Journal of molecular and cellular cardiology最新文献

{"title":"New insights into diabetes-induced cardiac pathology","authors":"K.L. Weeks ,&nbsp;B.C. Bernardo ,&nbsp;J.R. Bell ,&nbsp;L.M.D. Delbridge ,&nbsp;K.M. Mellor","doi":"10.1016/j.yjmcc.2025.04.008","DOIUrl":"10.1016/j.yjmcc.2025.04.008","url":null,"abstract":"<div><div>Individuals with diabetes have an elevated risk of heart disease, and there is a significant clinical need for evidence-based treatments. Heart disease in diabetes manifests as a distinct cardiopathology, with cardiac structural and functional remodeling underlying increased susceptibility to cardiac dysfunction and arrhythmias. An understanding of the mechanisms associated with cardiac vulnerability in diabetes is incomplete, but recent studies have advanced new insights into the roles of metabolic disturbances, gene dysregulation and epicardial adipose influence. This perspective article highlights these three promising new developments in proposed mechanisms, and discusses exciting advances in cardiac-targeting for potential treatment of diabetic heart disease.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 76-81"},"PeriodicalIF":4.9,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3-mediated N6-methyladenosine modification contributes to vascular calcification","authors":"Long Li ,&nbsp;Quanyou Chai ,&nbsp;Chunling Guo ,&nbsp;Junyi Wei ,&nbsp;Yuqiao Qin ,&nbsp;Huimin Liu ,&nbsp;Zhaoyang Lu","doi":"10.1016/j.yjmcc.2025.04.006","DOIUrl":"10.1016/j.yjmcc.2025.04.006","url":null,"abstract":"<div><h3>Aim</h3><div>Vascular calcification (VC) is a major adverse cardiovascular event in chronic kidney disease (CKD) patients. N6-methyladenosine (m6A) modification is vital for many biological processes, but its function and possible molecular mechanisms in VC are poorly understood. This study aimed to clarify the function and molecular mechanisms of N6-adenosine-methyltransferase-like 3 (METTL3) in VC.</div></div><div><h3>Methods and results</h3><div>The results of the bioinformatic analysis showed that METTL3 expression was significantly upregulated in calcified VSMCs. This finding was corroborated by phosphate-induced VSMCs calcification models and 5/6 nephrectomy-induced CKD mouse VC models. Afterward, Alizarin Red S staining and m6A dot blot analysis demonstrated METTL3 overexpression elevated m6A levels and encouraged calcification in VSMCs and mouse aortic rings, while METTL3 knockdown decreased m6A levels and inhibited calcium deposition in these experimental models. Furthermore, METTL3 promoted VC via the PTEN/AKT pathway, and MeRIP verified that METTL3 induced PTEN mRNA degradation by modifying it with m6A. In addition, molecular docking simulations and DARTS assays revealed that quercetin is a natural small-molecule inhibitor of METTL3. The current investigation demonstrated that quercetin mitigated VC by reducing METTL3-dependent m6A levels in vivo and in vitro.</div></div><div><h3>Conclusion</h3><div>In conclusion, this study unraveled the pathogenic mechanism of METTL3-mediated m6A modification in VC and provided new insights to establish METTL3 as a therapeutic target for VC.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 22-34"},"PeriodicalIF":4.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The L348P point mutation in cardiac myosin binding protein-C alters transient responses to stretch, slows cardiac relaxation, and is embryonic lethal in homozygous CRISPR gene-edited mice","authors":"Rachel L. Sadler ,&nbsp;Angela C. Greenman ,&nbsp;Mei Methawasin ,&nbsp;Julie Fan ,&nbsp;Samantha P. Harris","doi":"10.1016/j.yjmcc.2025.04.007","DOIUrl":"10.1016/j.yjmcc.2025.04.007","url":null,"abstract":"<div><div>Mutations in cardiac myosin binding protein-C (cMyBP-C) are a common cause of hypertrophic cardiomyopathy (HCM), an inherited autosomal dominant disease affecting 1 in 250–500 people. We previously identified a single amino acid substitution (L348P) in the regulatory motif (M-domain) of cMyBP-C that slowed relaxation and caused diastolic dysfunction in transgenic mice. Here we attempted to increase expression of the mutant protein by creating a CRISPR gene-edited knock-in mouse model (L348P-CR) and breeding mice to homozygosity for the mutant allele. Results showed that L348P-CR homozygous mice died in utero, but that heterozygous knock-in mice developed contractile deficits and diastolic dysfunction comparable to transgenic mice. To overcome the lethal homozygous expression of the L348P mutation, we used our “cut-and-paste” approach to fully replace endogenous wild-type cMyBP-C with recombinant L348P cMyBP-C in permeabilized cardiomyocytes from SpyC₃ mice. Results showed that replacement of wild-type cMyBP-C with recombinant L348P recapitulated mechanical effects seen in transgenic and L348P-CR mice, validating the utility of our cut-and-paste method for evaluating functional effects of cMyBP-C. We conclude that L348P-CR knock-in mice are a robust model of diastolic dysfunction due to a single point mutation in cMyBP-C and that the cut-and-paste approach offers a rapid and cost-effective approach for evaluating mutations in cMyBP-C, especially those that are lethal in traditional animal models.