Shiyu Fan, Mingming Zhao, Kang Wang, Yawen Deng, Xiaoyue Yu, Ketao Ma, Youyi Zhang, Han Xiao
{"title":"Exercise training attenuates cardiac dysfunction induced by excessive sympathetic activation through an AMPK-KLF4-FMO2 axis.","authors":"Shiyu Fan, Mingming Zhao, Kang Wang, Yawen Deng, Xiaoyue Yu, Ketao Ma, Youyi Zhang, Han Xiao","doi":"10.1016/j.yjmcc.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2024.10.015","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide and are associated with an overactivated sympathetic system. Although exercise training has shown promise in mitigating sympathetic stress-induced cardiac remodeling, the precise mechanisms remain elusive. Here, we demonstrate that exercise significantly upregulates cardiac flavin-containing monooxygenase 2 (FMO2) expression. Notably, we find that exercise training effectively counteracts sympathetic overactivation-induced cardiac dysfunction and fibrosis by enhancing FMO2 expression via adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Functional investigations employing FMO2 knockdown with adeno-associated virus 9 (AAV9) underscore the necessity for FMO2 expression to protect the heart during exercise in vivo. Furthermore, we identify the krüppel-like factor 4 (KLF4) as a transcriptional mediator of FMO2 that is crucial for the mechanism through which AMPK activation protects against sympathetic overactivation-induced cardiac dysfunction and fibrosis. Taken together, our study reveals a cardioprotective mechanism for exercise training through an AMPK-KLF4-FMO2 signaling pathway that underscores how exercise alleviates cardiac dysfunction induced by excessive sympathetic activation.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566354","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}
J Greiner, M Dente, S Orós-Rodrigo, B A Cameron, J Madl, W Kaltenbacher, T Kok, C M Zgierski-Johnston, R Peyronnet, P Kohl, L Sacconi, E A Rog-Zielinska
{"title":"Different effects of cardiomyocyte contractile activity on transverse and axial tubular system luminal content dynamics.","authors":"J Greiner, M Dente, S Orós-Rodrigo, B A Cameron, J Madl, W Kaltenbacher, T Kok, C M Zgierski-Johnston, R Peyronnet, P Kohl, L Sacconi, E A Rog-Zielinska","doi":"10.1016/j.yjmcc.2024.10.014","DOIUrl":"10.1016/j.yjmcc.2024.10.014","url":null,"abstract":"<p><strong>Background: </strong>Efficient excitation-contraction coupling of mammalian ventricular cardiomyocytes depends on the transverse-axial tubular system (TATS), a network of surface membrane invaginations. TATS enables tight coupling of sarcolemmal and sarcoplasmic reticulum membranes, which is essential for rapid Ca<sup>2+</sup>-induced Ca<sup>2+</sup> release, and uniform contraction upon electrical stimulation. The majority of TATS in healthy ventricular cardiomyocytes is composed of transverse tubules (TT, ∼90 % of TATS in rabbit). The remainder consists of mostly axial tubules (AT), which are less abundant and less well studied. In disease, however, the relative abundance of TT and AT changes. The mechanisms and relevance of this change are not known, and understanding them requires a more targeted effort to study the dynamics of AT structure and function. While TATS content is continuous with the interstitial space, it is contained within a domain of restricted diffusion. We have previously shown that TT are cyclically squeezed during stretch and contraction. This can contribute to TT content mixing and accelerates luminal content exchange with the environment. Here, we explore the effects of cardiomyocyte stretch and contraction on AT.</p><p><strong>Methods: </strong>TATS structure and diffusion dynamics were studied using 3D electron tomography of rabbit left ventricular cardiomyocytes, preserved at rest or during contraction, and ventricular tissue preserved at rest or during stretch, as well as live-cell TATS content exchange measurements.