Pub Date : 2025-09-02DOI: 10.1016/j.yjmcc.2025.09.001
Yilian Wang , Pieterjan Dierickx
Circadian rhythms are an endogenous timekeeping system with a period of approximately 24 h that regulate many aspects of body physiology to maintain organismal health. Dysregulation of circadian rhythmicity has been implicated in various human diseases such as cancer as well as metabolic and cardiovascular disorders. Intrinsic, biological oscillations are regulated by the circadian clock, a molecular transcriptional/translational feedback loop that involves activators such as BMAL1 and CLOCK, and repressors such as REV-ERBα/β and E4BP4. Recent studies have shown that REV-ERBs and E4BP4 play a key role in regulating cardiac gene expression programs and metabolism. Here, we discuss these findings and highlight the mechanisms of their role in healthy and diseased hearts. Since REV-ERBs are drug targets, they hold potential for the treatment of cardiovascular disorders that are linked to circadian dysregulation or metabolic imbalance.
{"title":"Circadian transcriptional repressors REV-ERBα/β and E4BP4 regulate cardiac function","authors":"Yilian Wang , Pieterjan Dierickx","doi":"10.1016/j.yjmcc.2025.09.001","DOIUrl":"10.1016/j.yjmcc.2025.09.001","url":null,"abstract":"<div><div>Circadian rhythms are an endogenous timekeeping system with a period of approximately 24 h that regulate many aspects of body physiology to maintain organismal health. Dysregulation of circadian rhythmicity has been implicated in various human diseases such as cancer as well as metabolic and cardiovascular disorders. Intrinsic, biological oscillations are regulated by the circadian clock, a molecular transcriptional/translational feedback loop that involves activators such as BMAL1 and CLOCK, and repressors such as REV-ERBα/β and E4BP4. Recent studies have shown that REV-ERBs and E4BP4 play a key role in regulating cardiac gene expression programs and metabolism. Here, we discuss these findings and highlight the mechanisms of their role in healthy and diseased hearts. Since REV-ERBs are drug targets, they hold potential for the treatment of cardiovascular disorders that are linked to circadian dysregulation or metabolic imbalance.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"208 ","pages":"Pages 23-31"},"PeriodicalIF":4.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000690","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}
Pub Date : 2025-08-26DOI: 10.1016/j.yjmcc.2025.08.010
Shuliang Guo , Yingwei Liu , Angela Ryan , Ana Laura Lopez Serrano , Isabelle Deschenes , Jihyun Jang , Deqiang Li
Establishment and maintenance of specialized CMs in the heart is critical for the proper cardiac structure and function. Conversely, loss or gain of their identities is associated with various heart diseases such as cardiac arrythmia and cardiomyopathy. CM identity is established during early heart development and continues to be maintained under normal physiological condition, and this is predominantly accomplished by gene regulation. Our understanding of potential genetic, epigenetic or posttranscriptional programs that regulate CM identity (e.g., atrial or ventricular CM identity) is still quite limited. To this end, we summarize current understandings on atrial and ventricular CM identity regulations and discuss potential future research directions to unveil the underlying regulatory mechanisms.
