Topic: Basic Research

Abstract

Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling.

Ljubojević-Holzer S, Kraler S, Djalinac N, Abdellatif M, ... Maack C, Sedej S
Aims
Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure.
Methods and results
RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload.
Conclusion
Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 May 2022; 118:1492-1505
Ljubojević-Holzer S, Kraler S, Djalinac N, Abdellatif M, ... Maack C, Sedej S
Cardiovasc Res: 06 May 2022; 118:1492-1505 | PMID: 33752242
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Abstract

Anxa1 in smooth muscle cells protects against acute aortic dissection.

Zhou C, Lin Z, Cao H, Chen Y, ... Pan B, Zheng L
Aims
Acute aortic dissection (AAD) is a life-threatening disease with high morbidity and mortality. Previous studies have showed that vascular smooth muscle cell (VSMC) phenotype switching modulates vascular function and AAD progression. However, whether an endogenous signalling system that protects AAD progression exists remains unknown. Our aim is to investigate the role of Anxa1 in VSMC phenotype switching and the pathogenesis of AAD.
Methods and results
We first assessed Anxa1 expression levels by immunohistochemical staining in control aorta and AAD tissue from mice. A strong increase of Anxa1 expression was seen in the mouse AAD tissues. In line with these findings, micro-CT scan results indicated that Anxa1 plays a role in the development of AAD in our murine model, with systemic deficiency of Anxa1 markedly progressing AAD. Conversely, administration of Anxa1 mimetic peptide, Ac2-26, rescued the AAD phenotype in Anxa1-/- mice. Transcriptomic studies revealed a novel role for Anxa1 in VSMC phenotype switching, with Anxa1 deficiency triggering the synthetic phenotype of VSMCs via down-regulation of the JunB/MYL9 pathway. The resultant VSMC synthetic phenotype rendered elevated inflammation and enhanced matrix metalloproteinases (MMPs) production, leading to augmented elastin degradation. VSMC-restricted deficiency of Anxa1 in mice phenocopied VSMC phenotype switching and the consequent exacerbation of AAD. Finally, our studies in human AAD aortic specimens recapitulated key findings in murine AAD, specifically that the decrease of Anxa1 is associated with VSMC phenotype switch, heightened inflammation, and enhanced MMP production in human aortas.
Conclusions
Our findings demonstrated that Anxa1 is a novel endogenous defender that prevents AAD by inhibiting VSMC phenotype switching, suggesting that Anxa1 signalling may be a potential target for AAD pharmacological therapy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 06 May 2022; 118:1564-1582
Zhou C, Lin Z, Cao H, Chen Y, ... Pan B, Zheng L
Cardiovasc Res: 06 May 2022; 118:1564-1582 | PMID: 33757117
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Abstract

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications.

Greenberg HZE, Zhao G, Shah AM, Zhang M
Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review, we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 May 2022; 118:1433-1451
Greenberg HZE, Zhao G, Shah AM, Zhang M
Cardiovasc Res: 06 May 2022; 118:1433-1451 | PMID: 33881501
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Abstract

Primary cilia control endothelial permeability by regulating expression and location of junction proteins.

Diagbouga MR, Morel S, Cayron AF, Haemmerli J, ... Bijlenga P, Kwak BR
Aims
Wall shear stress (WSS) determines intracranial aneurysm (IA) development. Polycystic kidney disease (PKD) patients have a high IA incidence and risk of rupture. Dysfunction/absence of primary cilia in PKD endothelial cells (ECs) may impair mechano-transduction of WSS and favour vascular disorders. The molecular links between primary cilia dysfunction and IAs are unknown.
Methods and results
Wild-type and primary cilia-deficient Tg737orpk/orpk arterial ECs were submitted to physiological (30 dynes/cm2) or aneurysmal (2 dynes/cm2) WSS, and unbiased transcriptomics were performed. Tg737orpk/orpk ECs displayed a fivefold increase in the number of WSS-responsive genes compared to wild-type cells. Moreover, we observed a lower trans-endothelial resistance and a higher endothelial permeability, which correlated with disorganized intercellular junctions in Tg737orpk/orpk cells. We identified ZO-1 as a central regulator of primary cilia-dependent endothelial junction integrity. Finally, clinical and histological characteristics of IAs from non-PKD and PKD patients were analysed. IAs in PKD patients were more frequently located in the middle cerebral artery (MCA) territory than in non-PKD patients. IA domes from the MCA of PKD patients appeared thinner with less collagen and reduced endothelial ZO-1 compared with IA domes from non-PKD patients.
Conclusion
Primary cilia dampen the endothelial response to aneurysmal low WSS. In absence of primary cilia, ZO-1 expression levels are reduced, which disorganizes intercellular junctions resulting in increased endothelial permeability. This altered endothelial function may not only contribute to the severity of IA disease observed in PKD patients, but may also serve as a potential diagnostic tool to determine the vulnerability of IAs.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 May 2022; 118:1583-1596
Diagbouga MR, Morel S, Cayron AF, Haemmerli J, ... Bijlenga P, Kwak BR
Cardiovasc Res: 06 May 2022; 118:1583-1596 | PMID: 33974072
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Abstract

Catheter ablation of short-coupled variant of torsade de pointes.

Steinfurt J, Nazer B, Aguilar M, Moss J, ... Tedrow UB, Bogossian H
Background
The short-coupled variant of torsade de pointes (sc-TdP) is a malignant arrhythmia that frequently presents with ventricular fibrillation (VF) electrical storm. Verapamil is considered the first-line therapy of sc-TdP while catheter ablation is not widely adopted. The aim of this study was to determine the origin of sc-TdP and to assess the outcome of catheter ablation using 3D-mapping.
Methods and results
We retrospectively analyzed five patients with sc-TdP who underwent 3D-mapping and ablation of sc-TdP at five different institutions. Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope as the first manifestation. All patients demonstrated a monomorphic premature ventricular contraction (PVC) with late transition left bundle branch block pattern, superior axis, and a coupling interval of less than 300 ms. triggering recurrent TdP and VF. In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients. Catheter ablation using 3D-mapping and intracardiac echocardiography eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up.
Conclusion
3D-mapping and intracardiac echocardiography demonstrate that sc-TdP predominantly originates from the MB free wall insertion and its Purkinje network. Catheter ablation of the culprit PVC at the MB free wall junction leads to excellent short- and long-term results and should be considered as first-line therapy in recurrent sc-TdP or electrical storm.

© 2021. The Author(s).

Clin Res Cardiol: 01 May 2022; 111:502-510
Steinfurt J, Nazer B, Aguilar M, Moss J, ... Tedrow UB, Bogossian H
Clin Res Cardiol: 01 May 2022; 111:502-510 | PMID: 33770204
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Abstract

Therapeutic application of genome editing in dyslipidemia.

Whittaker MN, Musunuru K
Purpose of review
To summarize recent advances with respect to the use of genome editing to modify blood lipid levels in vivo.
Recent findings
Genome-editing technologies have been successfully used to target the PCSK9 gene in the livers of nonhuman primates and significantly reduce blood LDL cholesterol levels.
Summary
Multiple proof-of-concept nonhuman primate studies raise the prospect of genome editing empowering \'one-and-done\' therapies for the treatment of dyslipidemic patients.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 01 Apr 2022; 33:133-138
Whittaker MN, Musunuru K
Curr Opin Lipidol: 01 Apr 2022; 33:133-138 | PMID: 34907967
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Impact:
Abstract

Current models of apolipoprotein A-I lipidation by adenosine triphosphate binding cassette transporter A1.

Hafiane A, Gianopoulos I, Sorci-Thomas MG, Daskalopoulou SS
Purpose of review
The primary cardioprotective function of high-density lipoprotein (HDL) is to remove excess cellular free cholesterol (FC) from peripheral tissues and deliver it to the liver. Here, we summarize recent research that examines apolipoprotein A-I (apoA-I) lipidation models by adenosine triphosphate binding cassette transporter A1 (ABCA1) and discuss its relevance in atherosclerotic cardiovascular disease (ASCVD).
Recent findings
The first step in HDL formation involves the interaction between apoA-I and ABCA1, where ABCA1 mediates the removal of FC and phospholipids from lipid-laden macrophages to form discoidal nascent HDL (nHDL). However, there are currently no clear-cut systematic models that characterize HDL formation. A number of recent studies have investigated the importance of apoA-I C- and N-terminal domains required for optimal cholesterol efflux and nHDL production. Furthermore, functional ABCA1 is required for direct or indirect binding to apoA-I where ABCA1 dimer-monomer interconversion facilitates apoA-I lipidation from plasma membrane microdomains. Microparticles are also another lipid source for apoA-I solubilization into nHDL.
Summary
ApoA-I and ABCA1 are key factors in macrophage-mediated cholesterol efflux and nHDL production. Understanding of the key steps in HDL formation may unlock the therapeutic potential of HDL and improve clinical management of ASCVD.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:139-145
Hafiane A, Gianopoulos I, Sorci-Thomas MG, Daskalopoulou SS
Curr Opin Lipidol: 31 Mar 2022; 33:139-145 | PMID: 34581311
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Abstract

Familial combined hyperlipidemia is a polygenic trait.

Gill PK, Hegele RA
Purpose of review
: Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been investigated to characterize its genetic basis. Despite almost half a century of searching, a single gene cause for the phenotype has not yet been identified.
Recent findings
: Recent studies using next-generation genetic analytic methods confirm that FCH has a polygenic basis, with a clear large contribution from the accumulation of small-to-moderate effect common single nucleotide polymorphisms (SNPs) throughout the genome that is associated with raising TG, and probably also those raising LDL cholesterol. On the other hand, rare monogenic variants, such as those causing familial hypercholesterolemia, play a negligible role, if any. Genetic profiling suggests that patients with FCH and hypertriglyceridemia share a strong polygenic basis and show a similar profile of multiple TG-raising common SNPs.
Summary
: Recent progress in genomics has shown that most if not all of the genetic susceptibility to FCH is polygenic in nature. Future research should include larger cohort studies, with wider ancestral diversity, ancestry-specific polygenic scores, and investigation of epigenetic and lifestyle factors to help further elucidate the causative agents at play in cases where the genetic etiology remains to be defined.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:126-132
Gill PK, Hegele RA
Curr Opin Lipidol: 31 Mar 2022; 33:126-132 | PMID: 34690300
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Abstract

ANGPTL4: a new mode in the regulation of intravascular lipolysis.