</p><p><strong>Results: </strong>We show (i) that cardiomyocyte contraction is associated with an increase in the apparent speed of diffusion of TT content that scales with beating rate and degree of cell shortening. In contrast, (ii) AT develop membrane folds and constrictions during contraction, (iii) with no effect of contraction on luminal exchange dynamics, while (iv) cardiomyocyte stretch is associated with AT straightening and AT and TT 'squeezing' that (v) supports an acceleration of the apparent speed of diffusion in AT and TT. Finally, (vi) we present a simple computational model outlining the potential relevance of AT in healthy and diseased cells.</p><p><strong>Conclusions: </strong>Our results indicate that TT and AT are differently affected by the cardiac contractile cycle, and suggest that AT may play a role in ensuring TATS network content homogeneity in diseased cardiomyocytes. Further research is needed to explore the interplay of structural and functional remodelling of different TATS components in failing myocardium.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568957","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":"Macrophages in the infarcted heart acquire a fibrogenic phenotype, expressing matricellular proteins, but do not undergo fibroblast conversion","authors":"","doi":"10.1016/j.yjmcc.2024.07.010","DOIUrl":"10.1016/j.yjmcc.2024.07.010","url":null,"abstract":"<div><div>Although some studies have suggested that macrophages may secrete structural collagens, and convert to fibroblast-like cells, macrophage to fibroblast transdifferentiation in infarcted and remodeling hearts remains controversial. Our study uses linage tracing approaches and single cell transcriptomics to examine whether macrophages undergo fibroblast conversion, and to characterize the extracellular matrix expression profile of myeloid cells in myocardial infarction. To examine whether infarct macrophages undergo fibroblast conversion, we identified macrophage-derived progeny using the inducible CX3CR1<sup>CreER</sup> mice crossed with the PDGFRα<sup>EGFP</sup> reporter line for reliable fibroblast identification. The abundant fibroblasts that infiltrated the infarcted myocardium after 7 and 28 days of coronary occlusion were not derived from CX3CR1+ macrophages. Infarct macrophages retained myeloid cell characteristics and did not undergo conversion to myofibroblasts, endothelial or vascular mural cells. Single cell RNA-seq of CSF1R+ myeloid cells harvested from control and infarcted hearts showed no significant expression of fibroblast identity genes by myeloid cell clusters. Moreover, infarct macrophages did not express significant levels of genes encoding structural collagens. However, infarct macrophage and monocyte clusters were the predominant source of the fibrogenic growth factors <em>Tgfb1</em> and <em>Pdgfb,</em> and of the matricellular proteins <em>Spp1</em>/Osteopontin, <em>Thbs1</em>/Thrombospondin-1, <em>Emilin2</em>, and <em>Fn1</em>/fibronectin, while expressing significant amounts of several other matrix genes, including <em>Vcan</em>/versican, <em>Ecm1</em> and <em>Sparc</em>. ScRNA-seq data suggested similar patterns of matrix gene expression in human myocardial infarction. In conclusion, infarct macrophages do not undergo fibroblast or myofibroblast conversion and do not exhibit upregulation of structural collagens but may contribute to fibrotic remodeling by producing several fibrogenic matricellular proteins.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875092","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":"Cardiac macrophages and fibroblasts: A synergistic partnership without cellular transition","authors":"","doi":"10.1016/j.yjmcc.2024.09.008","DOIUrl":"10.1016/j.yjmcc.2024.09.008","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289359","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":"Integrated proteomics and transcriptomics analysis reveals insights into differences in premature mortality associated with disparate pathogenic RBM20 variants","authors":"","doi":"10.1016/j.yjmcc.2024.10.013","DOIUrl":"10.1016/j.yjmcc.2024.10.013","url":null,"abstract":"<div><div>Variants in RNA binding motif protein 20 (RBM20) are causative in a severe form of dilated cardiomyopathy referred to as RBM20 cardiomyopathy, yet the mechanisms are unclear. Moreover, the reason(s) for phenotypic heterogeneity in carriers with different pathogenic variants are similarly opaque. To gain insight, we carried