Journal of molecular and cellular cardiology最新文献

{"title":"Ex vivo modelling of cardiac injury identifies ferroptosis-related pathways as a potential therapeutic avenue for translational medicine","authors":"Naisam Abbas ,&nbsp;Marco Bentele ,&nbsp;Florian J.G. Waleczek ,&nbsp;Maximilian Fuchs ,&nbsp;Annette Just ,&nbsp;Angelika Pfanne ,&nbsp;Andreas Pich ,&nbsp;Sophie Linke ,&nbsp;Susanne Neumüller ,&nbsp;Angelika Stucki-Koch ,&nbsp;Maria Jordan ,&nbsp;Filippo Perbellini ,&nbsp;Christopher Werlein ,&nbsp;Wilhelm Korte ,&nbsp;Fabio Ius ,&nbsp;Arjang Ruhparwar ,&nbsp;Natalie Weber ,&nbsp;Jan Fiedler ,&nbsp;Thomas Thum","doi":"10.1016/j.yjmcc.2024.09.012","DOIUrl":"10.1016/j.yjmcc.2024.09.012","url":null,"abstract":"<div><h3>Background</h3><div>Heart failure (HF) is a burgeoning health problem worldwide. Often arising as a result of cardiac injury, HF has become a major cause of mortality with limited availability of effective treatments. Ferroptotic pathways, triggering an iron-dependent form of cell death, are known to be potential key players in heart disease. This form of cell death does not exhibit typical characteristics of programmed cell death, and is mediated by impaired iron metabolism and lipid peroxidation signalling.</div></div><div><h3>Objectives</h3><div>The aim of this study is to establish an <em>ex-vivo</em> model of myocardial injury in living myocardial slices (LMS) and to identify novel underlying mechanisms and potential therapeutic druggable target(s).</div></div><div><h3>Methods and results</h3><div>In this study, we employed LMS as an <em>ex vivo</em> model of cardiac injury to investigate underlying mechanisms and potential therapeutic targets. Cryoinjury was induced in adult rat LMS, resulting in 30 % tissue damage. Cryoinjured LMS demonstrated impaired contractile function, cardiomyocyte hypertrophy, inflammation, and cardiac fibrosis, closely resembling <em>in vivo</em> cardiac injury characteristics. Proteomic analysis revealed an enrichment of factors associated with ferroptosis in the injured LMS, suggesting a potential causative role. To test this hypothesis, we pharmacologically inhibited ferroptotic pathways using ferrostatin (Fer-1) in the cryoinjured rat LMS, resulting in attenuation of structural changes and repression of pro-fibrotic processes. Furthermore, LMS generated from failing human hearts were used as a model of chronic heart failure. In this model, Fer-1 treatment was observed to reduce the expression of ferroptotic genes, enhances contractile function and improves tissue viability. Blocking ferroptosis-associated pathways in human cardiac fibroblasts (HCFs) resulted in a downregulation of fibroblast activation genes, a decrease in fibroblast migration capacity, and a reduction in reactive oxygen species production. RNA sequencing analysis of Fer-1-treated human LMS implicated metallothioneins as a potential underlying mechanism for the inhibition of these pathways. This effect is possibly mediated through the replenishment of glutathione reserves.</div></div><div><h3>Conclusions</h3><div>Our findings highlight the potential of targeting ferroptosis-related pathways and metallothioneins as a promising strategy for the treatment of heart disease.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 125-140"},"PeriodicalIF":4.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348447","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":"Oxidative stress and atrial fibrillation","authors":"Anna Pfenniger ,&nbsp;Shin Yoo ,&nbsp;Rishi Arora","doi":"10.1016/j.yjmcc.2024.09.011","DOIUrl":"10.1016/j.yjmcc.2024.09.011","url":null,"abstract":"<div><div>Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Though the pathogenesis of AF is complex and is not completely understood, many studies suggest that oxidative stress is a major mechanism in pathophysiology of AF. Through multiple mechanisms, reactive oxygen species (ROS) lead to the formation of an AF substrate that facilitates the development and maintenance of AF. In this review article, we provide an update on the different mechanisms by which oxidative stress promotes atrial remodeling. We then discuss several therapeutic strategies targeting oxidative stress for the prevention or treatment of AF. Considering the complex biology of ROS induced remodeling, and the evolution of ROS sources and compartmentalization during AF progression, there is a definite need for improvement in timing, targeting and reduction of off-target effects of therapeutic strategies targeting oxidative injury in AF.