Ploug M
Purpose of review
Lipoprotein lipase (LPL) is the rate-limiting enzyme for intravascular processing of circulating triglyceride-rich lipoproteins (TRLs). One emerging strategy for therapeutic lowering of plasma triglyceride levels aims at increasing the longevity of LPL activity by attenuating its inhibition from angiopoietin-like proteins (ANGPTL) 3, 4 and 8. This mini-review focuses on recent insights into the molecular mechanisms underpinning the regulation of LPL activity in the intravascular unit by ANGPTLs with special emphasis on ANGPTL4.
Recent findings
Our knowledge on the molecular interplays between LPL, its endothelial transporter GPIHBP1, and its inhibitor(s) ANGPTL4, ANGPTL3 and ANGPTL8 have advanced considerably in the last 2 years and provides an outlined on how these proteins regulate the activity and compartmentalization of LPL. A decisive determinant instigating this control is the inherent protein instability of LPL at normal body temperature, a property that is reciprocally impacted by the binding of GPIHBP1 and ANGPTLs. Additional layers in this complex LPL regulation is provided by the different modulation of ANGPTL4 and ANGPTL3 activities by ANGPTL8 and the inhibition of ANGPTL3/8 complexes by apolipoprotein A5 (APOA5).
Summary
Posttranslational regulation of LPL activity in the intravascular space is essential for the differential partitioning of TRLs across tissues and their lipolytic processing in response to nutritional cues.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:112-119
Ploug M
Curr Opin Lipidol: 31 Mar 2022; 33:112-119 | PMID: 34860701
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Abstract

Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension.

Li C, Ma L, Wang Q, Shao X, ... Wang W, Yu J
Objectives
Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we explored the role of the RhoA/Rho kinase (ROCK) signaling pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A nonspecific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated.
Methods
Normotensive female Wistar-Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for 2 weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular remodeling assessed.
Results
Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK II in the mid-aorta, more significant in the high-dose group. However, ROCK I expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dose-dependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen I, which were accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes.
Conclusion
These findings suggest that activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitor have potential therapeutic value.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

J Hypertens: 31 Mar 2022; 40:675-684
Li C, Ma L, Wang Q, Shao X, ... Wang W, Yu J
J Hypertens: 31 Mar 2022; 40:675-684 | PMID: 34862331
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Abstract

Association of dietary patterns and components with atherosclerosis risk biomarkers in familial hypercholesterolemia.

Antoniazi L, Arroyo-Olivares R, Mata P, Santos RD
Purpose of review
Familial hypercholesterolemia (FH) is a relatively common genetic disorder associated with elevated atherosclerotic risk. Dietary interventions can modulate processes associated with cardiovascular risk and potentiate the impact of pharmacological lipid-lowering therapies. This review evaluates recent findings of dietary patterns and their components on risk biomarkers in people with FH.
Recent findings
Diets lower in saturated fatty acids (SFA) may reduce low-density lipoprotein-cholesterol (LDL-C); however, their effects seem to be modest. A Mediterranean style diet apparently exerts more robust effects on plasma LDL-C, apolipoprotein B and C reactive protein concentrations than one restricted in SFA. Supplementation of plant sterols and stanols reduces LDL-C especially in children with FH. Caloric restricted diets may reduce weight and improve triglyceride levels in individuals with FH and excess body weight.
Summary
Despite the strong impact of genetic variants, dietary patterns mostly low in SFA and especially the Mediterranean diet may influence risk biomarkers in FH. However, most available studies are limited by cross-sectional design, small number of study subjects and short-term follow-ups. Robust interventional studies are necessary to test the impact of dietary patterns in people with FH.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:89-94
Antoniazi L, Arroyo-Olivares R, Mata P, Santos RD
Curr Opin Lipidol: 31 Mar 2022; 33:89-94 | PMID: 34907966
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Abstract

Metabolic dysfunction-associated fatty liver disease: advances in genetic and epigenetic implications.

Pirola CJ, Sookoian S
Purpose of review
Fatty liver associated with metabolic dysfunction, also known under the acronym NAFLD (nonalcoholic fatty liver disease) is the leading global cause of chronic liver disease. In this review, we address the state of research on genetics and epigenetics of NAFLD with focus on key discoveries and conceptual advances over the past 2 years.
Recent findings
The analysis of NAFLD-associated genetic variant effects on the whole-transcriptome, including quantitative trait loci (QTL) associated with gene expression (eQTL) or splicing (sQTL) may explain pleiotropic effects. Functional experiments on NAFLD-epigenetics, including profiling of liver chromatin accessibility quantitative trait loci (caQTL) show co-localization with numerous genome-wide association study signals linked to metabolic and cardiovascular traits. Novel studies provide insights into the modulation of the hepatic transcriptome and epigenome by tissue microbiotas. Genetic variation of components of the liver cellular respirasome may result in broad cellular and metabolic effects. Mitochondrial noncoding RNAs may regulate liver inflammation and fibrogenesis. RNA modifications as N6-methyladenosine may explain sex-specific differences in liver gene transcription linked to lipid traits.
Summary
The latest developments in the field of NAFLD-genomics can be leveraged for identifying novel disease mechanisms and therapeutic targets that may prevent the morbidity and mortality associated with disease progression.
Video abstract
http://links.lww.com/COL/A23.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:95-102
Pirola CJ, Sookoian S
Curr Opin Lipidol: 31 Mar 2022; 33:95-102 | PMID: 34966133
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Abstract

Mechanism of CircANKRD36 regulating cell heterogeneity and endothelial mesenchymal transition in aortic valve stromal cells by regulating miR-599 and TGF-β signaling pathway.

Zhang C, Liu M, Wang X, Chen S, ... Dong N, Shang X
Objective
To explore the mechanism of CircANKRD36 regulating cell heterogeneity and endothelial mesenchymal transition in aortic valve stromal cells by regulating miR-599 and TGF-β signaling pathway.
Methods
Human tissue specimens were divided into Control group (n = 25) and CAVD group (n = 25). The mRNA expressions of CircANKRD36 and miR-599 in tissue samples were analyzed by qRT-PCR. Western blot was used to analyze the protein expression of osteogenic differentiation related factors induced by OM.The expressions of ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 were detected by Western blot.
Results
The expression of CircANKRD36mRNA in CAVD tissue was lower than that in Control tissue (P < 0.05), and the expression of miR-599mRNA in CAVD tissue was higher than that in Control tissue (P < 0.05). CircANKRD36 was negatively correlated with ALP, osteocalcin, osteopontin, Runx2, Cadherin11 expression level after OM induced osteogenic differentiation. The expression level of miR-599 was positively correlated with ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 after OM induced osteogenic differentiation.The expression of ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 protein in circ+miR-599 group was lower than that in circ+miR-NC group (P < 0.05). Compared with Vector+miR-NC group, the protein expressions of TGF-β1, TGF-β2 and SMAD4 in circ+miR-NC group decreased (P < 0.05), while the protein expressions of TGF-β1, TGF-β2 and SMAD4 in circ+miR-599 group increased (P < 0.05).
Conclusion
CircANKRD36 can inhibit the expression of miR-599 and the activation of TGF-β signaling pathway, thus inhibiting the expression of differentiation-related factors of VIC osteogenesis and the formation of calcified nodules. Therefore, circANKRD36-miR-599-TGF-β axis can be a new theoretical basis for treating CAVD.

Copyright © 2022 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Mar 2022; 352:104-114
Zhang C, Liu M, Wang X, Chen S, ... Dong N, Shang X
Int J Cardiol: 31 Mar 2022; 352:104-114 | PMID: 35074490
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Abstract

Estimation of low-density lipoprotein cholesterol levels using machine learning.

Oh GC, Ko T, Kim JH, Lee MH, ... Kim KH, Lee HY
Background
Low-density lipoprotein-cholesterol (LDL-C) is used as a threshold and target for treating dyslipidemia. Although the Friedewald equation is widely used to estimate LDL-C, it has been known to be inaccurate in the case of high triglycerides (TG) or non-fasting states. We aimed to propose a novel method to estimate LDL-C using machine learning.
Methods
Using a large, single-center electronic health record database, we derived a ML algorithm to estimate LDL-C from standard lipid profiles. From 1,029,572 cases with both standard lipid profiles (total cholesterol, high-density lipoprotein-cholesterol, and TG) and direct LDL-C measurements, 823,657 tests were used to derive LDL-C estimation models. Patient characteristics such as sex, age, height, weight, and other laboratory values were additionally used to create separate data sets and algorithms.
Results
Machine learning with gradient boosting (LDL-CX) and neural network (LDL-CN) showed better correlation with directly measured LDL-C, compared with conventional methods (r = 0.9662, 0.9668, 0.9563, 0.9585; for LDL-CX, LDL-CN, Friedewald [LDL-CF], and Martin [LDL-CM] equations, respectively). The overall bias of LDL-CX (-0.27 mg/dL, 95% CI -0.30 to -0.23) and LDL-CN (-0.01 mg/dL, 95% CI -0.04-0.03) were significantly smaller compared with both LDL-CF (-3.80 mg/dL, 95% CI -3.80 to -3.60) or LDL-CM (-2.00 mg/dL, 95% CI -2.00 to -1.94), especially at high TG levels.
Conclusions
Machine learning algorithms were superior in estimating LDL-C compared with the conventional Friedewald or the more contemporary Martin equations. Through external validation and modification, machine learning could be incorporated into electronic health records to substitute LDL-C estimation.

Copyright © 2022 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Mar 2022; 352:144-149
Oh GC, Ko T, Kim JH, Lee MH, ... Kim KH, Lee HY
Int J Cardiol: 31 Mar 2022; 352:144-149 | PMID: 35065153
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Abstract

CD36 (SR-B2) as master regulator of cellular fatty acid homeostasis.

