Journal of molecular and cellular cardiology最新文献

Isolated mouse adult cardiomyocytes display minimal mitochondrial ATP demand and maximal reliance on glycolysis 分离的小鼠成年心肌细胞表现出最小的线粒体ATP需求和最大的糖酵解依赖

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-26 DOI: 10.1016/j.yjmcc.2025.04.012

Ushodaya Mattam , Noble Kumar Talari , Ashish Rao Sathyanarayana , Sobuj Mia , James Frazier , Jeyashree Alagarsamy , Sam Slone , Konstantinos Drosatos , Karthickeyan Chella Krishnan PhD

引用次数: 0

Population-based computational simulations elucidate mechanisms of focal arrhythmia following stem cell injection 基于群体的计算模拟阐明了干细胞注射后局灶性心律失常的机制

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-23 DOI: 10.1016/j.yjmcc.2025.04.010

Chelsea E. Gibbs , Patrick M. Boyle

{"title":"Population-based computational simulations elucidate mechanisms of focal arrhythmia following stem cell injection","authors":"Chelsea E. Gibbs , Patrick M. Boyle","doi":"10.1016/j.yjmcc.2025.04.010","DOIUrl":"10.1016/j.yjmcc.2025.04.010","url":null,"abstract":"<div><div>Following a myocardial infarction (MI), a large portion of ventricular cells are replaced by scar, leading to adverse structural remodeling and heart failure. The use of stem cell-derived cardiomyocytes has shown promise in restoring cardiac function in animal models following an MI but leads to rapid focal ventricular tachycardia (VT). The VT in these animals can be variable, and its underlying mechanisms remain unknown. In this study, we used three distinct computational models derived from histological images of post-MI non-human primate ventricles to understand how human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) grafts can affect focal VT individually and synergistically. Specifically, we explored whether grafts could work cooperatively to create new arrhythmia and if geometric features such as graft tortuosity, area, host isolation, and amount of surrounding scar inhibited or enhanced the effect. We observed at least one instance of graft-host excitation (GHE) for eleven of the twenty-five individual grafts examined. Since we used a stochastic population-of-models-based approach to generate graft boundaries, we found that the number of configurations with GHE varied from graft to graft. We also examined grafts in aggregate and found that the high prevalence of GHE when all grafts were included arose from combinations of individually arrhythmogenic grafts (i.e., the overall increase in arrhythmogenicity resulted from graft <em>complementarity</em> rather than graft <em>cooperativity</em>). Further analysis of graft spatial features showed that arrhythmogenic grafts tend to be in areas with high host isolation (i.e., spatially confined regions of surviving myocardium interdigitated with engrafted cells) and when graft area and tortuosity were also high. These insights can aid in the design of novel injection schemes that could result in safer therapy for patients.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"204 ","pages":"Pages 5-16"},"PeriodicalIF":4.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899774","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}

引用次数: 0

Cx45 regulation by kinases and impact of expression in heart failure Cx45的激酶调控及其对心力衰竭表达的影响

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-23 DOI: 10.1016/j.yjmcc.2025.04.011

Gaelle Spagnol, Andrew Trease, Li Zheng, Stephen Sobota, Marissa Schmidt, Sunayn Cheku, Paul L. Sorgen