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 141-151"},"PeriodicalIF":4.9,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289360","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":"Adrenergic orchestration of immune cell dynamics in response to cardiac stress","authors":"Tapas K. Nayak,&nbsp;Dev Parasania,&nbsp;Douglas G. Tilley","doi":"10.1016/j.yjmcc.2024.09.010","DOIUrl":"10.1016/j.yjmcc.2024.09.010","url":null,"abstract":"<div><div>Immune cells contribute approximately 5–10 % of the heart's total cell population, including several myeloid cell and lymphocyte cell subsets, which, despite their relatively small percentages, play important roles in cardiac homeostasis and remodeling responses to various forms of injury and long-term stress. Pathological cardiac stress activates the sympathetic nervous system (SNS), resulting in the release of the catecholamines epinephrine and norepinephrine either systemically or from sympathetic nerve terminals within various lymphoid organs. Acting at α- or β-adrenergic receptors (αAR, βAR), catecholamines regulate immune cell hematopoiesis, egress and migration in response to stress. Classically, αAR stimulation tends to promote inflammatory responses while βAR stimulation has typically been shown to be immunosuppressive, though the effects can be nuanced depending on the immune cells subtype, the site of regulation and pathophysiological context. Herein, we will discuss several facets of SNS-mediated regulation of immune cells and their response to cardiac stress, including: catecholamine response to cardiovascular stress and action at their receptors, adrenergic regulation of hematopoiesis, immune cell retention and release from the bone marrow, adrenergic regulation of splenic immune cells and their retention, as well as adrenergic regulation of immune cell recruitment to the injured heart, including neutrophils, monocytes and macrophages. A particular focus will be given to βAR-mediated effects on myeloid cells in response to acute or chronic cardiac stress.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 115-124"},"PeriodicalIF":4.9,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289358","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":"Retraction notice to “dATP elevation induces myocardial metabolic remodeling to support improved cardiac function” [Journal of Molecular and Cellular Cardiology 175 (2022) 1-12]","authors":"Ketaki N. Mhatre ,&nbsp;Jason D. Murray ,&nbsp;Galina Flint ,&nbsp;Timothy S. McMillen ,&nbsp;Gerhard Weber ,&nbsp;Majid Shakeri ,&nbsp;An-Yue Tu ,&nbsp;Sonette Steczina ,&nbsp;Robert Weiss ,&nbsp;David J. Marcinek ,&nbsp;Charles E. Murry ,&nbsp;Daniel Raftery ,&nbsp;Rong Tian ,&nbsp;Farid Moussavi-Harami ,&nbsp;Michael Regnier","doi":"10.1016/j.yjmcc.2024.09.006","DOIUrl":"10.1016/j.yjmcc.2024.09.006","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"197 ","pages":"Page 150"},"PeriodicalIF":4.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265601","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 function and energetics in mice with combined genetic augmentation of creatine and creatine kinase activity","authors":"Sevasti Zervou ,&nbsp;Debra J. McAndrew ,&nbsp;Hannah A. Lake ,&nbsp;Elina Kuznecova ,&nbsp;Christopher Preece ,&nbsp;Benjamin Davies ,&nbsp;Stefan Neubauer ,&nbsp;Craig A. Lygate","doi":"10.1016/j.yjmcc.2024.09.007","DOIUrl":"10.1016/j.yjmcc.2024.09.007","url":null,"abstract":"<div><p>Improving energy provision in the failing heart by augmenting the creatine kinase (CK) system is a desirable therapeutic target. However, over-expression of the creatine transporter (CrT-OE) has shown that very high creatine levels result in cardiac hypertrophy and dysfunction. We hypothesise this is due to insufficient endogenous CK activity to maintain thermodynamically favourable metabolite ratios. If correct, then double transgenic mice (dTg) overexpressing both CrT and the muscle isoform of CK (CKM-OE) would rescue the adverse phenotype. In Study 1, overexpressing lines were crossed and cardiac function assessed by invasive haemodynamics and echocardiography. This demonstrated that CKM-OE was safe, but too few hearts had creatine in the toxic range. In Study 2, a novel CrT-OE line was generated with higher, homogeneous, creatine levels and phenotyped as before. Myocardial creatine was 4-fold higher in CrT-OE and dTg hearts compared to wildtype and was associated with hypertrophy and contractile dysfunction. The inability of dTg hearts to rescue this phenotype was attributed to downregulation of CK activity, as occurs in the failing heart. Nevertheless, combining both studies in a linear regression analysis suggests a modest positive effect of CKM over a range of creatine concentrations. In conclusion, we confirm that moderate elevation of creatine is well tolerated, but very high levels are detrimental. Correlation analysis lends support to the theory that this may be a consequence of limited CK activity. Future studies should focus on preventing CKM downregulation to unlock the potential synergy of augmenting both creatine and CK in the heart.