Glatz JFC, Nabben M, Luiken JJFP
Purpose of review
Transmembrane glycoprotein cluster of differentiation 36 (CD36) is a scavenger receptor class B protein (SR-B2) that serves various functions in lipid metabolism and signaling, in particular facilitating the cellular uptake of long-chain fatty acids. Recent studies have disclosed CD36 to play a prominent regulatory role in cellular fatty acid metabolism in both health and disease.
Recent findings
The rate of cellular fatty acid uptake is short-term (i.e., minutes) regulated by the subcellular recycling of CD36 between endosomes and the plasma membrane. This recycling is governed by the activity of vacuolar-type H+-ATPase (v-ATPase) in the endosomal membrane via assembly and disassembly of two subcomplexes. The latter process is being influenced by metabolic substrates including fatty acids, glucose and specific amino acids, together resulting in a dynamic interplay to modify cellular substrate preference and uptake rates. Moreover, in cases of metabolic disease v-ATPase activity was found to be affected while interventions aimed at normalizing v-ATPase functioning had therapeutic potential.
Summary
The emerging central role of CD36 in cellular lipid homeostasis and recently obtained molecular insight in the interplay among metabolic substrates indicate the applicability of CD36 as target for metabolic modulation therapy in disease. Experimental studies already have shown the feasibility of this approach.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Curr Opin Lipidol: 31 Mar 2022; 33:103-111
Glatz JFC, Nabben M, Luiken JJFP
Curr Opin Lipidol: 31 Mar 2022; 33:103-111 | PMID: 35125400
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Impact:
Abstract

Tissue-engineered vascular grafts and regeneration mechanisms.

Wei Y, Wang F, Guo Z, Zhao Q
Cardiovascular diseases (CVDs) are life-threatening diseases with high morbidity and mortality worldwide. Vascular bypass surgery is still the ultimate strategy for CVD treatment. Autografts are the gold standard for graft transplantation, but insufficient sources limit their widespread application. Therefore, alternative tissue engineered vascular grafts (TEVGs) are urgently needed. In this review, we summarize the major strategies for the preparation of vascular grafts, as well as the factors affecting their patency and tissue regeneration. Finally, the underlying mechanisms of vascular regeneration that are mediated by host cells are discussed.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 31 Mar 2022; 165:40-53
Wei Y, Wang F, Guo Z, Zhao Q
J Mol Cell Cardiol: 31 Mar 2022; 165:40-53 | PMID: 34971664
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Abstract

Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020.

Wall SM
Intercalated cells make up about a third of all cells within the connecting tubule and the collecting duct and are subclassified as type A, type B and non-A, non-B based on the subcellular distribution of the H+-ATPase, which dictates whether it secretes H+ or HCO3-. Type B intercalated cells mediate Cl- absorption and HCO3- secretion, which occurs largely through the anion exchanger pendrin. Pendrin is stimulated by angiotensin II via the angiotensin type 1a receptor and by aldosterone through MR (mineralocorticoid receptor). Aldosterone stimulates pendrin expression and function, in part, through the alkalosis it generates. Pendrin-mediated HCO3- secretion increases in models of metabolic alkalosis, which attenuates the alkalosis. However, pendrin-positive intercalated cells also regulate blood pressure, at least partly, through pendrin-mediated Cl- absorption and through their indirect effect on the epithelial Na+ channel, ENaC. This aldosterone-induced increase in pendrin secondarily stimulates ENaC, thereby contributing to the aldosterone pressor response. This review describes the contribution of pendrin-positive intercalated cells to Na+, K+, Cl- and acid-base balance.



Hypertension: 30 Mar 2022; 79:706-716
Wall SM
Hypertension: 30 Mar 2022; 79:706-716 | PMID: 35109661
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Impact:
Abstract

Advances in treatment of chronic thromboembolic pulmonary hypertension.

Tzoumas A, Peppas S, Sagris M, Papanastasiou CA, ... Kokkinidis DG, Giannakoulas G
Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a progressive pulmonary vascular disease which can lead to right heart failure and death, if left untreated. CTEPH is caused by persistent obstruction of large, middle-sized, or distal pulmonary arteries due to limited thromboembolic resolution in the pulmonary vascular arterial tree. Every patient with CTEPH should undergo evaluation for Pulmonary Endarterectomy (PEA) after referral to institutions with an experienced multidisciplinary CTEPH team. Although management of distal thromboembolic lesions with PEA remains a challenge due to their difficult accessibility, limited distal CTEPH is not considered an absolute contraindication for PEA, as more expertise surgical teams operate on them successfully. Furthermore, in up to 30-50% of patients who undergo PEA, curative treatment is not achieved due to incomplete thrombi removal or extensive pulmonary microvascular disease. Medical therapies that target the underlying pulmonary microvascular disease can offer symptomatic and hemodynamic benefits, although they do not deal with the core mechanism of the disease which is the removal of thromboembolic material from pulmonary vasculature. Recent research has provided evidence suggesting balloon pulmonary angioplasty (BPA) is a reasonable treatment option for inoperable CTEPH and recurrent/persistent pulmonary hypertension after PEA. Advancements in diagnostic modalities and refinements of BPA technique have decreased the complication rate and increased its beneficial effects in hemodynamics, symptoms, right ventricular function and long-term survival. Ongoing trials and future prospective cohorts will provide evidence regarding the optimal selection of patients and lesions prone to BPA treatment along with hybrid therapeutic strategies combining pharmacological therapy, PEA and BPA, which can potentially change the standard of care in CTEPH.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Thromb Res: 30 Mar 2022; 212:30-37
Tzoumas A, Peppas S, Sagris M, Papanastasiou CA, ... Kokkinidis DG, Giannakoulas G
Thromb Res: 30 Mar 2022; 212:30-37 | PMID: 35217332
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Abstract

Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics.

Swerdlow DI, Rider DA, Yavari A, Wikström Lindholm M, Campion GV, Nissen SE
Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein(a) [Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining \'high risk\' is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 25 Mar 2022; 118:1218-1231
Swerdlow DI, Rider DA, Yavari A, Wikström Lindholm M, Campion GV, Nissen SE
Cardiovasc Res: 25 Mar 2022; 118:1218-1231 | PMID: 33769464
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Abstract

The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation.

Immler R, Nadolni W, Bertsch A, Morikis V, ... Pruenster M, Sperandio M
Aims
Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signalling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signalling.
Methods and results
Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store-operated Ca2+ entry through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signalling, thereby preventing cellular spreading, adhesion strengthening, and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of Escherichia coli particles by neutrophils in the absence of KV1.3.
Conclusion
We show that the voltage-gated potassium channel KV1.3 is critical for Ca2+ signalling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signalling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 25 Mar 2022; 118:1289-1302
Immler R, Nadolni W, Bertsch A, Morikis V, ... Pruenster M, Sperandio M
Cardiovasc Res: 25 Mar 2022; 118:1289-1302 | PMID: 33881519
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Abstract

Assessment of arrhythmia mechanism and burden of the infarcted ventricles following remuscularization with pluripotent stem cell-derived cardiomyocyte patches using patient-derived models.

Yu JK, Liang JA, Franceschi WH, Huang Q, ... Boyle PM, Trayanova NA
Aims
Direct remuscularization with pluripotent stem cell-derived cardiomyocytes (PSC-CMs) seeks to address the onset of heart failure post-myocardial infarction (MI) by treating the persistent muscle deficiency that underlies it. However, direct remuscularization with PSC-CMs could potentially be arrhythmogenic. We investigated two possible mechanisms of arrhythmogenesis-focal vs. re-entrant-arising from direct remuscularization with PSC-CM patches in two personalized, human ventricular computer models of post-MI. Moreover, we developed a principled approach for evaluating arrhythmogenicity of direct remuscularization that factors in the VT propensity of the patient-specific post-MI fibrotic substrate and use it to investigate different conditions of patch remuscularization.
Methods and results
Two personalized, human ventricular models of post-MI (P1 and P2) were constructed from late gadolinium enhanced (LGE)-magnetic resonance images (MRIs). In each model, remuscularization with PSC-CM patches was simulated under different treatment conditions that included patch engraftment, patch myofibril orientation, remuscularization site, patch size (thickness and diameter), and patch maturation. To determine arrhythmogenicity of treatment conditions, VT burden of heart models was quantified prior to and after simulated remuscularization and compared. VT burden was quantified based on inducibility (i.e. weighted sum of pacing sites that induced) and severity (i.e. the number of distinct VT morphologies induced). Prior to remuscularization, VT burden was significant in P1 (0.275) and not in P2 (0.0, not VT inducible). We highlight that re-entrant VT mechanisms would dominate over focal mechanisms; spontaneous beats emerging from PSC-CM grafts were always a fraction of resting sinus rate. Moreover, incomplete patch engraftment can be particularly arrhythmogenic, giving rise to particularly aberrant electrical activation and conduction slowing across the PSC-CM patches along with elevated VT burden when compared with complete engraftment. Under conditions of complete patch engraftment, remuscularization was almost always arrhythmogenic in P2 but certain treatment conditions could be anti-arrhythmogenic in P1. Moreover, the remuscularization site was the most important factor affecting VT burden in both P1 and P2. Complete maturation of PSC-CM patches, both ionically and electrotonically, at the appropriate site could completely alleviate VT burden.
Conclusion
We identified that re-entrant VT would be the primary VT mechanism in patch remuscularization. To evaluate the arrhythmogenicity of remuscularization, we developed a principled approach that factors in the propensity of the patient-specific fibrotic substrate for VT. We showed that arrhythmogenicity is sensitive to the patient-specific fibrotic substrate and remuscularization site. We demonstrate that targeted remuscularization can be safe in the appropriate individual and holds the potential to non-destructively eliminate VT post-MI in addition to addressing muscle deficiency underlying heart failure progression.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 25 Mar 2022; 118:1247-1261
Yu JK, Liang JA, Franceschi WH, Huang Q, ... Boyle PM, Trayanova NA
Cardiovasc Res: 25 Mar 2022; 118:1247-1261 | PMID: 33881518
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Abstract

Epidermal growth factor receptor-dependent maintenance of cardiac contractility.