{"title":"Cx45 regulation by kinases and impact of expression in heart failure","authors":"Gaelle Spagnol, Andrew Trease, Li Zheng, Stephen Sobota, Marissa Schmidt, Sunayn Cheku, Paul L. Sorgen","doi":"10.1016/j.yjmcc.2025.04.011","DOIUrl":"10.1016/j.yjmcc.2025.04.011","url":null,"abstract":"<div><div>Phosphorylation plays a crucial role in connexin regulation by modulating gap junction intercellular communication (GJIC), localization, stability, and interactions with signaling proteins. Few kinases are known to phosphorylate Cx45, and their target residues remain unknown. A phosphorylation screen identified several Cx45-targeting kinases activated in heart disease, among which c-Src was found by mass spectroscopy to phosphorylate residues Y324 and Y356. Unlike Cx43, c-Src phosphorylation of Cx45 did not impair GJIC, alter junctional localization, or affect interactions with cytoskeletal proteins β-tubulin, Drebrin, and ZO-1. In LA-25 cells where Cx43 is internalized after temperature sensitive activation of v-Src, expression of Cx45 unexpectedly maintained Cx43 at the plasma membrane. Phospho-specific antibodies helped identify that while Cx43 had a tyrosine phosphorylation pattern favoring turnover, the serine phosphorylation pattern was conducive for GJIC. Furthermore, in a rat model of heart failure, Cx45 was expressed in the ventricle and co-localized with Cx43, leading to altered dye coupling indicative of a shift toward Cx45-like channel permeability. Altogether, our data suggests that in heart failure, c-Src activation on its own would not have an adverse effect on Cx45 function and that aberrant Cx45 expression helps Cx43 transport to and maintain at the intercalated disc. Yet the dominant effect of Cx45 in heteromeric channels could ultimately make Cx45 a key driver of cardiac dysfunction. Finally, the observation that Cx45-mediated coupling remains functional even in the same pathological environment where Cx43-mediated communication is inhibited suggests that kinase regulation of connexins is isoform-specific and not universally predictable.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 91-105"},"PeriodicalIF":4.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882477","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}

引用次数: 0

Screening single nucleotide changes to tropomyosin to identify novel cardiomyopathy mutants 筛选原肌球蛋白的单核苷酸变化以鉴定新型心肌病突变体

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-21 DOI: 10.1016/j.yjmcc.2025.04.009

Jian Wen (Jake) , Stuart Campbell , Jeffrey Moore , William Lehman , Michael Rynkiewicz

{"title":"Screening single nucleotide changes to tropomyosin to identify novel cardiomyopathy mutants","authors":"Jian Wen (Jake) , Stuart Campbell , Jeffrey Moore , William Lehman , Michael Rynkiewicz","doi":"10.1016/j.yjmcc.2025.04.009","DOIUrl":"10.1016/j.yjmcc.2025.04.009","url":null,"abstract":"<div><div>Inherited cardiomyopathy is a broad class of heart disease that includes pathological cardiac remodeling such as hypertrophic and dilated cardiomyopathy, affecting 1/250–1/500 people worldwide. In many cases, mutations in proteins that make up the sarcomere, the basic subcellular unit of contraction, alter thin filament regulation and are the root cause of hypertrophic and dilated cardiomyopathy. Initially, compensations can maintain cardiac function, so patients may remain asymptomatic for years before a major cardiac episode. Early therapeutic intervention could rescue the deleterious effects of mutations thereby avoiding pathological remodeling, so prediction of potential outcomes and severity of as yet uncharacterized and known mutants of uncertain significance is critical. To accomplish this goal, we begin with the structure of the thin filament containing actin, tropomyosin, and troponin in its regulatory B- and C-states, incorporate all potential single nucleotide mutations to the tropomyosin sequence (over 1700 unique mutations), and then measure the interaction energy between tropomyosin and actin after energy minimization. Analysis of the database thus generated shows the tropomyosin residues resulting in large changes in tropomyosin-actin interaction, and therefore most likely to be deleterious to function. Some of these mutants have been observed in human patients, whereas others are novel. Global analysis further refines hotspots of mutation-sensitive, coiled-coil tropomyosin residues affecting actin interactions. Altogether, the database will allow research to focus in great depth on key candidates for functional analysis, for instance, by assaying in vitro motility and engineered heart tissue mechanics and assessing outcomes in animal models.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"203 ","pages":"Pages 82-90"},"PeriodicalIF":4.9,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869996","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}

引用次数: 0

New insights into diabetes-induced cardiac pathology 糖尿病引起的心脏病理的新见解

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-20 DOI: 10.1016/j.yjmcc.2025.04.008