{"title":"Regulation of atrial and ventricular cardiomyocyte identity","authors":"Shuliang Guo , Yingwei Liu , Angela Ryan , Ana Laura Lopez Serrano , Isabelle Deschenes , Jihyun Jang , Deqiang Li","doi":"10.1016/j.yjmcc.2025.08.010","DOIUrl":"10.1016/j.yjmcc.2025.08.010","url":null,"abstract":"<div><div>Establishment and maintenance of specialized CMs in the heart is critical for the proper cardiac structure and function. Conversely, loss or gain of their identities is associated with various heart diseases such as cardiac arrythmia and cardiomyopathy. CM identity is established during early heart development and continues to be maintained under normal physiological condition, and this is predominantly accomplished by gene regulation. Our understanding of potential genetic, epigenetic or posttranscriptional programs that regulate CM identity (e.g., atrial or ventricular CM identity) is still quite limited. To this end, we summarize current understandings on atrial and ventricular CM identity regulations and discuss potential future research directions to unveil the underlying regulatory mechanisms.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"208 ","pages":"Pages 11-22"},"PeriodicalIF":4.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912310","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}
Pub Date : 2025-08-21DOI: 10.1016/j.yjmcc.2025.08.009
Yin Wang , Di Ren , Randy Kang , Kai Zhang , Yunqian Peng , Heather Zhou , Geming Lu , Junjie Guo , Adolfo Garcia-Ocaña , Yingfeng Deng , June-Wha Rhee , Zhao V. Wang
The emergence of single nucleus multiome sequencing (snMultiome-seq) technology has greatly advanced our understanding of various biological processes. However, existing experimental protocols fail to isolate high-quality nuclei from cryopreserved fibrous tissues, such as the heart, leading to low-quality downstream sequencing data. Here, we develop a simple and inexpensive approach for nuclei isolation from frozen tissues, named douncer-filter-gradient-centrifugation (DFGC). This protocol takes approximately 1.5 h to complete, including mincing (1 min), douncing (3 min), filtration (20 min), and density gradient centrifugation (40 min). To evaluate the effectiveness of the DFGC approach, we compare it with two commonly used methods for nuclei isolation – micro-beads and fluorescence-activated cell sorting (FACS). We demonstrate that the DFGC method performs in a preferred manner for the generation of both single nucleus gene expression and chromatin transposase accessibility data. We anticipate the DFGC method to be a mainstream approach for high-quality nuclei isolation in snMultiome-seq.
{"title":"A simple approach of nuclei isolation for single nucleus multiome sequencing","authors":"Yin Wang , Di Ren , Randy Kang , Kai Zhang , Yunqian Peng , Heather Zhou , Geming Lu , Junjie Guo , Adolfo Garcia-Ocaña , Yingfeng Deng , June-Wha Rhee , Zhao V. Wang","doi":"10.1016/j.yjmcc.2025.08.009","DOIUrl":"10.1016/j.yjmcc.2025.08.009","url":null,"abstract":"<div><div>The emergence of single nucleus multiome sequencing (snMultiome-seq) technology has greatly advanced our understanding of various biological processes. However, existing experimental protocols fail to isolate high-quality nuclei from cryopreserved fibrous tissues, such as the heart, leading to low-quality downstream sequencing data. Here, we develop a simple and inexpensive approach for nuclei isolation from frozen tissues, named douncer-filter-gradient-centrifugation (DFGC). This protocol takes approximately 1.5 h to complete, including mincing (1 min), douncing (3 min), filtration (20 min), and density gradient centrifugation (40 min). To evaluate the effectiveness of the DFGC approach, we compare it with two commonly used methods for nuclei isolation – micro-beads and fluorescence-activated cell sorting (FACS). We demonstrate that the DFGC method performs in a preferred manner for the generation of both single nucleus gene expression and chromatin transposase accessibility data. We anticipate the DFGC method to be a mainstream approach for high-quality nuclei isolation in snMultiome-seq.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"208 ","pages":"Pages 1-10"},"PeriodicalIF":4.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903170","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}
Pub Date : 2025-08-20DOI: 10.1016/j.yjmcc.2025.08.007
Brijesh Sathian, Javed Iqbal, Syed Muhammad Ali
{"title":"Cytoplasmic RBM20 gain-of-function induces atrial arrhythmogenicity independent of splicing defects in a novel murine model","authors":"Brijesh Sathian, Javed Iqbal, Syed Muhammad Ali","doi":"10.1016/j.yjmcc.2025.08.007","DOIUrl":"10.1016/j.yjmcc.2025.08.007","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Page 92"},"PeriodicalIF":4.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892953","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}
Pub Date : 2025-08-20DOI: 10.1016/j.yjmcc.2025.08.002
Baihui Ma , Qingyi Zeng , Fangfang Yang , Hang Yang , Wenke Li , Rei Fu , Zeyu Cai , Guoyan Zhu , Mingyao Luo , Zhou Zhou