Guo S, Okyere AD, McEachern E, Strong JL, ... Cheung JY, Tilley DG
Aims
Epidermal growth factor receptor (EGFR) is essential to the development of multiple tissues and organs and is a target of cancer therapeutics. Due to the embryonic lethality of global EGFR deletion and conflicting reports of cardiac-overexpressed EGFR mutants, its specific impact on the adult heart, normally or in response to chronic stress, has not been established. Using complimentary genetic strategies to modulate cardiomyocyte-specific EGFR expression, we aim to define its role in the regulation of cardiac function and remodelling.
Methods and results
A floxed EGFR mouse model with α-myosin heavy chain-Cre-mediated cardiomyocyte-specific EGFR downregulation (CM-EGFR-KD mice) developed contractile dysfunction by 9 weeks of age, marked by impaired diastolic relaxation, as monitored via echocardiographic, haemodynamic, and isolated cardiomyocyte contractility analyses. This contractile defect was maintained over time without overt cardiac remodelling until 10 months of age, after which the mice ultimately developed severe heart failure and reduced lifespan. Acute downregulation of EGFR in adult floxed EGFR mice with adeno-associated virus 9 (AAV9)-encoded Cre with a cardiac troponin T promoter (AAV9-cTnT-Cre) recapitulated the CM-EGFR-KD phenotype, while AAV9-cTnT-EGFR treatment of adult CM-EGFR-KD mice rescued the phenotype. Notably, chronic administration of the β-adrenergic receptor agonist isoproterenol effectively and reversibly compensated for the contractile dysfunction in the absence of cardiomyocyte hypertrophy in CM-EGFR-KD mice. Mechanistically, EGFR downregulation reduced the expression of protein phosphatase 2A regulatory subunit Ppp2r3a/PR72, which was associated with decreased phosphorylation of phospholamban and Ca2+ clearance, and whose re-expression via AAV9-cTnT-PR72 rescued the CM-EGFR-KD phenotype.
Conclusions
Altogether, our study highlights a previously unrecognized role for EGFR in maintaining contractile homeostasis under physiologic conditions in the adult heart via regulation of PR72 expression.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 25 Mar 2022; 118:1276-1288
Guo S, Okyere AD, McEachern E, Strong JL, ... Cheung JY, Tilley DG
Cardiovasc Res: 25 Mar 2022; 118:1276-1288 | PMID: 33892492
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Abstract

Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis.

de Haan W, Dheedene W, Apelt K, Décombas-Deschamps S, ... Huylebroeck D, Luttun A
Aims
Hepatic capillaries are lined with specialized liver sinusoidal endothelial cells (LSECs) which support macromolecule passage to hepatocytes and prevent fibrosis by keeping hepatic stellate cells (HSCs) quiescent. LSEC specialization is co-determined by transcription factors. The zinc-finger E-box-binding homeobox (Zeb)2 transcription factor is enriched in LSECs. Here, we aimed to elucidate the endothelium-specific role of Zeb2 during maintenance of the liver and in liver fibrosis.
Methods and results
To study the role of Zeb2 in liver endothelium we generated EC-specific Zeb2 knock-out (ECKO) mice. Sequencing of liver EC RNA revealed that deficiency of Zeb2 results in prominent expression changes in angiogenesis-related genes. Accordingly, the vascular area was expanded and the presence of pillars inside ECKO liver vessels indicated that this was likely due to increased intussusceptive angiogenesis. LSEC marker expression was not profoundly affected and fenestrations were preserved upon Zeb2 deficiency. However, an increase in continuous EC markers suggested that Zeb2-deficient LSECs are more prone to dedifferentiation, a process called \'capillarization\'. Changes in the endothelial expression of ligands that may be involved in HSC quiescence together with significant changes in the expression profile of HSCs showed that Zeb2 regulates LSEC-HSC communication and HSC activation. Accordingly, upon exposure to the hepatotoxin carbon tetrachloride (CCl4), livers of ECKO mice showed increased capillarization, HSC activation, and fibrosis compared to livers from wild-type littermates. The vascular maintenance and anti-fibrotic role of endothelial Zeb2 was confirmed in mice with EC-specific overexpression of Zeb2, as the latter resulted in reduced vascularity and attenuated CCl4-induced liver fibrosis.
Conclusion
Endothelial Zeb2 preserves liver angioarchitecture and protects against liver fibrosis. Zeb2 and Zeb2-dependent genes in liver ECs may be exploited to design novel therapeutic strategies to attenuate hepatic fibrosis.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 25 Mar 2022; 118:1262-1275
de Haan W, Dheedene W, Apelt K, Décombas-Deschamps S, ... Huylebroeck D, Luttun A
Cardiovasc Res: 25 Mar 2022; 118:1262-1275 | PMID: 33909875
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Abstract

Arginase II protein regulates Parkin-dependent p32 degradation that contributes to Ca2+-dependent eNOS activation in endothelial cells.

Koo BH, Won MH, Kim YM, Ryoo S
Aims
Arginase II (ArgII) plays a key role in the regulation of Ca2+ between the cytosol and mitochondria in a p32-dependent manner. p32 contributes to endothelial nitric oxide synthase (eNOS) activation through the Ca2+/CaMKII/AMPK/p38MAPK/Akt signalling cascade. Therefore, we investigated a novel function of ArgII in the regulation of p32 stability.
Methods and results
mRNA levels were measured by quantitative reverse transcription-PCR, and protein levels and activation were confirmed by western blot analysis. Ca2+ concentrations were measured by FACS analysis and a vascular tension assay was performed. ArgII bound to p32, and ArgII protein knockdown using siArgII facilitated the ubiquitin-dependent proteasomal degradation of p32. β-lactone, a proteasome inhibitor, inhibited the p32 degradation associated with endothelial dysfunction in a Ca2+-dependent manner. The amino acids Lys154, Lys 180, and Lys220 of the p32 protein were identified as putative ubiquitination sites. When these sites were mutated, p32 was resistant to degradation in the presence of siArgII, and endothelial function was impaired. Knockdown of Pink/Parkin as an E3-ubiquitin ligase with siRNAs resulted in increased p32, decreased [Ca2+]c, and attenuated CaMKII-dependent eNOS activation by siArgII. siArgII-dependent Parkin activation was attenuated by KN93, a CaMKII inhibitor. Knockdown of ArgII mRNA and its gene, but not inhibition of its activity, accelerated the interaction between p32 and Parkin and reduced p32 levels. In aortas of ArgII-/- mice, p32 levels were reduced by activated Parkin and inhibition of CaMKII attenuated Parkin-dependent p32 lysis. siParkin blunted the phosphorylation of the activated CaMKII/AMPK/p38MAPK/Akt/eNOS signalling cascade. However, ApoE-/- mice fed a high-cholesterol diet had greater ArgII activity, significantly attenuated phosphorylation of Parkin, and increased p32 levels. Incubation with siArgII augmented p32 ubiquitination through Parkin activation, and induced signalling cascade activation.
Conclusion
The results suggest a novel function for ArgII protein in Parkin-dependent ubiquitination of p32 that is associated with Ca2+-mediated eNOS activation in endothelial cells.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 25 Mar 2022; 118:1344-1358
Koo BH, Won MH, Kim YM, Ryoo S
Cardiovasc Res: 25 Mar 2022; 118:1344-1358 | PMID: 33964139
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Abstract

Senescence mechanisms and targets in the heart.

Chen MS, Lee RT, Garbern JC
Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, and cardiac fibrosis. While age-related telomere shortening represents a major cause of replicative senescence, the senescent state can also be induced by oxidative stress, metabolic dysfunction, and epigenetic regulation, among other stressors. It is critical that we understand the molecular pathways that lead to cellular senescence and the consequences of cellular senescence in order to develop new therapeutic approaches to treat CVD. In this review, we discuss molecular mechanisms of cellular senescence, explore how cellular senescence of different cardiac cell types (including cardiomyocytes, cardiac endothelial cells, cardiac fibroblasts, vascular smooth muscle cells, and valve interstitial cells) can lead to CVD, and highlight potential therapeutic approaches that target molecular mechanisms of cellular senescence to prevent or treat CVD.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 25 Mar 2022; 118:1173-1187
Chen MS, Lee RT, Garbern JC
Cardiovasc Res: 25 Mar 2022; 118:1173-1187 | PMID: 33963378
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Abstract

Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signalling.

van Kuijk K, Demandt JAF, Perales-Patón J, Theelen TL, ... Saez-Rodriguez J, Sluimer JC
Aims
Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis.
Methods and results
Myeloid-specific PHD knockout (PHDko) mice were obtained via bone marrow transplantation (PHD1ko, PHD3ko) or conditional knockdown through lysozyme M-driven Cre recombinase (PHD2cko). Mice were fed high cholesterol diet for 6-12 weeks to induce atherosclerosis. Aortic root plaque size was significantly augmented 2.6-fold in PHD2cko, and 1.4-fold in PHD3ko compared to controls but was unchanged in PHD1ko mice. Macrophage apoptosis was promoted in PHD2cko and PHD3ko mice in vitro and in vivo, via the hypoxia-inducible factor (HIF) 1α/BNIP3 axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1α/BNIP3 signalling, which was validated in vitro by siRNA silencing. Human plaque BNIP3 mRNA was positively associated with plaque necrotic core size, suggesting similar pro-apoptotic effects in human. Furthermore, PHD2cko plaques displayed enhanced fibrosis, while macrophage collagen breakdown by matrix metalloproteinases, collagen production, and proliferation were unaltered. Instead, PHD2cko BMDMs enhanced fibroblast collagen secretion in a paracrine manner. In silico analysis of macrophage-fibroblast communication predicted SPP1 (osteopontin) signalling as regulator, which was corroborated by enhanced plaque SPP1 protein in vivo. Increased SPP1 mRNA expression upon PHD2cko was preferentially observed in foamy plaque macrophages expressing \'triggering receptor expressed on myeloid cells-2\' (TREM2hi) evidenced by single-cell RNA, but not in neutrophils. This confirmed enhanced fibrotic signalling by PHD2cko macrophages to fibroblasts, in vitro as well as in vivo.
Conclusion
Myeloid PHD2cko and PHD3ko enhanced atherosclerotic plaque growth and macrophage apoptosis, while PHD2cko macrophages further activated collagen secretion by fibroblasts in vitro, likely via paracrine SPP1 signalling through TREM2hi macrophages.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 25 Mar 2022; 118:1232-1246
van Kuijk K, Demandt JAF, Perales-Patón J, Theelen TL, ... Saez-Rodriguez J, Sluimer JC
Cardiovasc Res: 25 Mar 2022; 118:1232-1246 | PMID: 33913468
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Abstract

Single-cell transcriptomic analyses of cardiac immune cells reveal that Rel-driven CD72-positive macrophages induce cardiomyocyte injury.