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 35-46"},"PeriodicalIF":4.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coronary microcirculation in myocardial ischemia: A genetic perspective","authors":"Paolo Severino ,&nbsp;Andrea D'Amato ,&nbsp;Silvia Prosperi ,&nbsp;Vincenzo Myftari ,&nbsp;Rosanna Germanò ,&nbsp;Stefanie Marek-Iannucci ,&nbsp;Andrea De Prisco ,&nbsp;Marco Valerio Mariani ,&nbsp;Ludovica Marchiori ,&nbsp;Corinne Battaglia ,&nbsp;Leonardo Tabacco ,&nbsp;Camilla Segato ,&nbsp;Massimo Mancone ,&nbsp;Francesco Fedele ,&nbsp;Carmine Dario Vizza","doi":"10.1016/j.yjmcc.2025.04.002","DOIUrl":"10.1016/j.yjmcc.2025.04.002","url":null,"abstract":"<div><div>Coronary microvascular dysfunction (CMD) is a major contributor to ischemic heart disease (IHD), acting both independently and together with atherosclerosis. CMD encompasses structural and functional microcirculatory changes that result in dysregulated coronary blood flow. Structural abnormalities include microvascular remodeling, resulting in arteriolar and capillary narrowing, perivascular fibrosis and capillary rarefaction. Endothelial dysfunction and smooth muscle cell hyperactivity further impair microcirculation. Genetic factors may play a crucial role in the pathophysiology of CMD, mainly due to single nucleotide polymorphisms (SNPs) in genes that regulate coronary blood flow and microcirculation structural modifications. This manuscript aims to review the genetic determinants of CMD, with particular focus on ion channels, microRNAs (miRNAs), and proteins involved in the endothelial environment. The improving knowledge about genetic aspects of CMD opens the possibility to have new biomarkers, improving diagnosis and the development of targeted treatments in light of an even more patient-tailored approach.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 67-75"},"PeriodicalIF":4.9,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen sulfide preserves the function of senescent endothelium through SIRT2 mediated inflammatory inhibition","authors":"Xueyuan Qin ,&nbsp;Fan Lu ,&nbsp;Jie Wan ,&nbsp;Xu Teng ,&nbsp;Sheng Jin ,&nbsp;Lin Xiao ,&nbsp;Hongmei Xue ,&nbsp;Qi Guo ,&nbsp;Danyang Tian ,&nbsp;Yuming Wu","doi":"10.1016/j.yjmcc.2025.04.005","DOIUrl":"10.1016/j.yjmcc.2025.04.005","url":null,"abstract":"<div><div>Endothelial aging is an independent risk factor of cardiovascular diseases, and this study aims to explore the mechanism of endothelial aging. We first applied two animal aging models and two cellular aging models to observe the characteristics of senescent endothelium at the morphological, functional, and molecular levels. It was confirmed that the aging of endothelial cells was accompanied by activation of Nod like receptor protein 3 (NLRP3) inflammasome pathway, reduced levels of hydrogen sulfide (H₂S) and sirtuin2 (SIRT2) activity. Endothelial specific knockout of cystathionine-γ-lyase (CSE) led to premature aging of blood vessels, and excessive activation of the SIRT2/NLRP3 inflammasome. Finally, H₂S supplementation improved vascular and endothelial cell function, normalized inflammatory cytokine levels, and thereby reversed endothelial aging through SIRT2/NLRP3 mediated pathway. In this study, we found that the decrease in SIRT2 activity in aging endothelial cells increased the level of NLRP3 inflammasome and H₂S inhibited inflammation to improve endothelial aging through the SIRT2/NLRP3 pathway. This provided H₂S could be a new target for improving endothelial aging, and offered new strategies for defending human aging.