out multi-omics analysis, including the first analysis of gene expression changes at the protein level, of mice carrying two different pathogenic variants in the RBM20 nuclear localization signal (NLS). Direct comparison of the phenotypes confirmed greater premature morality in S639G variant carrying mice compared to mice with the S637A variant despite similar cardiac remodeling and dysfunction. Analysis of differentially spliced genes uncovered alterations in the splicing of both RBM20 target genes and non-target genes, including several genes previously implicated in arrhythmia. Global proteomics analysis found that a greater number of proteins were differentially expressed in the hearts of <em>Rbm20</em><sup>S639G</sup> mice relative to WT than in <em>Rbm20</em><sup>S637A</sup> versus WT. Gene ontology analysis suggested greater mitochondrial dysfunction in <em>Rbm20</em><sup>S639G</sup> mice, although direct comparison of protein expression in the hearts of <em>Rbm20</em><sup>S639G</sup> versus <em>Rbm20</em><sup>S637A</sup> mice failed to identify any significant differences. Similarly, few differences were found by direct comparison of gene expression at the transcript level in <em>Rbm20</em><sup>S639G</sup> and <em>Rbm20</em><sup>S637A</sup> despite greater coverage. Our data provide a comprehensive overview of gene splicing and expression differences associated with pathogenic variants in RBM20, as well as insights into the molecular underpinnings of phenotypic heterogeneity associated with different dilated cardiomyopathy-associated variants.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553014","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}
Leonoor F J M Wijdeveld, Amelie C T Collinet, Fabries G Huiskes, Bianca J J M Brundel
{"title":"Metabolomics in atrial fibrillation - A review and meta-analysis of blood, tissue and animal models.","authors":"Leonoor F J M Wijdeveld, Amelie C T Collinet, Fabries G Huiskes, Bianca J J M Brundel","doi":"10.1016/j.yjmcc.2024.10.011","DOIUrl":"10.1016/j.yjmcc.2024.10.011","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia associated with severe cardiovascular complications. AF presents a growing global challenge, however, current treatment strategies for AF do not address the underlying pathophysiology. To advance diagnosis and treatment of AF, a deeper understanding of AF root causes is needed. Metabolomics is a fast approach to identify, quantify and analyze metabolites in a given sample, such as human serum or atrial tissue. In the past two decades, metabolomics have enabled research on metabolite biomarkers to predict AF, metabolic features of AF, and testing metabolic mechanisms of AF in animal models. Due to the field's rapid evolution, the methods of AF metabolomics studies have not always been optimal. Metabolomics research has lacked standardization and requires expertise to face methodological challenges.</p><p><strong>Purpose of the review: </strong>We summarize and meta-analyze metabolomics research on AF in human plasma and serum, atrial tissue, and animal models. We present the current progress on metabolic biomarkers candidates, metabolic features of clinical AF, and the translation of metabolomics findings from animal to human. We additionally discuss strengths and weaknesses of the metabolomics method and highlight opportunities for future AF metabolomics research.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545973","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}
Zhen Yuan, Li Shu, Peipei Yang, Jie Sun, Mengsha Zheng, Jiantao Fu, Yidong Wang, Shen Song, Zhenjie Liu, Zhejun Cai
