revealed that vascular density and blood flow perfusion was enhanced, vessel wall thickening and neutrophil infiltration were diminished, and the weight and number of live fetuses as well as the weight of the placentas were improved with UTI.<br /><b>Conclusion</b><br />Preventive use of UTI in the PE rat model induced by L-NAME partially alleviated hypertension, proteinuria, and impaired renal function; improved fetal growth restriction; diminished vascular endothelial injury; and ameliorated placental vasculogenesis abnormality and malperfusion by inhibiting the systemic and placental inflammatory response, suggesting that UTI is a potential drug for PE prevention or treatment.<br /><br />Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.<br /><br /><small>J Hypertens: 01 Jan 2023; 41:150-158</small></div>
Abstract
<div><h4>Serum Opacity Factor Rescues Fertility among Female Scarb1 Mice by Reducing HDL-Free Cholesterol Bioavailability.</h4><i>Rosales C, Yelamanchili D, Gillard BK, Liu J, Gotto AM, Pownall HJ</i><br /><AbstractText>Human female infertility, 20% of which is idiopathic, is a public health problem for which better diagnostics and therapeutics are needed. A novel cause of infertility emerged from studies of female mice deficient in the HDL receptor gene (Scarb1). These mice are infertile and have high plasma HDL cholesterol (C) concentrations, due to elevated HDL-free cholesterol (FC), which transfers from HDL to all tissues. Previous studies have indicated that oral delivery of probucol, an HDL-lowering drug, to female Scarb1<sup>-/-</sup> mice reduces plasma HDL-C concentrations and rescues fertility. Additionally, serum opacity factor (SOF), a bacterial virulence factor, disrupts HDL structure, and bolus SOF injection into mice reduces plasma HDL-C concentrations. Here, we discovered that delivering SOF to female Scarb1<sup>-/-</sup> mice with an adeno-associated virus (AAV<sub>SOF</sub>) induces constitutive SOF expression, reduces HDL-FC concentrations, and rescues fertility while normalizing ovary morphology. Although AAV<sub>SOF</sub> did not alter ovary-FC content, the ovary-mol% FC correlated with plasma HDL-mol% FC in a fertility-dependent way. Therefore, reversing the abnormal plasma microenvironment of high plasma HDL-mol% FC in female Scarb1<sup>-/-</sup> mice rescues fertility. These data provide the rationale to search for similar mechanistic links between HDL-mol% FC and infertility and the rescue of fertility in women by reducing plasma HDL-mol% FC.</AbstractText><br /><br />Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Lipid Res: 31 Dec 2022:100327; epub ahead of print</small></div>
Rosales C, Yelamanchili D, Gillard BK, Liu J, Gotto AM, Pownall HJ
J Lipid Res: 31 Dec 2022:100327; epub ahead of print | PMID: 36596339
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<div><h4>Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia.</h4><i>Sabe SA, Xu CM, Sabra M, Harris DD, ... Abid MR, Sellke FW</i><br /><AbstractText><br /><b>Background:</b><br/>Sodium-glucose cotransporter-2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium-glucose cotransporter-2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate-activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. <br /><b>Conclusions:</b><br/>In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate-activated protein kinase, and antioxidant signaling may contribute to these effects.</AbstractText><br /><br /><br /><br /><small>J Am Heart Assoc: 30 Dec 2022:e028623; epub ahead of print</small></div>
Sabe SA, Xu CM, Sabra M, Harris DD, ... Abid MR, Sellke FW
J Am Heart Assoc: 30 Dec 2022:e028623; epub ahead of print | PMID: 36583437
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<div><h4>Recent Advances in Hypertension: Epigenetic Mechanism Involved in Development of Salt-Sensitive Hypertension.