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 10-21"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143820551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP1R upregulation in mitral regurgitation observed at a single nucleus level","authors":"Sameeksha Tiwari ,&nbsp;Martin Beyer ,&nbsp;Sary F. Aranki ,&nbsp;Meraj Neyazi ,&nbsp;Gavin Y. Oudit ,&nbsp;Olivia Layton ,&nbsp;J.G. Seidman ,&nbsp;Christine E. Seidman ,&nbsp;Jochen D. Muehlschlegel","doi":"10.1016/j.yjmcc.2025.04.003","DOIUrl":"10.1016/j.yjmcc.2025.04.003","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 7-9"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143820552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A chronology of basic and clinical research in the coronary microcirculation","authors":"William M. Chilian ,&nbsp;Taha Ahmed ,&nbsp;C. Noel Bairey Merz ,&nbsp;Carl J. Pepine ,&nbsp;Catherine Nicole Domingo ,&nbsp;Puja K. Mehta","doi":"10.1016/j.yjmcc.2025.04.004","DOIUrl":"10.1016/j.yjmcc.2025.04.004","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 59-66"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and electrophysiological characterization of a SCN5A gain-of-function mutation associated with CPVT-like arrhythmia","authors":"Pia Dahlberg ,&nbsp;Serena Pozzi ,&nbsp;Linda Bulmer ,&nbsp;Alessia Golluscio ,&nbsp;Michelle Nilsson ,&nbsp;Anders Nygren ,&nbsp;H. Peter Larsson ,&nbsp;Antonios Pantazis ,&nbsp;Anders Gummesson","doi":"10.1016/j.yjmcc.2025.04.001","DOIUrl":"10.1016/j.yjmcc.2025.04.001","url":null,"abstract":"<div><div>The present study aimed to characterize the <em>SCN5A</em> variant I1333V, found in five families with a history of suspected catecholaminergic polymorphic ventricular tachycardia (CPVT). <em>SCN5A</em> encodes the pore-forming subunit of the cardiac voltage-gated sodium channel Na_V1.5. Gain of <em>SCN5A</em> function causes long QT syndrome type 3 (LQT3), but its involvement in CPVT is disputed. Nineteen patients harboring the I1333V variant were identified across five families, commonly presenting with exercise-induced arrhythmia, including polymorphic premature ventricular contractions, ventricular bigeminy, couplets, and ventricular tachycardias. Prolonged QT interval was a less consistent finding, and structural myocardial changes were absent. Human Na_V1.5/β1 complexes were expressed in <em>Xenopus laevis</em> oocytes, using RNA combinations to emulate homozygous wild-type, heterozygous and homozygous I1333V-mutant conditions. Cells were studied using the cut-open oocyte Vaseline gap voltage-clamp to evaluate effects of I1333V on Na_V1.5 function. Na_V1.5(I1333V) channels required less depolarization to activate, classifying this variant as gain-of-function. Fast inactivation was unaffected, and action-potential (AP) clamp showed no significant differences in late Na⁺ current. A computational model of human ventricular myocyte excitability predicted no effect of I1333V on AP duration; instead, it showed stronger Na⁺ influx during the AP upstroke, concurrent with elevated Ca²⁺ import <em>via</em> the sodium‑calcium exchanger. Finally, Na_V1.5(I1333V) channels exhibited a diminished response to cAMP (emulating adrenergic stimulation), which also likely contributes to arrhythmogenesis. In conclusion, I1333V is a gain-of-function variant of <em>SCN5A</em> with a unique set of functional consequences. It is associated with cardiac arrhythmia disease characterized by overlapping CPVT-like and LQT3 features. Our findings support that <em>SCN5A</em> should be considered in genetic screening of suspected CPVT.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 47-58"},"PeriodicalIF":4.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth characterization of S-glutathionylation in ventricular myosin light chain 1 across species by top-down proteomics","authors":"Emily A. Chapman ,&nbsp;Holden T. Rogers ,&nbsp;Zhan Gao ,&nbsp;Hsin-Ju Chan ,&nbsp;Francisco J. Alvarado ,&nbsp;Ying Ge","doi":"10.1016/j.yjmcc.2025.03.012","DOIUrl":"10.1016/j.yjmcc.2025.03.012","url":null,"abstract":"<div><div>S-glutathionylation (SSG) is increasingly recognized as a critical signaling mechanism in the heart, yet SSG modifications in cardiac sarcomeric proteins remain understudied. Here we identified SSG of the ventricular isoform of myosin light chain 1 (MLC-1v) in human, swine, and mouse cardiac tissues using top-down mass spectrometry (MS)-based proteomics. Our results enabled the accurate identification, quantification, and site-specific localization of SSG in MLC-1v across different species. Notably, the endogenous SSG of MLC-1v was observed in human and swine cardiac tissues but not in mice. Treating non-reduced cardiac tissue lysates with GSSG elevated MLC-1v SSG levels across all three species.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 1-6"},"PeriodicalIF":4.9,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heartbreak and trauma: Unraveling sex-specific effects of post-traumatic stress disorder on cardiovascular disease","authors":"W. Glen Pyle","doi":"10.1016/j.yjmcc.2025.03.011","DOIUrl":"10.1016/j.yjmcc.2025.03.011","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"202 ","pages":"Pages 153-154"},"PeriodicalIF":4.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}