Ni SH, Xu JD, Sun SN, Li Y, ... Wang LJ, Lu L
Aims 
The goal of our study was to investigate the heterogeneity of cardiac macrophages (CMφs) in mice with transverse aortic constriction (TAC) via single-cell sequencing and identify a subset of macrophages associated with heart injury.
Methods and results 
We selected all CMφs from CD45+ cells using single-cell mRNA sequencing data. Through dimension reduction, clustering, and enrichment analyses, CD72hi CMφs were identified as a subset of pro-inflammatory macrophages. The pseudo-time trajectory and ChIP-Seq analyses identified Rel as the key transcription factor that induces CD72hi CMφ differentiation. Rel KD and Rel-/- bone marrow chimaera mice subjected to TAC showed features of mitigated cardiac injury, including decreased levels of cytokines and ROS, which prohibited cardiomyocyte death. The transfer of adoptive Rel-overexpressing monocytes and CD72hi CMφ injection directly aggravated heart injury in the TAC model. The CD72hi macrophages also exerted pro-inflammatory and cardiac injury effects associated with myocardial infarction. In humans, patients with heart failure exhibit increased CD72hi CMφ levels following dilated cardiomyopathy and ischaemic cardiomyopathy.
Conclusion 
Bone marrow-derived, Rel-mediated CD72hi macrophages play a pro-inflammatory role, induce cardiac injury and, thus, may serve as a therapeutic target for multiple cardiovascular diseases.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 25 Mar 2022; 118:1303-1320
Ni SH, Xu JD, Sun SN, Li Y, ... Wang LJ, Lu L
Cardiovasc Res: 25 Mar 2022; 118:1303-1320 | PMID: 34100920
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Abstract

Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans.

O\'Gallagher K, Puledda F, O\'Daly O, Ryan M, ... Goadsby PJ, Shah AM
Aims
Neuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signalling is implicated in cerebrovascular ischaemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesized that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow (CBF), as well as changes in functional brain connectivity.
Methods and results
We investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on CBF and brain functional connectivity in healthy human volunteers (n = 19). We performed a randomized, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. SMTC infusion induced an ∼4% decrease in resting global CBF [-2.3 (-0.3, -4.2) mL/100g/min, mean (95% confidence interval, CI), P = 0.02]. In a whole-brain voxel-wise factorial-design comparison of CBF maps, we identified a localized decrease in regional blood flow in the right hippocampus and parahippocampal gyrus following SMTC vs. placebo (2921 voxels; T = 7.0; x = 36; y = -32; z = -12; P < 0.001). This was accompanied by a decrease in functional connectivity to the left superior parietal lobule vs. placebo (484 voxels; T = 5.02; x = -14; y = -56; z = 74; P = 0.009). These analyses adjusted for the modest changes in mean arterial blood pressure induced by SMTC as compared to placebo [+8.7 mmHg (+1.8, +15.6), mean (95% CI), P = 0.009].
Conclusions
These data suggest a fundamental physiological role of nNOS in regulating regional CBF and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 25 Mar 2022; 118:1321-1329
O'Gallagher K, Puledda F, O'Daly O, Ryan M, ... Goadsby PJ, Shah AM
Cardiovasc Res: 25 Mar 2022; 118:1321-1329 | PMID: 34120160
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Abstract

Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome.

Nieto-Marín P, Tinaquero D, Utrilla RG, Cebrián J, ... Delpón E, ITACA Consortium Investigators
Aims
The transcription factor Tbx5 controls cardiogenesis and drives Scn5a expression in mice. We have identified two variants in TBX5 encoding p. D111Y and p. F206L Tbx5, respectively, in two unrelated patients with structurally normal hearts diagnosed with long QT (LQTS) and Brugada (BrS) syndrome. Here, we characterized the consequences of each variant to unravel the underlying disease mechanisms.
Methods and results
We combined clinical analysis with in vivo and in vitro electrophysiological and molecular techniques in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), HL-1 cells, and cardiomyocytes from mice trans-expressing human wild-type (WT) or mutant proteins. Tbx5 increased transcription of SCN5A encoding cardiac Nav1.5 channels, while repressing CAMK2D and SPTBN4 genes encoding Ca/calmodulin kinase IIδ (CaMKIIδ) and βIV-spectrin, respectively. These effects significantly increased Na current (INa) in hiPSC-CMs and in cardiomyocytes from mice trans-expressing Tbx5. Consequently, action potential (AP) amplitudes increased and QRS interval narrowed in the mouse electrocardiogram. p. F206L Tbx5 bound to the SCN5A promoter failed to transactivate it, thus precluding the pro-transcriptional effect of WT Tbx5. Therefore, p. F206L markedly decreased INa in hiPSC-CM, HL-1 cells and mouse cardiomyocytes. The INa decrease in p. F206L trans-expressing mice translated into QRS widening and increased flecainide sensitivity. p. D111Y Tbx5 increased SCN5A expression but failed to repress CAMK2D and SPTBN4. The increased CaMKIIδ and βIV-spectrin significantly augmented the late component of INa (INaL) which, in turn, significantly prolonged AP duration in both hiPSC-CMs and mouse cardiomyocytes. Ranolazine, a selective INaL inhibitor, eliminated the QT and QTc intervals prolongation seen in p. D111Y trans-expressing mice.
Conclusions
In addition to peak INa, Tbx5 critically regulates INaL and the duration of repolarization in human cardiomyocytes. Our original results suggest that TBX5 variants associate with and modulate the intensity of the electrical phenotype in LQTS and BrS patients.

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Cardiovasc Res: 16 Mar 2022; 118:1046-1060
Nieto-Marín P, Tinaquero D, Utrilla RG, Cebrián J, ... Delpón E, ITACA Consortium Investigators
Cardiovasc Res: 16 Mar 2022; 118:1046-1060 | PMID: 33576403
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Abstract

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

Murphy KA, Harsch BA, Healy CL, Joshi SS, ... Shearer GC, O\'Connell TD
Aims
Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress.
Methods and results
In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC.
Conclusion
Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.

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Cardiovasc Res: 16 Mar 2022; 118:1061-1073
Murphy KA, Harsch BA, Healy CL, Joshi SS, ... Shearer GC, O'Connell TD
Cardiovasc Res: 16 Mar 2022; 118:1061-1073 | PMID: 33752243
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Abstract

The subfornical organ drives hypertension in polycystic kidney disease via the hypothalamic paraventricular nucleus.

Underwood CF, McMullan S, Goodchild AK, Phillips JK, Hildreth CM
Aims
Hypertension is a prevalent yet poorly understood feature of polycystic kidney disease. Previously, we demonstrated that increased glutamatergic neurotransmission within the hypothalamic paraventricular nucleus produces hypertension in the Lewis Polycystic Kidney (LPK) rat model of polycystic kidney disease. Here, we tested the hypothesis that augmented glutamatergic drive to the paraventricular nucleus in Lewis polycystic kidney rats originates from the forebrain lamina terminalis, a sensory structure that relays blood-borne information throughout the brain.
Methods and results
Anatomical experiments revealed that 38% of paraventricular nucleus-projecting neurons in the subfornical organ of the lamina terminalis expressed Fos/Fra, an activation marker, in LPK rats while <1% of neurons were Fos/Fra+ in Lewis control rats (P = 0.01, n = 8). In anaesthetized rats, subfornical organ neuronal inhibition using isoguvacine produced a greater reduction in systolic blood pressure in LPK vs. Lewis rats (-21±4 vs. -7±2 mmHg, P < 0.01; n = 10), which could be prevented by prior blockade of paraventricular nucleus ionotropic glutamate receptors using kynurenic acid. Blockade of ionotropic glutamate receptors in the paraventricular nucleus produced an exaggerated depressor response in LPK relative to Lewis rats (-23±4 vs. -2±3 mmHg, P < 0.001; n = 13), which was corrected by prior inhibition of the subfornical organ with muscimol but unaffected by chronic systemic angiotensin II type I receptor antagonism or lowering of plasma hyperosmolality through high-water intake (P > 0.05); treatments that both nevertheless lowered blood pressure in LPK rats (P < 0.0001).
Conclusion
Our data reveal multiple independent mechanisms contribute to hypertension in polycystic kidney disease, and identify high plasma osmolality, angiotensin II type I receptor activation and, importantly, a hyperactive subfornical organ to paraventricular nucleus glutamatergic pathway as potential therapeutic targets.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 16 Mar 2022; 118:1138-1149
Underwood CF, McMullan S, Goodchild AK, Phillips JK, Hildreth CM
Cardiovasc Res: 16 Mar 2022; 118:1138-1149 | PMID: 33774660
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Abstract

Zebrafish Scube1 and Scube2 cooperate in promoting Vegfa signalling during embryonic vascularization.

Tsao KC, Lin YC, Chen YT, Lai SL, Yang RB
Aims
The secreted and membrane-anchored signal peptide-CUB-EGF domain-containing proteins (SCUBE) gene family composed of three members was originally identified from endothelial cells (ECs). We recently showed that membrane SCUBE2 binds vascular endothelial growth factor (VEGF) and acts as a co-receptor for VEGF receptor 2 to modulate EC migration, proliferation, and tube formation during postnatal and tumour angiogenesis. However, whether these SCUBE genes cooperate in modulating VEGF signalling during embryonic vascular development remains unknown.
Methods and results
To further dissect the genetic interactions of these scube genes, transcription activator-like effector nuclease-mediated genome editing was used to generate knockout (KO) alleles of each scube gene. No overt vascular phenotypes were seen in any single scube KO mutants because of compensation by other scube genes during zebrafish development. However, scube1 and scube2 double KO (DKO) severely impaired EC filopodia extensions, migration, and proliferation, thus disrupting proper vascular lumen formation during vasculogenesis and angiogenesis as well as development of the organ-specific intestinal vasculature. Further genetic, biochemical, and molecular analyses revealed that Scube1 and Scube2 might act cooperatively at the cell-surface receptor level to facilitate Vegfa signalling during zebrafish embryonic vascularization.
Conclusions
We showed for the first time that cooperation between scube1 and scube2 is critical for proper regulation of angiogenic cell behaviours and formation of functional vessels during zebrafish embryonic development.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 16 Mar 2022; 118:1074-1087
Tsao KC, Lin YC, Chen YT, Lai SL, Yang RB
Cardiovasc Res: 16 Mar 2022; 118:1074-1087 | PMID: 33788916
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Abstract

SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy.