{"title":"Inhibitory interferon regulatory factor 5 binding peptide suppresses abdominal aortic aneurysm expansion in vivo.","authors":"Zhen Yuan, Li Shu, Peipei Yang, Jie Sun, Mengsha Zheng, Jiantao Fu, Yidong Wang, Shen Song, Zhenjie Liu, Zhejun Cai","doi":"10.1016/j.yjmcc.2024.10.012","DOIUrl":"10.1016/j.yjmcc.2024.10.012","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is a critical condition characterized by the expansion of the infrarenal aorta, often leading to high mortality upon rupture. The absence of treatment for asymptomatic AAAs urgently necessitates uncovering the underlying mechanisms of their development. This study utilized mice to induce AAA through porcine pancreatic elastase with BAPN feeding and found that mice receiving the IRF5-binding peptide (IBP) demonstrated significantly slowed AAA expansion and reduced adventitia degradation compared to the control group. Additionally, the IBP group showed decreased macrophage infiltration and reduced matrix metalloproteinase-9 (MMP9) activity. Targeting IRF5 with IBP offers new avenues for potential treatments for asymptomatic AAAs.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566355","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":"Long noncoding RNA VENTHEART is required for ventricular cardiomyocyte specification and function","authors":"","doi":"10.1016/j.yjmcc.2024.10.009","DOIUrl":"10.1016/j.yjmcc.2024.10.009","url":null,"abstract":"<div><h3>Rationale</h3><div>Cardiac-expressed long noncoding RNAs (lncRNAs) are important for cardiomyocyte (CM) differentiation and function. Several lncRNAs have been identified and characterized for early CM lineage commitment, however those in later CM lineage specification and maturation remain less well studied. Moreover, unique atrial / ventricular lncRNA expression has never been studied in detail.</div></div><div><h3>Objectives</h3><div>Here, we characterized a novel ventricular myocyte-restricted lncRNA, not expressed in atrial myocytes, and conserved only in primates.</div></div><div><h3>Methods and results</h3><div>First, we performed single cell RNA-seq on human pluripotent stem cell derived cardiomyocytes (hPSC-CM) at the late stages of 2, 6 and 12 weeks of differentiation. Weighted correlation network analysis identified core gene modules, including a set of lncRNAs highly abundant and predominantly expressed in the human heart. A lncRNA (we call <em>VENTHEART</em>, <em>VHRT</em>) co-expressed with cardiac maturation and ventricular-specific genes <em>MYL2</em> and <em>MYH7</em>, and was expressed in fetal and adult human ventricles, but not atria. CRISPR-mediated deletion of the <em>VHRT</em> gene led to impaired CM sarcomere formation and significant disruption of the ventricular CM gene program. Indeed, a similar disruption was not observed in <em>VHRT</em> KO hPSC-derived atrial CM, suggesting that <em>VHRT</em> exhibits only ventricular myocyte subtype-specific effects. Optical recordings validated that loss of <em>VHRT</em> significantly prolonged action potential duration at 90 % repolarization (APD<sub>90</sub>) for ventricular-like, but not atrial-like, CMs.</div></div><div><h3>Conclusion</h3><div>This reports the first lncRNA that is exclusively required for proper ventricular, and not atrial, CM specification and function.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Human sclerostin gene expression is associated with asymptomatic carotid atherosclerosis and plaque stability features","authors":"","doi":"10.1016/j.yjmcc.2024.10.010","DOIUrl":"10.1016/j.yjmcc.2024.10.010","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502282","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":"Inhibition of cardiomyocyte neddylation impairs embryonic cardiac morphogenesis","authors":"","doi":"10.1016/j.yjmcc.2024.10.006","DOIUrl":"10.1016/j.yjmcc.2024.10.006","url":null,"abstract":"<div><div>Heart development is a complex spatiotemporal process involving a series of orchestrated morphogenic events that result in the formation of an efficient pumping organ. How posttranslational mechanisms regulate heart development remains poorly understood. Therefore, we investigate how neddylation, the attachment of NEDD8 to target proteins, coordinates cardiogenesis. Abrogation of neddylation by deleting <em>Nae1</em> in the heart via <em>Sm22α</em><sup><em>Cre</em></sup> led to early embryonic lethality. Mutant hearts exhibited deficits in trabeculation and expansion of the compact layer due to reduced cardiomyocyte proliferation, which was linked to abnormal Notch signaling in the developing heart. Overall, our findings demonstrate an essential role for neddylation in cardiogenesis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502283","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}