{"title":"Corrigendum to “MMP19 in vascular smooth muscle cells protects against thoracic aortic aneurysm and dissection via the MMP19/Aggrecan/Wnt/β-catenin axis”[J Mol Cell Cardiol. 202 (2025) 35–49]","authors":"Baihui Ma , Qingyi Zeng , Fangfang Yang , Hang Yang , Wenke Li , Rei Fu , Zeyu Cai , Guoyan Zhu , Mingyao Luo , Zhou Zhou","doi":"10.1016/j.yjmcc.2025.08.002","DOIUrl":"10.1016/j.yjmcc.2025.08.002","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 107-108"},"PeriodicalIF":4.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957621","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}
Pub Date : 2025-08-19DOI: 10.1016/j.yjmcc.2025.08.006
Kensuke Ihara
{"title":"Response to: Cytoplasmic RBM20 gain-of-function induces atrial arrhythmogenicity independent of splicing defects in a novel murine model by Brijesh Sathian et al.","authors":"Kensuke Ihara","doi":"10.1016/j.yjmcc.2025.08.006","DOIUrl":"10.1016/j.yjmcc.2025.08.006","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 64-65"},"PeriodicalIF":4.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889316","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}
Pub Date : 2025-08-19DOI: 10.1016/j.yjmcc.2025.08.005
Martin E. Young , Vanya Khanna , Mallory Metcalfe , Niruththaan Rameshkumar , Sarah Harington , Leo H. Li , Janan Shoja Doost , Heinrich Taegtmeyer , Tami A. Martino
This review tracks the discovery of circadian biology in cardiovascular science, starting with early clinical observations of daily changes in heart rate, blood pressure, and cardiovascular events. These patterns suggested that time of day matters, but it was not until the past two decades that the mechanisms and knowledge translation of these rhythms were uncovered. We describe the heart's intrinsic circadian properties and importantly how this leads to regulation of cardiac gene and protein expression, neuroendocrine and vascular rhythms, metabolism, cellular electrophysiology, and cell signaling pathways. Next, we explore emerging themes, including the impact of circadian timing on ischemic injury, cardiac aging, and trends in circadian desynchrony, sex, and interorgan crosstalk. Building on these discoveries, circadian medicine is beginning to reshape clinical care including timing of surgery, chronotherapies, biomarkers, ICU design, novel molecular drugs targeting the circadian clock, the role of the microbiome and time restricted eating, the new field of rest, and the concept of One Health and applications to veterinary medicine. Looking ahead we address new frontiers such as epigenetics, gene editing, and spaceflight. Together, these advances offer a roadmap for how circadian rhythms can be harnessed to improve cardiovascular health and disease outcomes, supporting longer and healthier lives.
{"title":"A brief history of circadian time in the heart","authors":"Martin E. Young , Vanya Khanna , Mallory Metcalfe , Niruththaan Rameshkumar , Sarah Harington , Leo H. Li , Janan Shoja Doost , Heinrich Taegtmeyer , Tami A. Martino","doi":"10.1016/j.yjmcc.2025.08.005","DOIUrl":"10.1016/j.yjmcc.2025.08.005","url":null,"abstract":"<div><div>This review tracks the discovery of circadian biology in cardiovascular science, starting with early clinical observations of daily changes in heart rate, blood pressure, and cardiovascular events. These patterns suggested that time of day matters, but it was not until the past two decades that the mechanisms and knowledge translation of these rhythms were uncovered. We describe the heart's intrinsic circadian properties and importantly how this leads to regulation of cardiac gene and protein expression, neuroendocrine and vascular rhythms, metabolism, cellular electrophysiology, and cell signaling pathways. Next, we explore emerging themes, including the impact of circadian timing on ischemic injury, cardiac aging, and trends in circadian desynchrony, sex, and interorgan crosstalk. Building on these discoveries, circadian medicine is beginning to reshape clinical care including timing of surgery, chronotherapies, biomarkers, ICU design, novel molecular drugs targeting the circadian clock, the role of the microbiome and time restricted eating, the new field of rest, and the concept of One Health and applications to veterinary medicine. Looking ahead we address new frontiers such as epigenetics, gene editing, and spaceflight. Together, these advances offer a roadmap for how circadian rhythms can be harnessed to improve cardiovascular health and disease outcomes, supporting longer and healthier lives.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 66-80"},"PeriodicalIF":4.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891963","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}
Pub Date : 2025-08-19DOI: 10.1016/j.yjmcc.2025.08.008
Attila Oláh , Beáta Bódi , Bálint András Barta , Olívia Bottlik , Alex Ali Sayour , Mihály Ruppert , Karolina Katarzyna Kolodziejska , Andrea Kovács , Zoltán V. Varga , Péter Ferdinandy , Oliver Schilling , Zoltán Papp , Béla Merkely , Tamás Radovits
Background
Research projects have focused on exercise-induced alterations of the right ventricle (RV) of the heart, because the exercise-associated disproportionate load on the RV might lead to pathological consequences, such as interstitial fibrosis, chamber dilation or pro-arrhytmic remodelling. We aimed at providing a complex characterization of RV alterations induced by regular training in a rat model of exercise-induced cardiac remodelling.
