Veronika Ramovs,H Sophia Chen,Athina Patra,Rayman Tjokrodirijo,Peter van Veelen,Aat A Mulder,Roman I Koning,Lauran Stöger,Catalina Hubner,Rodrigo Ibañez-Arenas,Bernardo Morales Catalan,Pilar Morandé,Rosario dell'Oro,Cristian Poblete,Andrés Schuster,María Joao Yubero,Francis Palisson,Cristina Has,Monique Jongbloed,Ignacia Fuentes,Christine L Mummery,Karine Raymond
AIMSA striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening deterioration of heart function. KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase. KLHL24mut is thought to represent a gain-of-function mutation, with associated cardiac and skin pathologies arising from the excessive degradation of its target proteins. Although reduced desmin levels in cardiomyocytes (CMs) have already been documented, the potential involvement of additional mechanisms in KLHL24mut -driven heart pathology remains unexplored.METHODS AND RESULTSWe report on two patients with KLHL24mut who recently manifested heart failure. To gain insights into their physiopathology, we integrated clinical data with proteomic analyses of heart tissue as well as human induced pluripotent stem cell (hiPSC) models carrying KLHL24mut. Mass spectrometry analysis of CMs differentiated from patient-derived hiPSCs mirrored the proteomic profile of their corresponding left ventricle tissue samples. KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature. By utilising various hiPSC-derived cardiac models along with flow cytometry, immunofluorescence, and western blot analyses, we confirmed that the excessive proteasomal activity of endogenous KLHL24mut caused a decrease in levels of desmin, synemin and vimentin, IF proteins of CMs and cardiac fibroblasts. Moreover, KLHL24mut led to mitochondrial mislocalization and increased mitophagy, reduced PKA activity, and sarcomere shortening in CMs.CONCLUSIONThe deterioration of heart function in patients with KLHL24mut is driven by excessive proteasome-dependent degradation of multiple IF proteins across various cardiac cell types. Monotypic hiPSC-derived CMs and end-stage patient-derived cardiac explants from patients exhibit similar features, uncovering early pathological mechanisms and identifying a list of potential novel KLHL24mut target proteins. Finally, our findings validate that hiPSC-derived CMs represent a relevant model for future studies.
{"title":"KLHL24 mutation drives intermediate filament degradation, mitochondrial dysfunction and fibrosis in heart failure patients.","authors":"Veronika Ramovs,H Sophia Chen,Athina Patra,Rayman Tjokrodirijo,Peter van Veelen,Aat A Mulder,Roman I Koning,Lauran Stöger,Catalina Hubner,Rodrigo Ibañez-Arenas,Bernardo Morales Catalan,Pilar Morandé,Rosario dell'Oro,Cristian Poblete,Andrés Schuster,María Joao Yubero,Francis Palisson,Cristina Has,Monique Jongbloed,Ignacia Fuentes,Christine L Mummery,Karine Raymond","doi":"10.1093/cvr/cvaf231","DOIUrl":"https://doi.org/10.1093/cvr/cvaf231","url":null,"abstract":"AIMSA striking aspect of epidermolysis bullosa patients with a mutation in KLHL24 (KLHL24mut) is their life-threatening deterioration of heart function. KLHL24 is a component of the ubiquitin-proteasome system and acts as a substrate-specific adaptor protein for E3 ubiquitin ligase. KLHL24mut is thought to represent a gain-of-function mutation, with associated cardiac and skin pathologies arising from the excessive degradation of its target proteins. Although reduced desmin levels in cardiomyocytes (CMs) have already been documented, the potential involvement of additional mechanisms in KLHL24mut -driven heart pathology remains unexplored.METHODS AND RESULTSWe report on two patients with KLHL24mut who recently manifested heart failure. To gain insights into their physiopathology, we integrated clinical data with proteomic analyses of heart tissue as well as human induced pluripotent stem cell (hiPSC) models carrying KLHL24mut. Mass spectrometry analysis of CMs differentiated from patient-derived hiPSCs mirrored the proteomic profile of their corresponding left ventricle tissue samples. KLHL24mut resulted in a reduction of several intermediate filaments (IF), mitochondrial and muscle fibre proteins as well as the emergence of an early fibrotic signature. By utilising various hiPSC-derived cardiac models along with flow cytometry, immunofluorescence, and western blot analyses, we confirmed that the excessive proteasomal activity of endogenous KLHL24mut caused a decrease in levels of desmin, synemin and vimentin, IF proteins of CMs and cardiac fibroblasts. Moreover, KLHL24mut led to mitochondrial mislocalization and increased mitophagy, reduced PKA activity, and sarcomere shortening in CMs.CONCLUSIONThe deterioration of heart function in patients with KLHL24mut is driven by excessive proteasome-dependent degradation of multiple IF proteins across various cardiac cell types. Monotypic hiPSC-derived CMs and end-stage patient-derived cardiac explants from patients exhibit similar features, uncovering early pathological mechanisms and identifying a list of potential novel KLHL24mut target proteins. Finally, our findings validate that hiPSC-derived CMs represent a relevant model for future studies.