Torre E, Arici M, Lodrini AM, Ferrandi M, ... Bianchi G, Rocchetti M
Aims 
Diabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the dual properties to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). This project aims to characterize istaroxime effects at a concentration (100 nmol/L) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in an animal model of mild diabetes.
Methods and results 
Streptozotocin (STZ) treated diabetic rats were studied at 9  weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed (i) marked DD not associated to cardiac fibrosis, (ii) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, (iii) reduced LV SERCA2 protein level and activity and (iv) slower SR Ca2+ uptake rate, (v) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, (vi) increased diastolic Ca2+, and (vii) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nmol/L) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent.
Conclusions 
SERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 16 Mar 2022; 118:1020-1032
Torre E, Arici M, Lodrini AM, Ferrandi M, ... Bianchi G, Rocchetti M
Cardiovasc Res: 16 Mar 2022; 118:1020-1032 | PMID: 33792692
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Abstract

Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS programme and CREDENCE trial.

Yu J, Li J, Leaver PJ, Arnott C, ... Neal B, Figtree GA
Aims
Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post hoc analysis of CANVAS Programme and CREDENCE trial.
Methods and results
Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Programme) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was canagliflozin 100 or 300 mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI, and type 1 MI or type 2 MI. A total of 421 first MI events in the CANVAS Programme and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed [hazard ratio (HR) 0.89; 95% confidence interval (CI) 0.75, 1.05]. Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93).
Conclusion
Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Programme and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation.
Trial registration
ClinicalTrials.gov identifiers: NCT01032629, NCT01989754, and NCT02065791.

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Cardiovasc Res: 16 Mar 2022; 118:1103-1114
Yu J, Li J, Leaver PJ, Arnott C, ... Neal B, Figtree GA
Cardiovasc Res: 16 Mar 2022; 118:1103-1114 | PMID: 33826709
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Abstract

FAK in the nucleus prevents VSMC proliferation by promoting p27 and p21 expression via Skp2 degradation.

Jeong K, Murphy JM, Ahn EE, Lim SS
Aims
Vascular smooth muscle cells (VSMCs) normally exhibit a very low proliferative rate. Vessel injury triggers VSMC proliferation, in part, through focal adhesion kinase (FAK) activation, which increases transcription of cyclin D1, a key activator for cell cycle-dependent kinases (CDKs). At the same time, we also observe that FAK regulates the expression of the CDK inhibitors (CDKIs) p27 and p21. However, the mechanism of how FAK controls CDKIs in cell cycle progression is not fully understood.
Methods and results
We found that pharmacological and genetic FAK inhibition increased p27 and p21 by reducing stability of S-phase kinase-associated protein 2 (Skp2), which targets theCDKIs for degradation. FAK N-terminal domain interacts with Skp2 and an APC/C E3 ligase activator fizzy-related 1 (Fzr1) in the nucleus, which promote ubiquitination and degradation of both Skp2 and Fzr1. Notably, overexpression of cyclin D1 alone failed to promote proliferation of genetic FAK kinase-dead (KD) VSMCs, suggesting that the FAK-Skp2-CDKI signalling axis is distinct from the FAK-cyclin D1 pathway. However, overexpression of both cyclin D1 and Skp2 enabled proliferation of FAK-KD VSMCs, implicating that FAK ought to control both activating and inhibitory switches for CDKs. In vivo, wire injury activated FAK in the cytosol, which increased Skp2 and decreased p27 and p21 levels.
Conclusion
Both pharmacological FAK and genetic FAK inhibition reduced Skp2 expression in VSMCs upon injury, which significantly reduced intimal hyperplasia through elevated expression of p27 and p21. This study revealed that nuclear FAK-Skp2-CDKI signalling negatively regulates CDK activity in VSMC proliferation.

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Cardiovasc Res: 16 Mar 2022; 118:1150-1163
Jeong K, Murphy JM, Ahn EE, Lim SS
Cardiovasc Res: 16 Mar 2022; 118:1150-1163 | PMID: 33839758
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Abstract

Extracellular histones are a target in myocardial ischaemia-reperfusion injury.

Shah M, He Z, Rauf A, Beikoghli Kalkhoran S, ... Davidson SM, Yellon D
Aims 
Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction.
Methods and results 
Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone-H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralizing compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size.
Conclusion 
Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 16 Mar 2022; 118:1115-1125
Shah M, He Z, Rauf A, Beikoghli Kalkhoran S, ... Davidson SM, Yellon D
Cardiovasc Res: 16 Mar 2022; 118:1115-1125 | PMID: 33878183
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Abstract

Arrhythmogenesis in the aged heart following ischaemia-reperfusion: role of transient receptor potential vanilloid 4.

Peana D, Polo-Parada L, Domeier TL
Aims
Cardiomyocyte Ca2+ homoeostasis is altered with ageing and predisposes the heart to Ca2+ intolerance and arrhythmia. Transient receptor potential vanilloid 4 (TRPV4) is an osmotically activated cation channel with expression in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in Ca2+ handling and arrhythmogenesis following ischaemia-reperfusion (I/R), a pathological scenario associated with osmotic stress.
Methods and results
Cardiomyocyte membrane potential was monitored prior to and following I/R in Langendorff-perfused hearts of Aged (19-28 months) male and female C57BL/6 mice ± TRPV4 inhibition (1 μM HC067047, HC). Diastolic resting membrane potential was similar between Aged and Aged HC at baseline, but following I/R Aged exhibited depolarized diastolic membrane potential vs. Aged HC. The effects of TRPV4 on cardiomyocyte Ca2+ signalling following I/R were examined in isolated hearts of Aged cardiac-specific GCaMP6f mice (±HC) using high-speed confocal fluorescence microscopy, with cardiomyocytes of Aged exhibiting an increased incidence of pro-arrhythmic Ca2+ signalling vs. Aged HC. In the isolated cell environment, cardiomyocytes of Aged responded to sustained hypoosmotic stress (250mOsm) with an increase in Ca2+ transient amplitude (fluo-4) and higher incidence of pro-arrhythmic diastolic Ca2+ signals vs. Aged HC. Intracardiac electrocardiogram measurements in isolated hearts following I/R revealed an increased arrhythmia incidence, an accelerated time to ventricular arrhythmia, and increased arrhythmia score in Aged vs. Aged HC. Aged exhibited depolarized resting membrane potential, increased pro-arrhythmic diastolic Ca2+ signalling, and greater incidence of arrhythmia when compared with Young (3-5 months).
Conclusion
TRPV4 contributes to pro-arrhythmic cardiomyocyte Ca2+ signalling, electrophysiological abnormalities, and ventricular arrhythmia in the aged mouse heart.

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Cardiovasc Res: 16 Mar 2022; 118:1126-1137
Peana D, Polo-Parada L, Domeier TL
Cardiovasc Res: 16 Mar 2022; 118:1126-1137 | PMID: 33881517
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Abstract

Clinical efficacy and safety of angiogenesis inhibitors: sex differences and current challenges.

Cignarella A, Fadini GP, Bolego C, Trevisi L, ... Rossi GP, Barton M
Vasoactive molecules, such as vascular endothelial growth factor (VEGF) and endothelins, share cytokine-like activities and regulate endothelial cell (EC) growth, migration, and inflammation. Some endothelial mediators and their receptors are targets for currently approved angiogenesis inhibitors, drugs that are either monoclonal antibodies raised towards VEGF, or inhibitors of vascular receptor protein kinases and signalling pathways. Pharmacological interference with the protective functions of ECs results in a similar spectrum of adverse effects. Clinically, the most common side effects of VEGF signalling pathway inhibition include an increase in arterial pressure, left ventricular dysfunction facilitating the development of heart failure, thromboembolic events including pulmonary embolism and stroke, and myocardial infarction. Sex steroids, such as androgens, progestins, and oestrogens and their receptors (ERα, ERβ, GPER; PR-A, PR-B; AR) have been identified as important modifiers of angiogenesis, and sex differences have been reported for anti-angiogenic drugs. This review article discusses the current challenges clinicians are facing with regard to angiogenesis inhibitor therapy, including the need to consider sex differences affecting clinical efficacy and safety. We also propose areas for future research taking into account the role of sex hormone receptors and sex chromosomes. Development of new sex-specific drugs with improved target- and cell-type selectivity likely will open the way to personalized medicine in men and women requiring anti-angiogenic therapy to reduce adverse effects and to improve therapeutic efficacy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 15 Mar 2022; 118:988-1003
Cignarella A, Fadini GP, Bolego C, Trevisi L, ... Rossi GP, Barton M
Cardiovasc Res: 15 Mar 2022; 118:988-1003 | PMID: 33739385
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Abstract

The role of autophagy in cardiovascular pathology.

Gatica D, Chiong M, Lavandero S, Klionsky DJ
Macroautophagy/autophagy is a conserved catabolic recycling pathway in which cytoplasmic components are sequestered, degraded, and recycled to survive various stress conditions. Autophagy dysregulation has been observed and linked with the development and progression of several pathologies, including cardiovascular diseases, the leading cause of death in the developed world. In this review, we aim to provide a broad understanding of the different molecular factors that govern autophagy regulation and how these mechanisms are involved in the development of specific cardiovascular pathologies, including ischemic and reperfusion injury, myocardial infarction, cardiac hypertrophy, cardiac remodelling, and heart failure.

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Cardiovasc Res: 15 Mar 2022; 118:934-950
Gatica D, Chiong M, Lavandero S, Klionsky DJ
Cardiovasc Res: 15 Mar 2022; 118:934-950 | PMID: 33956077
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Abstract

Acute Increase of Renal Perfusion Pressure Causes Rapid Activation of mTORC1 (Mechanistic Target Of Rapamycin Complex 1) and Leukocyte Infiltration.