Methods
Young, adult rats were divided into control (Co) and exercised (Ex) groups. Exercised rats swam 200 min/day for 12 weeks. In vivo cardiac electrophysiological study and in vitro force measurements on isolated permeabilized RV cardiomyocytes were performed to investigate electrical and functional alterations, respectively. Molecular biological and histological investigations were carried out.
Results
Exercise training was associated with mild increased RV hypertrophy (cardiomyocyte diameter: 12.5 ± 0.1 μm Co vs. 13.7 ± 0.2 μm Ex, p < 0.05) and corresponding hyperphosphorylation of protein kinase B (Akt). Absence of pathological remodelling was revealed by unchanged pro-fibrotic and pro-apoptotic markers. We found increased maximal force development (12.1 ± 1.0kN/m2 Co vs. 16.7 ± 1.1 kN/m2 Ex, p < 0.05) and improved calcium sensitivity in the cardiomyocytes of exercised animals. Sarcomere protein investigations revealed marked overall and site-specific (Ser22/23, Ser43 and Thr143) hypophosphorylation of troponinI. We found prolonged QT interval (repolarization) and RV effective refracter period along with decreased gene expression of potassium channels. We could not induce any ventricular arrhythmia by programmed stimulation.
Conclusions
Regular swim training induced physiological RV hypertrophy that was associated with functional improvement related to unique hypophosphorilation pattern of troponin I. A balanced exercise program without excessive exercise sessions might not be associated with induction of pathological alterations.
研究项目主要关注运动引起的右心室（RV）的改变，因为运动相关的右心室不成比例的负荷可能导致病理后果，如间质纤维化、心室扩张或促心律失常重构。我们的目的是在大鼠运动诱导的心脏重构模型中，提供由常规训练引起的右心室改变的复杂特征。方法将幼年、成年大鼠分为对照组（Co）和运动组（Ex）。运动后的大鼠每天游泳200分钟，持续12周。在体内进行心脏电生理研究，并对分离的渗透性心室心肌细胞进行体外力测量，分别研究电和功能的改变。进行了分子生物学和组织学研究。结果运动训练与轻度增加的右心室肥大（心肌细胞直径：12.5±0.1 μm Co vs. 13.7±0.2 μm Ex, p < 0.05）和相应的蛋白激酶B （Akt）高磷酸化相关。未改变的促纤维化和促凋亡标志物显示病理重构的缺失。我们发现运动动物心肌细胞的最大力量发展增加（Co为12.1±1.0kN/m2， Ex为16.7±1.1 kN/m2, p < 0.05），钙敏感性提高。肌瘤蛋白研究显示肌钙蛋白的整体和位点特异性（Ser22/23， Ser43和Thr143）低磷酸化。我们发现QT间期延长（复极）和RV有效折射期随钾通道基因表达减少而延长。程序性刺激不能诱发室性心律失常。结论：定期游泳训练诱导的生理性右心室肥大与肌钙蛋白i独特的低磷酸化模式相关的功能改善有关。没有过度运动的平衡运动计划可能与诱导病理改变无关。
{"title":"Long-term exercise training is associated with unique cardiac troponin I phosphorylation pattern and benign myocardial hypertrophy in the right ventricle in an experimental model of exercise-induced myocardial remodelling","authors":"Attila Oláh , Beáta Bódi , Bálint András Barta , Olívia Bottlik , Alex Ali Sayour , Mihály Ruppert , Karolina Katarzyna Kolodziejska , Andrea Kovács , Zoltán V. Varga , Péter Ferdinandy , Oliver Schilling , Zoltán Papp , Béla Merkely , Tamás Radovits","doi":"10.1016/j.yjmcc.2025.08.008","DOIUrl":"10.1016/j.yjmcc.2025.08.008","url":null,"abstract":"<div><h3>Background</h3><div>Research projects have focused on exercise-induced alterations of the right ventricle (RV) of the heart, because the exercise-associated disproportionate load on the RV might lead to pathological consequences, such as interstitial fibrosis, chamber dilation or pro-arrhytmic remodelling. We aimed at providing a complex characterization of RV alterations induced by regular training in a rat model of exercise-induced cardiac remodelling.