K.L. Weeks , B.C. Bernardo , J.R. Bell , L.M.D. Delbridge , K.M. Mellor

引用次数: 0

METTL3-mediated N6-methyladenosine modification contributes to vascular calcification mettl3介导的n6 -甲基腺苷修饰有助于血管钙化

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-11 DOI: 10.1016/j.yjmcc.2025.04.006

Long Li , Quanyou Chai , Chunling Guo , Junyi Wei , Yuqiao Qin , Huimin Liu , Zhaoyang Lu

{"title":"METTL3-mediated N6-methyladenosine modification contributes to vascular calcification","authors":"Long Li , Quanyou Chai , Chunling Guo , Junyi Wei , Yuqiao Qin , Huimin Liu , 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}

引用次数: 0

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 在纯合子CRISPR基因编辑的小鼠中，心肌肌球蛋白结合蛋白c的L348P点突变改变了对拉伸的短暂反应，减慢了心脏舒张，并且是胚胎致死的

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-11 DOI: 10.1016/j.yjmcc.2025.04.007

Rachel L. Sadler , Angela C. Greenman , Mei Methawasin , Julie Fan , Samantha P. Harris

{"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 , Angela C. Greenman , Mei Methawasin , Julie Fan , 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 SpyC<sub>3</sub> 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}

引用次数: 0

Coronary microcirculation in myocardial ischemia: A genetic perspective 心肌缺血的冠状动脉微循环：遗传学的观点

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-10 DOI: 10.1016/j.yjmcc.2025.04.002

Paolo Severino , Andrea D'Amato , Silvia Prosperi , Vincenzo Myftari , Rosanna Germanò , Stefanie Marek-Iannucci , Andrea De Prisco , Marco Valerio Mariani , Ludovica Marchiori , Corinne Battaglia , Leonardo Tabacco , Camilla Segato , Massimo Mancone , Francesco Fedele , Carmine Dario Vizza

{"title":"Coronary microcirculation in myocardial ischemia: A genetic perspective","authors":"Paolo Severino , Andrea D'Amato , Silvia Prosperi , Vincenzo Myftari , Rosanna Germanò , Stefanie Marek-Iannucci , Andrea De Prisco , Marco Valerio Mariani , Ludovica Marchiori , Corinne Battaglia , Leonardo Tabacco , Camilla Segato , Massimo Mancone , Francesco Fedele , 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}

引用次数: 0

Hydrogen sulfide preserves the function of senescent endothelium through SIRT2 mediated inflammatory inhibition 硫化氢通过SIRT2介导的炎症抑制保护衰老内皮细胞的功能

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-08 DOI: 10.1016/j.yjmcc.2025.04.005

Xueyuan Qin , Fan Lu , Jie Wan , Xu Teng , Sheng Jin , Lin Xiao , Hongmei Xue , Qi Guo , Danyang Tian , Yuming Wu

{"title":"Hydrogen sulfide preserves the function of senescent endothelium through SIRT2 mediated inflammatory inhibition","authors":"Xueyuan Qin , Fan Lu , Jie Wan , Xu Teng , Sheng Jin , Lin Xiao , Hongmei Xue , Qi Guo , Danyang Tian , 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 (H<sub>2</sub>S) 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, H<sub>2</sub>S 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 H<sub>2</sub>S inhibited inflammation to improve endothelial aging through the SIRT2/NLRP3 pathway. This provided H<sub>2</sub>S 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}

引用次数: 0

GLP1R upregulation in mitral regurgitation observed at a single nucleus level 单核水平观察二尖瓣反流中GLP1R的上调

IF 4.9 2区医学

Journal of molecular and cellular cardiology Pub Date : 2025-04-08 DOI: 10.1016/j.yjmcc.2025.04.003

Sameeksha Tiwari , Martin Beyer , Sary F. Aranki , Meraj Neyazi , Gavin Y. Oudit , Olivia Layton , J.G. Seidman , Christine E. Seidman , Jochen D. Muehlschlegel

引用次数: 0