Shimada S, Yang C, Kumar V, Mattson DL, Cowley AW
Background
The present study in Sprague-Dawley rats determined the effects of a rapid rise of renal perfusion pressure (RPP) upon the activation of mTOR (mechanistic target of rapamycin), and the effects upon the infiltration of CD68-positive macrophages/monocytes and CD3-positive T lymphocytes into the kidneys.
Methods
RPP was elevated by 40 mm Hg for 30 minutes in male Sprague-Dawley rats while measuring renal blood flow and urine flow rate. Sham rats were studied in the same way, but RPP was not changed. Since initial studies found that the acute increase of RPP resulted in activation of mTORC1 (phosphorylation of S6S235/236), the effects of inhibition of mTORC1 with rapamycin pretreatment were then determined.
Results
It was found that a 30-minute increase of RPP (≈40 mm Hg) resulted in an 8-fold increase of renal sodium excretion which was blunted by rapamycin treatment. Renal blood flow was not affected by the elevation of RPP. Activation of mTORC1 was observed. Significant increases in CD68-positive macrophages were found in both the cortex (intraglomerular and periglomerular regions) and in the outer medullary interstitial regions of the kidney and prevented by rapamycin treatment. Increases in CD3-positive T lymphocytes were observed exclusively in the periglomerular regions and prevented by rapamycin treatment. Upregulation of several proinflammatory markers was observed.
Conclusions
We conclude that elevation of RPP rapidly activates mTORC1 resulting in infiltration of immune cells into the kidney.



Hypertension: 15 Mar 2022:HYPERTENSIONAHA12118643; epub ahead of print
Shimada S, Yang C, Kumar V, Mattson DL, Cowley AW
Hypertension: 15 Mar 2022:HYPERTENSIONAHA12118643; epub ahead of print | PMID: 35291809
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Abstract

Migraine-Associated Mutation in the Na,K-ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function.

Staehr C, Rohde PD, Krarup NT, Ringgaard S, ... Aalkjaer C, Matchkov V

Background:
Mutations in ATP1A2 gene encoding the Na,K-ATPase α2 isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K-ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2-associated G301R mutation in the Atp1a2 gene (α2+/G301R mice) and matching wild-type controls were compared. Reduced expression of the Na,K-ATPase α2 isoform and increased expression of the α1 isoform were observed in hearts from α2+/G301R mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8-month-old α2+/G301R mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3-month-old α2+/G301R mice were similar to wild-type mice. Amplified Na,K-ATPase-dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen-activated protein kinase) signaling was observed in hearts from 8-month-old α2+/G301R mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure-associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´-tetrachloro-1,1´,3,3´-tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8-month-old α2+/G301R mice.
Conclusions:
Our findings suggest that ATP1A2 mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K-ATPase-dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.




J Am Heart Assoc: 14 Mar 2022:e021814; epub ahead of print
Staehr C, Rohde PD, Krarup NT, Ringgaard S, ... Aalkjaer C, Matchkov V
J Am Heart Assoc: 14 Mar 2022:e021814; epub ahead of print | PMID: 35289188
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Abstract

Small dense low-density lipoprotein particles: clinically relevant?

Krauss RM
Purpose of review
Levels of small, dense low-density lipoprotein (LDL) (sdLDL) particles determined by several analytic procedures have been associated with risk of atherosclerotic cardiovascular disease (ASCVD). This review focuses on the clinical significance of sdLDL measurement.
Recent findings
Results of multiple prospective studies have supported earlier evidence that higher levels of sdLDL are significantly associated with greater ASCVD risk, in many cases independent of other lipid and ASCVD risk factors as well as levels of larger LDL particles. A number of properties of sdLDL vs. larger LDL, including reduced LDL receptor affinity and prolonged plasma residence time as well as greater oxidative susceptibility and affinity for arterial proteoglycans, are consistent with their heightened atherogenic potential. Nevertheless, determination of the extent to which sdLDL can preferentially impact ASCVD risk compared with other apoprotein B-containing lipoproteins has been confounded by their metabolic interrelationships and statistical collinearity, as well as differences in analytic procedures and definitions of sdLDL.
Summary
A growing body of data points to sdLDL concentration as a significant determinant of ASCVD risk. Although future studies should be aimed at determining the clinical benefit of reducing sdLDL levels, there is sufficient evidence to warrant consideration of sdLDL measurement in assessing and managing risk of cardiovascular disease.
Video abstract
https://www.dropbox.com/s/lioohr2ead7yx2p/zoom_0.mp4?dl=0.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 10 Mar 2022; epub ahead of print
Krauss RM
Curr Opin Lipidol: 10 Mar 2022; epub ahead of print | PMID: 35276699
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Abstract

Cardiorenal protective effects of sodium-glucose cotransporter 2 inhibition in combination with angiotensin II type 1 receptor blockade in salt-sensitive Dahl rats.

Ito H, Okamoto R, Ali Y, Zhe Y, ... Ito M, Dohi K
Objective
The kidney plays a central role in regulating the salt sensitivity of blood pressure (BP) by governing sodium excretion and reabsorption via renal sodium transporters. We hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibition and angiotensin II type 1 receptor (AT1R) blockade can synergistically reduce renal sodium reabsorption by beneficially effects on these transporters, leading to lower BP and ameliorating renal and cardiac damage.
Methods and results
Dahl salt-sensitive rats were treated orally for 8 weeks with a normal salt diet (0.3% NaCl), a high-salt diet (8% NaCl), high-salt diet with ipragliflozin (0.04%), high-salt diet with losartan (0.05%) or high-salt diet with a combination of ipragliflozin and losartan. The combination treatment significantly reduced BP and increased daily urine sodium excretion compared with losartan or ipragliflozin monotherapy, leading to greater improvement in BP salt sensitivity than ipragliflozin monotherapy. The combination treatment significantly ameliorated glomerulosclerosis and reduced cardiomyocyte hypertrophy compared with losartan or ipragliflozin monotherapy. The protein expression levels of Na+/H+ exchanger isoform 3 (NHE3) and Na+-K+-Cl- cotransporter 2 (NKCC2) in the kidney were significantly decreased with losartan monotherapy and combination treatment, but not with ipragliflozin monotherapy.
Conclusion
Inhibition of SGLT2 in combination with an angiotensin II receptor blocker effectively improved BP salt sensitivity by reducing renal expression levels of sodium transporters including NHE3 and NKCC2, which eventually led to improvement of BP salt sensitivity and cardiorenal protection.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 10 Mar 2022; epub ahead of print
Ito H, Okamoto R, Ali Y, Zhe Y, ... Ito M, Dohi K
J Hypertens: 10 Mar 2022; epub ahead of print | PMID: 35285452
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Abstract

Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation.

Shi J, Tong R, Zhou M, Gao Y, ... Lu X, Pu J
Aims
Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported.
Methods and results
Here, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway.
Conclusion
We provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.
Key question
Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Whether circadian nuclear receptor Rev-erba is present in platelets and regulates platelet function remains unknown.
Key finding
We provide the first evidence that Rev-erba is functionally expressed in platelets and acts as a positive regulator of platelet activation/thrombus formation through the oligophrenin-1-mediated RhoA/ERM signalling pathway.
Take home message
Our observations highlight the importance of circadian clock machinery in platelet physiology and support the notion that Rev-erba may serve as a novel therapeutic target for managing thrombosis-based cardiovascular diseases.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 09 Mar 2022; epub ahead of print
Shi J, Tong R, Zhou M, Gao Y, ... Lu X, Pu J
Eur Heart J: 09 Mar 2022; epub ahead of print | PMID: 35267019
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Abstract

A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration.

El-Sammak H, Yang B, Guenther S, Chen W, Marín-Juez R, Stainier DYR
Background
Ischemic heart disease following the obstruction of coronary vessels leads to the death of cardiac tissue and the formation of a fibrotic scar. In contrast to adult mammals, zebrafish can regenerate their heart after injury, enabling the study of the underlying mechanisms. One of the earliest responses following cardiac injury in adult zebrafish is coronary revascularization. Defects in this process lead to impaired cardiomyocyte repopulation and scarring. Hence, identifying and investigating factors that promote coronary revascularization holds great therapeutic potential.
Methods
We used whole mount imaging, immunohistochemistry and histology to assess various aspects of zebrafish cardiac regeneration. Deep transcriptomic analysis allowed us to identify targets and potential effectors of Vegfc (vascular endothelial growth factor C) signaling. We used newly generated loss- and gain-of-function genetic tools to investigate the role of Emilin2a and Cxcl8a-Cxcr1 signaling in cardiac regeneration.
Results
We first show that regenerating coronary endothelial cells upregulate vegfc upon cardiac injury in adult zebrafish and that Vegfc signaling is required for their proliferation during regeneration. Notably, blocking Vegfc signaling also significantly reduces cardiomyocyte dedifferentiation and proliferation. Using transcriptomic analyses, we identified emilin2a as an effector of Vegfc signaling and found that manipulation of emilin2a expression can modulate coronary revascularization as well as cardiomyocyte proliferation. Mechanistically, Emilin2a induces the expression of the chemokine gene cxcl8a in epicardium-derived cells, while cxcr1, the Cxcl8a receptor gene, is expressed in coronary endothelial cells. We further show that Cxcl8a-Cxcr1 signaling is also required for coronary endothelial cell proliferation during cardiac regeneration.
Conclusions
These data show that after cardiac injury, coronary endothelial cells upregulate vegfc to promote coronary network reestablishment and cardiac regeneration. Mechanistically, Vegfc signaling upregulates epicardial emilin2a and cxcl8a expression to promote cardiac regeneration. These studies aid in understanding the mechanisms underlying coronary revascularization in zebrafish, with potential therapeutic implications to enhance revascularization and regeneration in injured human hearts.



Circ Res: 09 Mar 2022:CIRCRESAHA121319929; epub ahead of print
El-Sammak H, Yang B, Guenther S, Chen W, Marín-Juez R, Stainier DYR
Circ Res: 09 Mar 2022:CIRCRESAHA121319929; epub ahead of print | PMID: 35264012
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Abstract

Gut Microbiome-Derived Glycine Lipids Are Diet-Dependent Modulators of Hepatic Injury and Atherosclerosis.