</div></div><div><h3>Methods</h3><div>Young, adult rats were divided into control (Co) and exercised (Ex) groups. Exercised rats swam 200 min/day for 12 weeks. In vivo cardiac electrophysiological study and in vitro force measurements on isolated permeabilized RV cardiomyocytes were performed to investigate electrical and functional alterations, respectively. Molecular biological and histological investigations were carried out.</div></div><div><h3>Results</h3><div>Exercise training was associated with mild increased RV hypertrophy (cardiomyocyte diameter: 12.5 ± 0.1 μm Co vs. 13.7 ± 0.2 μm Ex, <em>p</em> < 0.05) and corresponding hyperphosphorylation of protein kinase B (Akt). Absence of pathological remodelling was revealed by unchanged pro-fibrotic and pro-apoptotic markers. We found increased maximal force development (12.1 ± 1.0kN/m<sup>2</sup> Co vs. 16.7 ± 1.1 kN/m<sup>2</sup> Ex, <em>p</em> < 0.05) and improved calcium sensitivity in the cardiomyocytes of exercised animals. Sarcomere protein investigations revealed marked overall and site-specific (Ser22/23, Ser43 and Thr143) hypophosphorylation of troponinI. We found prolonged QT interval (repolarization) and RV effective refracter period along with decreased gene expression of potassium channels. We could not induce any ventricular arrhythmia by programmed stimulation.</div></div><div><h3>Conclusions</h3><div>Regular swim training induced physiological RV hypertrophy that was associated with functional improvement related to unique hypophosphorilation pattern of troponin I. A balanced exercise program without excessive exercise sessions might not be associated with induction of pathological alterations.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 81-91"},"PeriodicalIF":4.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892222","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}
Pub Date : 2025-08-17DOI: 10.1016/j.yjmcc.2025.08.004
Shah R. Ali , Ngoc Uyen Nhi Nguyen , Waleed Elhelaly , Ching-Cheng Hsu , Shujuan Li , Ivan Menendez-Montes , Zhaoning Wang , Miao Cui , Abdallah Elnwasany , Feng Xiao , Jisheng Sun , Suwannee Thet , Nicholas T. Lam , Alisson Cardoso , Ana Helena Pereira , Jinhu Wang , Eric N. Olson , Michael T. Kinter , Luke I. Szweda , John Shelton , Hesham A. Sadek
We hypothesized that the microenvironment of the regenerating neonatal mouse heart contains pro-mitotic factors. To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating hearts for differentially expressed secreted proteins. We identified IGFBP3 in this screen as a neonatal injury-associated secreted protein. IGFBP3 belongs to a family of proteins that can stabilize and sequester IGF growth factors, as well as exert IGF-independent functions. In the neonatal heart, IGFBP3 is expressed and secreted predominantly by endothelial cells following injury, notably in the border zone of the infarct. We generated loss-of-function and gain-of-function mouse models to dissect the role of IGFBP3 in myocardial regeneration. Global deletion of Igfbp3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 or a tissue-specific ectopic Igfbp3 mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the murine heart. The temporal and spatial expression of an IGFBP3 protease (PAPPA2) and IGFBP3 in the infarct zone suggests that IGFBP3 proteolysis is coordinated to locally release IGF2, which can activate an Insulin/IGF-based growth pathway to stimulate cardiomyocyte division. Collectively, our work illuminates an endothelial-cardiomyocyte crosstalk involving IGFBP3 that can mediate myocardial regeneration in the neonatal heart.