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 105-114"},"PeriodicalIF":4.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S002228282400155X/pdfft?md5=075c48c34f5868de40e2c10bda8d51e2&pid=1-s2.0-S002228282400155X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142241982","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":"Gene therapy for atrial fibrillation","authors":"Weilan Mo,&nbsp;J. Kevin Donahue","doi":"10.1016/j.yjmcc.2024.09.004","DOIUrl":"10.1016/j.yjmcc.2024.09.004","url":null,"abstract":"<div><p>Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Current limitations of pharmacological and ablative therapies motivate the development of novel therapies as next generation treatments for AF. The arrhythmia mechanisms creating and sustaining AF are key elements in the development of this novel treatment. Gene therapy provides a useful platform that allows us to regulate the mechanisms of interest using a suitable transgene(s), vector, and delivery method. Effective gene therapy strategies in the literature have targeted maladaptive electrical or structural remodeling that increase vulnerability to AF. In this review, we will summarize key elements of gene therapy for AF, including molecular targets, gene transfer vectors, atrial gene delivery and preclinical efficacy and toxicity testing. Recent advances and challenges in the field will be also discussed.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 84-93"},"PeriodicalIF":4.9,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230296","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 multi-omics atlas of sex-specific differences in obstructive hypertrophic cardiomyopathy","authors":"Ramin Garmany ,&nbsp;Surendra Dasari ,&nbsp;J. Martijn Bos ,&nbsp;Evelyn T. Kim ,&nbsp;Martina Gluscevic ,&nbsp;Katherine A. Martinez ,&nbsp;David J. Tester ,&nbsp;Cristobal dos Remedios ,&nbsp;Joseph J. Maleszewski ,&nbsp;Joseph A. Dearani ,&nbsp;Steve R. Ommen ,&nbsp;Jeffrey B. Geske ,&nbsp;John R. Giudicessi ,&nbsp;Michael J. Ackerman","doi":"10.1016/j.yjmcc.2024.09.005","DOIUrl":"10.1016/j.yjmcc.2024.09.005","url":null,"abstract":"<div><h3>Background</h3><p>Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown.</p></div><div><h3>Methods</h3><p>Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples.</p></div><div><h3>Results</h3><p>The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1983 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males.</p></div><div><h3>Conclusion</h3><p>There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 26-34"},"PeriodicalIF":4.9,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142164719","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":"SGK1 contributes to ferroptosis in coronary heart disease through the NEDD4L/NF-κB pathway","authors":"Yong Peng ,&nbsp;Yu Jiang ,&nbsp;Qingfeng Zhou,&nbsp;Zheng Jia,&nbsp;Han Tang","doi":"10.1016/j.yjmcc.2024.09.001","DOIUrl":"10.1016/j.yjmcc.2024.09.001","url":null,"abstract":"<div><p>The prevalence of coronary heart disease (CHD) has increased significantly with the aging population worldwide. It is unclear whether ferroptosis occurs during CHD. Hence, we aimed to investigate the potential mechanisms associated with ferroptosis in CHD. Bioinformatics was used to characterize differentially expressed genes (DEGs) in CHD-related datasets (GSE21610 and GSE66360). There were 76 and 689 DEGs in the GSE21610 and GSE66360, respectively, and they predominantly associated with immune and inflammatory responses. DDX3Y, EIF1AY, KDM5D, RPS4Y1, SGK1, USP9Y, and NSG1 were intersecting DEGs of GSE21610 and GSE66360. Their expression pattern in circulating endothelial cells (ECs) derived from healthy individuals and CHD patients are consistent with the results of bioinformatics analysis, especially SGK1. <em>In vitro</em>, SGK1 knockdown alleviated the Erastin-induced downregulation of SLC7A11, GPX4, GSH, and GSSG, as well as the upregulation of lipid peroxidation, Fe accumulation, and mitochondrial damage in mouse aortic ECs (MAECs). Notably, SGK1 may interact with NEDD4L according to the String database. Moreover, SGK1 promoted NEDD4L and p-P65 expression in MAECs. Interestingly, the effect of SGK1 knockdown on ferroptosis in MAECs was rescued by overexpression of NEDD4L or PMA (NF-κB pathway activator). <em>In vivo</em>, SGK1 knockdown facilitated the recovery of body weight, blood lipids, and aortic tissue structure in CHD animal models. Furthermore, SGK1 knockdown alleviated Fe accumulation in the aorta and inactivated the NEDD4L-NF-κB pathway. In conclusion, SGK1 contributes to EC ferroptosis by regulating the NEDD4L-NF-κB pathway. SGK1 could be recognized as a therapeutic target related to ferroptosis in CHD.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 71-83"},"PeriodicalIF":4.