Millar CL, Anto L, Garcia C, Kim MB, ... Nichols FC, Blesso CN
Oral and gut Bacteroidetes produce unique classes of serine-glycine lipodipeptides and glycine aminolipids that signal through host Toll-like receptor 2. These glycine lipids have also been detected in human arteries, but their effects on atherosclerosis are unknown. Here we sought to investigate the bioactivity of bacterial glycine lipids in mouse models of atherosclerosis. Lipid 654 (L654), a serine-glycine lipodipeptide species, was first tested in a high-fat diet (HFD)-fed Ldlr-/- model of atherosclerosis. Intraperitoneal (I.P.) administration of L654 over 7 weeks to HFD-fed Ldlr-/- mice resulted in hypocholesterolemic effects and significantly attenuated the progression of atherosclerosis. We found that L654 also reduced liver inflammatory and extracellular matrix gene expression, which may be related to inhibition of macrophage activation as demonstrated in vivo by lower MHC-class II gene expression and confirmed in cell experiments. In addition, L654 and other bacterial glycine lipids in feces, liver, and serum were markedly reduced alongside changes in Bacteroidetes relative abundance in HFD-fed mice. Finally, we tested the bioactivities of L654 and related lipid 567 (L567) in chow-fed Apoe-/- mice, which displayed much higher fecal glycine lipids relative to HFD-fed Ldlr-/- mice. Administration of L654 or L567 for 7 weeks to these mice reduced the liver injury marker alanine aminotransferase, but other effects seen in Ldlr-/- were not observed. Therefore, we conclude that conditions in which gut microbiome-derived glycine lipids are lost, such as HFD, may exacerbate the development of atherosclerosis and liver injury, while correction of such depletion may protect from these disorders.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Lipid Res: 08 Mar 2022:100192; epub ahead of print
Millar CL, Anto L, Garcia C, Kim MB, ... Nichols FC, Blesso CN
J Lipid Res: 08 Mar 2022:100192; epub ahead of print | PMID: 35278409
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Abstract

CCL17 Aggravates Myocardial Injury by Suppressing Recruitment of Regulatory T Cells.

Feng G, Bajpai G, Ma P, Koenig A, ... Kreisel D, Lavine KJ
Background
Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2+ monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation.
Methods
We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used Ccl17 knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects.
Results
We demonstrated that CCL17 is expressed in CCR2+ macrophages and cluster of differentiation 11b+ conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17+ macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of STAT5 (signal transducer and activator of transcription 5) and canonical NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling. Ccl17 deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function after myocardial infarction and angiotensin II and phenylephrine infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured Ccl17 knockout mice. CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 (C-C chemokine ligand 22) activated both Gq and ARRB (β-arrestin) signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated ARRB signaling and Treg migration. We provide evidence that Tregs mediated the protective effects of Ccl17 deletion on myocardial inflammation and adverse LV remodeling.
Conclusions
These findings identify CCL17 as a proinflammatory mediator of CCR2+ macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.



Circulation: 07 Mar 2022; 145:765-782
Feng G, Bajpai G, Ma P, Koenig A, ... Kreisel D, Lavine KJ
Circulation: 07 Mar 2022; 145:765-782 | PMID: 35113652
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Abstract

SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.

Han Y, Zhu J, Yang L, Nilsson-Payant BE, ... Evans T, Chen S
Background
Increasing evidence suggests that cardiac arrhythmias are frequent clinical features of coronavirus disease 2019 (COVID-19). Sinus node damage may lead to bradycardia. However, it is challenging to explore human sinoatrial node (SAN) pathophysiology due to difficulty in isolating and culturing human SAN cells. Embryonic stem cells (ESCs) can be a source to derive human SAN-like pacemaker cells for disease modeling.
Methods
We used both a hamster model and human ESC (hESC)-derived SAN-like pacemaker cells to explore the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pacemaker cells of the heart. In the hamster model, quantitative real-time polymerase chain reaction and immunostaining were used to detect viral RNA and protein, respectively. We then created a dual knock-in SHOX2:GFP;MYH6:mCherry hESC reporter line to establish a highly efficient strategy to derive functional human SAN-like pacemaker cells, which was further characterized by single-cell RNA sequencing. Following exposure to SARS-CoV-2, quantitative real-time polymerase chain reaction, immunostaining, and RNA sequencing were used to confirm infection and determine the host response of hESC-SAN-like pacemaker cells. Finally, a high content chemical screen was performed to identify drugs that can inhibit SARS-CoV-2 infection, and block SARS-CoV-2-induced ferroptosis.
Results
Viral RNA and spike protein were detected in SAN cells in the hearts of infected hamsters. We established an efficient strategy to derive from hESCs functional human SAN-like pacemaker cells, which express pacemaker markers and display SAN-like action potentials. Furthermore, SARS-CoV-2 infection causes dysfunction of human SAN-like pacemaker cells and induces ferroptosis. Two drug candidates, deferoxamine and imatinib, were identified from the high content screen, able to block SARS-CoV-2 infection and infection-associated ferroptosis.
Conclusions
Using a hamster model, we showed that primary pacemaker cells in the heart can be infected by SARS-CoV-2. Infection of hESC-derived functional SAN-like pacemaker cells demonstrates ferroptosis as a potential mechanism for causing cardiac arrhythmias in patients with COVID-19. Finally, we identified candidate drugs that can protect the SAN cells from SARS-CoV-2 infection.



Circ Res: 07 Mar 2022:CIRCRESAHA121320518; epub ahead of print
Han Y, Zhu J, Yang L, Nilsson-Payant BE, ... Evans T, Chen S
Circ Res: 07 Mar 2022:CIRCRESAHA121320518; epub ahead of print | PMID: 35255712
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Abstract

SIRT1 in the cardiomyocyte counteracts doxorubicin-induced cardiotoxicity via regulating histone H2AX.

Kuno A, Hosoda R, Tsukamoto M, Sato T, ... Iwahara N, Horio Y
Aims
Cardiotoxicity by doxorubicin predicts worse prognosis of patients. Accumulation of damaged DNA has been implicated in doxorubicin-induced cardiotoxicity. SIRT1, an NAD+-dependent histone/protein deacetylase, protects cells by deacetylating target proteins. We investigated whether SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating Ser139 phosphorylation of histone H2AX, a critical signal of the DNA damage response.
Methods and results
Doxorubicin (5 mg/kg per week, x4) was administered to mice with intact SIRT1 (Sirt1f/f) and mice that lack SIRT1 activity in cardiomyocytes (Sirt1f/f; MHCcre/+). Reductions in left ventricular fractional shortening and ejection fraction by doxorubicin treatment were more severe in Sirt1f/f; MHCcre/+ than in Sirt1f/f. Myocardial expression level of type-B natriuretic peptide was 2.5-fold higher in Sirt1f/f; MHCcre/+ than in Sirt1f/f after doxorubicin treatment. Sirt1f/f; MHCcre/+ showed larger fibrotic areas and higher nitrotyrosine levels in the heart after doxorubicin treatment. Although doxorubicin-induced DNA damage evaluated by TUNEL staining was enhanced in Sirt1f/f; MHCcre/+, the myocardium from Sirt1f/f; MHCcre/+ showed blunted Ser139 phosphorylation of H2AX by doxorubicin treatment. In H9c2 cardiomyocytes, SIRT1 knockdown attenuated Ser139 phosphorylation of H2AX, increased DNA damage, and enhanced caspase-3 activation under doxorubicin treatment. Immunostaining revealed that acetylation level of H2AX at Lys5 was higher in hearts from Sirt1f/f; MHCcre/+. In H9c2 cells, acetyl-Lys5-H2AX level was increased by SIRT1 knockdown and reduced by SIRT1 overexpression. Ser139 phosphorylation in response to doxorubicin treatment was blunted in a mutant H2AX with substitution of Lys5 to Gln (K5Q) that mimics acetylated lysine compared with that in wild-type H2AX. Expression of K5Q-H2AX as well as S139A-H2AX, which cannot be phosphorylated at Ser139, augmented doxorubicin-induced caspase-3 activation. Treatment of mice with resveratrol, a SIRT1 activator, attenuated doxorubicin-induced cardiac dysfunction, which was associated with a reduction in acetyl-Lys5-H2AX level and a preserved phospho-Ser139-H2AX level.
Conclusion
These findings suggest that SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating H2AX phosphorylation through its deacetylation in cardiomyocytes.
Translational perspective
Doxorubicin-induced cardiotoxicity limits the further use of doxorubicin for cancer treatment and determines prognosis of patients. This work shows for the first time the protective effect of SIRT1, an NAD+-dependent deacetylase, on doxorubicin-induced cardiotoxicity using a genetically modified mouse model. We identified histone H2AX as a target of SIRT1 for proper DNA damage response. Therefore, DNA repair by SIRT1 could be a potential therapeutic target to attenuate doxorubicin cardiotoxicity. SIRT1 activity may also help to predict a risk of developing cardiotoxicity in patients treated with doxorubicin.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 07 Mar 2022; epub ahead of print
Kuno A, Hosoda R, Tsukamoto M, Sato T, ... Iwahara N, Horio Y
Cardiovasc Res: 07 Mar 2022; epub ahead of print | PMID: 35258628
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Abstract

Remote and Wearable ECG Devices with Diagnostic Abilities in Adults: A State-of-the-Science Scoping Review.

Bouzid Z, Al-Zaiti SS, Bond R, Sejdic E
The electrocardiogram (ECG) records the electrical activity in the heart in real-time, providing an important opportunity to detecting various cardiac pathologies. The 12-lead ECG currently serves as the \"standard\" ECG acquisition technique for diagnostic purposes for many cardiac pathologies other than arrhythmias. However, the technical aspects of acquiring a 12-lead ECG are not easy and its usage is currently restricted to trained medical personnel, limiting the scope of its usefulness. Remote and wearable ECG devices have attempted to bridge this gap by enabling patients to take their own ECG using a simplified method at the expense of a reduced number of leads, usually a single-lead ECG. In this review article, we summarize the studies which investigate the use of remote ECG devices and their clinical utility in diagnosing cardiac pathologies. Eligible studies discussed FDA-cleared, commercially available devices that were validated on an adult population. We summarize technical logistics of signal quality and device reliability, dimensional and functional features, and diagnostic value. In summary, our synthesis shows that reduced-set ECG wearables have huge potential for long-term monitoring, particularly if paired with real-time notification techniques. Such capabilities make them primarily useful for abnormal rhythm detection and there is sufficient evidence that a remote ECG device can be more superior to traditional 12-lead ECG in diagnosing specific arrhythmias such as atrial fibrillation. However, this review identifies important challenges faced by this technology, highlighting the limited availability of clinical research examining their usefulness.

Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 07 Mar 2022; epub ahead of print
Bouzid Z, Al-Zaiti SS, Bond R, Sejdic E
Heart Rhythm: 07 Mar 2022; epub ahead of print | PMID: 35276320
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