{"title":"Paracrine IGFBP3 spatially coordinates IGF signaling to induce myocardial regeneration in mice","authors":"Shah R. Ali , Ngoc Uyen Nhi Nguyen , Waleed Elhelaly , Ching-Cheng Hsu , Shujuan Li , Ivan Menendez-Montes , Zhaoning Wang , Miao Cui , Abdallah Elnwasany , Feng Xiao , Jisheng Sun , Suwannee Thet , Nicholas T. Lam , Alisson Cardoso , Ana Helena Pereira , Jinhu Wang , Eric N. Olson , Michael T. Kinter , Luke I. Szweda , John Shelton , Hesham A. Sadek","doi":"10.1016/j.yjmcc.2025.08.004","DOIUrl":"10.1016/j.yjmcc.2025.08.004","url":null,"abstract":"<div><div>We hypothesized that the microenvironment of the regenerating neonatal mouse heart contains pro-mitotic factors. To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating hearts for differentially expressed secreted proteins. We identified IGFBP3 in this screen as a neonatal injury-associated secreted protein. IGFBP3 belongs to a family of proteins that can stabilize and sequester IGF growth factors, as well as exert IGF-independent functions. In the neonatal heart, IGFBP3 is expressed and secreted predominantly by endothelial cells following injury, notably in the border zone of the infarct. We generated loss-of-function and gain-of-function mouse models to dissect the role of IGFBP3 in myocardial regeneration. Global deletion of Igfbp3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 or a tissue-specific ectopic Igfbp3 mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the murine heart. The temporal and spatial expression of an IGFBP3 protease (PAPPA2) and IGFBP3 in the infarct zone suggests that IGFBP3 proteolysis is coordinated to locally release IGF2, which can activate an Insulin/IGF-based growth pathway to stimulate cardiomyocyte division. Collectively, our work illuminates an endothelial-cardiomyocyte crosstalk involving IGFBP3 that can mediate myocardial regeneration in the neonatal heart.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 93-106"},"PeriodicalIF":4.7,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883037","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}
Pub Date : 2025-08-15DOI: 10.1016/j.yjmcc.2025.08.003
Jin Guan, Dominic P. Del Re
The Hippo-YAP pathway is an evolutionarily conserved signaling module that regulates cell survival, proliferation, and differentiation to control organ size. Recent work has demonstrated critical roles for Hippo-YAP signaling in cardiac development and disease, including its ability to modulate both pathological and regenerative responses in the heart. Therefore, targeting the Hippo-YAP pathway for therapeutic benefit has gained attention and holds substantial promise for improving outcomes in patients with heart disease. Importantly, however, much of our understanding of cardiac Hippo-YAP signaling is based on studies in cardiomyocytes, and far less is known in other cell types in the heart. This review will focus primarily on the role of Hippo-YAP signaling in cardiomyocytes, cardiac fibroblasts, and macrophages, and explore how cell type-specific functions can impact heart development, as well as injury responses that can drive divergent outcomes in heart disease.
{"title":"Cell type specificity of Hippo-YAP signaling in cardiac development and disease","authors":"Jin Guan, Dominic P. Del Re","doi":"10.1016/j.yjmcc.2025.08.003","DOIUrl":"10.1016/j.yjmcc.2025.08.003","url":null,"abstract":"<div><div>The Hippo-YAP pathway is an evolutionarily conserved signaling module that regulates cell survival, proliferation, and differentiation to control organ size. Recent work has demonstrated critical roles for Hippo-YAP signaling in cardiac development and disease, including its ability to modulate both pathological and regenerative responses in the heart. Therefore, targeting the Hippo-YAP pathway for therapeutic benefit has gained attention and holds substantial promise for improving outcomes in patients with heart disease. Importantly, however, much of our understanding of cardiac Hippo-YAP signaling is based on studies in cardiomyocytes, and far less is known in other cell types in the heart. This review will focus primarily on the role of Hippo-YAP signaling in cardiomyocytes, cardiac fibroblasts, and macrophages, and explore how cell type-specific functions can impact heart development, as well as injury responses that can drive divergent outcomes in heart disease.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 51-63"},"PeriodicalIF":4.7,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867527","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}
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