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824001433/pdfft?md5=cd134ff6ffefeb22005200a700a4bbb1&pid=1-s2.0-S0022282824001433-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154389","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":"The cAMP/PKA signaling pathway conditions cardiac performance in experimental animals with metabolic syndrome","authors":"Emanuele Pizzo ,&nbsp;Daniel O. Cervantes ,&nbsp;Valentina Ripa ,&nbsp;Andrea Filardo ,&nbsp;Silvia Berrettoni ,&nbsp;Harshada Ketkar ,&nbsp;Vineeta Jagana ,&nbsp;Valeria Di Stefano ,&nbsp;Kanwardeep Singh ,&nbsp;Asha Ezzati ,&nbsp;Kash Ghadirian ,&nbsp;Anna Kouril ,&nbsp;Jason T. Jacobson ,&nbsp;Malik Bisserier ,&nbsp;Sudhir Jain ,&nbsp;Marcello Rota","doi":"10.1016/j.yjmcc.2024.09.002","DOIUrl":"10.1016/j.yjmcc.2024.09.002","url":null,"abstract":"<div><p>Metabolic syndrome (MetS) increases the risk of coronary artery disease, but effects of this condition on the working myocardium remain to be fully elucidated. In the present study we evaluated the consequences of diet-induced metabolic disorders on cardiac function and myocyte performance using female mice fed with Western diet. Animals maintained on regular chow were used as control (Ctrl). Mice on the Western diet (WesD) had increased body weight, impaired glucose metabolism, preserved diastolic and systolic function, but increased left ventricular (LV) mass, with respect to Ctrl animals. Moreover, WesD mice had reduced heart rate variability (HRV), indicative of altered cardiac sympathovagal balance. Myocytes from WesD mice had increased volume, enhanced cell mechanics, and faster kinetics of contraction and relaxation. Moreover, levels of cAMP and protein kinase A (PKA) activity were enhanced in WesD myocytes, and interventions aimed at stabilizing cAMP/PKA abrogated functional differences between Ctrl and WesD cells. Interestingly, <em>in vivo</em> β-adrenergic receptor (β-AR) blockade normalized the mechanical properties of WesD myocytes and revealed defective cardiac function in WesD mice, with respect to Ctrl. Collectively, these results indicate that metabolic disorders induced by Western diet enhance the cAMP/PKA signaling pathway, a possible adaptation required to maintain cardiac function.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 35-51"},"PeriodicalIF":4.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168120","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":"Quantitative label-free digital holographic imaging of cardiomyocyte optical volume, nucleation, and cell division","authors":"Herman Huang ,&nbsp;Sangsoon Park ,&nbsp;Ines Ross ,&nbsp;Joseph Moreno ,&nbsp;Sheamin Khyeam ,&nbsp;Jacquelyn Simmons ,&nbsp;Guo N. Huang ,&nbsp;Alexander Y. Payumo","doi":"10.1016/j.yjmcc.2024.09.003","DOIUrl":"10.1016/j.yjmcc.2024.09.003","url":null,"abstract":"<div><p>Cardiac regeneration in newborn rodents depends on the ability of pre-existing cardiomyocytes to proliferate and divide. This capacity is lost within the first week of postnatal development when these cells rapidly switch from hyperplasia to hypertrophy, withdraw from the cell cycle, become binucleated, and increase in size. How these dynamic changes in cell size and nucleation impact cardiomyocyte proliferative potential is not well understood. In this study, we innovate the application of a commercially available digital holographic imaging microscope, the Holomonitor M4, to evaluate the proliferative responses of mononucleated and binucleated cardiomyocytes after CHIR99021 treatment, a model proliferative stimulus. This system enables long-term label-free quantitative tracking of primary cardiomyocyte dynamics in real-time with single-cell resolution. Our results confirm that chemical inhibition of glycogen synthase kinase 3 with CHIR99021 promotes complete cell division of both mononucleated and binucleated cardiomyocytes with high frequency. Quantitative tracking of cardiomyocyte volume dynamics during these proliferative events revealed that both mononucleated and binucleated cardiomyocytes reach a similar size-increase threshold prior to attempted cell division. Binucleated cardiomyocytes attempt to divide with lower frequency than mononucleated cardiomyocytes, which may be associated with inadequate increases in cell size. By defining the interrelationship between cardiomyocyte size, nucleation, and cell cycle control, we may better understand the cellular mechanisms that drive the loss of mammalian cardiac regenerative capacity after birth.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"196 ","pages":"Pages 94-104"},"PeriodicalIF":4.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824001457/pdfft?md5=e3e8bd168c1b2980f60aacfa736715f4&pid=1-s2.0-S0022282824001457-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227393","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}