</h4><i>Fujita T</i><br /><AbstractText>This review highlights recent insights into the epigenetic mechanism of salt-sensitive hypertension from the fetus to the elderly population, mainly focusing on the DNA methylation and histone modification-mediated regulation of hypertension-associated genes. Maternal malnutrition during pregnancy induces upregulation of angiotensin receptor 1a (<i>AT1a</i>) by aberrant DNA methylation, and increased AT1A activity in the hypothalamus develops prenatally programmed salt-sensitive hypertension through renal sympathetic overactivity. In addition, maternal lipopolysaccharide exposure during pregnancy induces upregulation of the <i>Rac1</i> gene through histone modification by H3K9me2 across generations, resulting in salt-induced activation of the Rac1-MR (mineralocorticoid receptor) pathway in the kidney and the development of salt-sensitive hypertension in F4 and F5 offspring. In mice, aberrant DNA methylation of the <i>Klotho</i> gene, which regulates aging-associated hypertension, decreases the circulating soluble Klotho levels, leading to activation of the vascular Wnt5a-RhoA pathway and vasoconstriction and development of salt-sensitive hypertension because of decreased renal blood flow. A detailed understanding of the environmentally-induced epigenetic modulations related to salt-induced hypertension could be promising for developing preventive and therapeutic approaches to hypertension.</AbstractText><br /><br /><br /><br /><small>Hypertension: 30 Dec 2022; epub ahead of print</small></div>
Fujita T
Hypertension: 30 Dec 2022; epub ahead of print | PMID: 36583382
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<div><h4>RyR2 Serine-2030 PKA Site Governs Ca Release Termination and Ca Alternans.</h4><i>Wei J, Guo W, Wang R, Paul Estillore J, ... Hove-Madsen L, Chen SRW</i><br /><b>Background</b><br />PKA (protein kinase A)-mediated phosphorylation of cardiac RyR2 (ryanodine receptor 2) has been extensively studied for decades, but the physiological significance of PKA phosphorylation of RyR2 remains poorly understood. Recent determination of high-resolution 3-dimensional structure of RyR2 in complex with CaM (calmodulin) reveals that the major PKA phosphorylation site in RyR2, serine-2030 (S2030), is located within a structural pathway of CaM-dependent inactivation of RyR2. This novel structural insight points to a possible role of PKA phosphorylation of RyR2 in CaM-dependent inactivation of RyR2, which underlies the termination of Ca<sup>2+</sup> release and induction of cardiac Ca<sup>2+</sup> alternans. To determine the role of the PKA phosphorylation site RyR2-S2030 in Ca<sup>2+</sup> release termination in vitro and cardiac Ca<sup>2+</sup> alternans in intact hearts.<br /><b>Methods and results</b><br />We performed single-cell endoplasmic reticulum Ca<sup>2+</sup> imaging to assess the impact of S2030 mutations on Ca<sup>2+</sup> release termination in HEK293 cells. We found that mutations, S2030D, S2030G, S2030L, S2030V, and S2030W reduced the endoplasmic reticulum luminal Ca<sup>2+</sup> level at which Ca<sup>2+</sup> release terminates (the termination threshold), whereas S2030P and S2030R increased the termination threshold. S2030A and S2030T had no significant impact on release termination. Furthermore, CaM-wild-type increased, whereas Ca<sup>2+</sup> binding deficient CaM mutant (CaM-M [a loss-of-function CaM mutation with all 4 EF-hand motifs mutated]), PKA, and Ca<sup>2+</sup>/CaMKII (CaM-dependent protein kinase II) reduced the termination threshold. The S2030L mutation abolished the actions of CaM-wild-type, CaM-M, and PKA, but not CaMKII, in Ca<sup>2+</sup> release termination. To determine the role of the PKA site RyR2-S2030 in a physiological setting, we generated a novel mouse model harboring the S2030L mutation. Using confocal Ca<sup>2+</sup> imaging, we found that isoproterenol and CaM-M suppressed pacing-induced Ca<sup>2+</sup> alternans and accelerated Ca<sup>2+</sup> transient recovery in intact working hearts, whereas CaM-wild-type exerted an opposite effect. The impact of isoproterenol was partially and fully reversed by the PKA inhibitor H89 and the CaMKII inhibitor KN93 individually and together, respectively. S2030L abolished the impact of CaM-wild-type, CaM-M, and H89-sensitive component, but not the KN93-sensitive component, of isoproterenol.<br /><b>Conclusions</b><br />These data demonstrate, for the first time, that the PKA phosphorylation site RyR-S2030 is an important determinant of PKA-regulated, CaM-dependent Ca<sup>2+</sup> release termination, and Ca<sup>2+</sup> alternans.<br /><br /><br /><br /><small>Circ Res: 30 Dec 2022; epub ahead of print</small></div>
Wei J, Guo W, Wang R, Paul Estillore J, ... Hove-Madsen L, Chen SRW
Circ Res: 30 Dec 2022; epub ahead of print | PMID: 36583384
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