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"37 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aims Pericardial drainage fluid (PCF) offers a non-invasive and direct window to detect surgery-induced microenvironmental changes implicated in postoperative atrial fibrillation (POAF) onset. We hypothesized that cardiac surgery elicits release of extracellular vesicles (EVs) in PCF, serving as a conduit transmitting proarrhythmic and profibrotic miRNAs and contributing to atrial remodeling and POAF. Methods and Results We investigated the role of PCF-EVs derived miRNAs in POAF in prospective, multicenter discovery and validation cohorts and spontaneous POAF (sPOAF) mouse model. PCF-EVs from POAF patients elicited marked atrial collagen deposition and a higher incidence of sPOAF in mice compared to non-POAF controls. Strikingly, EV blockage in sPOAF mouse model provided complete sPOAF protection (50% vs 0). A distinct profibrotic miRNA signature was identified in PCF-EVs from POAF patients. Among these, miR-4324, a previously unreported murine miRNA, emerged as a potent inducer of AF, triggered sPOAF in 83% of treated mice, and demonstrating excellent predictive accuracy (AUC=0.921) in a clinical validation cohort. Visualization of miR-4324 trajectory using miRNAscope demonstrated that miR-4324-containing EVs, originating from the surgically-damaged left ventricle, rapidly transported to thin-walled atria via PCF, where miR-4324 activated TGF-β1/Smad3 signaling by targeting SKP1. This facilitated collagen deposition and a proarrhythmic atrial substrate. In contrast, miR-4324 inhibition blocked these effects. Conclusion These findings uncover a previously unrecognized high-speed PCF-EVs pathway that propagates proarrhythmic miR-4324 signals from surgical sites to reshape the atrial microenvironment into a proarrhythmic milieu via SKP1-TGF-β1/Smad3 axis. PCF, typically discarded, could be repurposed for POAF prophylaxis.
{"title":"miR-4324-containing extracellular vesicles released in pericardial drainage fluid facilitate postoperative atrial fibrillation","authors":"Yisi Liu, Pan Shen, Gaofu Li, Taiwei Wang, Chaoyue Gao, Yue Sun, Yongqiang Zhou, Lin Luo, Jiamiao Li, Xinyu Wang, Jiangang Wang, Chen Bai, Shu Ding, Ying Wu, Yue Gao, Wei Zhou","doi":"10.1093/cvr/cvaf239","DOIUrl":"https://doi.org/10.1093/cvr/cvaf239","url":null,"abstract":"Aims Pericardial drainage fluid (PCF) offers a non-invasive and direct window to detect surgery-induced microenvironmental changes implicated in postoperative atrial fibrillation (POAF) onset. We hypothesized that cardiac surgery elicits release of extracellular vesicles (EVs) in PCF, serving as a conduit transmitting proarrhythmic and profibrotic miRNAs and contributing to atrial remodeling and POAF. Methods and Results We investigated the role of PCF-EVs derived miRNAs in POAF in prospective, multicenter discovery and validation cohorts and spontaneous POAF (sPOAF) mouse model. PCF-EVs from POAF patients elicited marked atrial collagen deposition and a higher incidence of sPOAF in mice compared to non-POAF controls. Strikingly, EV blockage in sPOAF mouse model provided complete sPOAF protection (50% vs 0). A distinct profibrotic miRNA signature was identified in PCF-EVs from POAF patients. Among these, miR-4324, a previously unreported murine miRNA, emerged as a potent inducer of AF, triggered sPOAF in 83% of treated mice, and demonstrating excellent predictive accuracy (AUC=0.921) in a clinical validation cohort. Visualization of miR-4324 trajectory using miRNAscope demonstrated that miR-4324-containing EVs, originating from the surgically-damaged left ventricle, rapidly transported to thin-walled atria via PCF, where miR-4324 activated TGF-β1/Smad3 signaling by targeting SKP1. This facilitated collagen deposition and a proarrhythmic atrial substrate. In contrast, miR-4324 inhibition blocked these effects. Conclusion These findings uncover a previously unrecognized high-speed PCF-EVs pathway that propagates proarrhythmic miR-4324 signals from surgical sites to reshape the atrial microenvironment into a proarrhythmic milieu via SKP1-TGF-β1/Smad3 axis. PCF, typically discarded, could be repurposed for POAF prophylaxis.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"1 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Graft versus atheroma in a battle of host dominion.","authors":"Anton Gisterå,Hannes Lindahl","doi":"10.1093/cvr/cvaf266","DOIUrl":"https://doi.org/10.1093/cvr/cvaf266","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"128 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Netra Nambiar Veetil,Tara Gransar,Shao-Fei Liu,Ahed Almalla,Marieluise Kirchner,Robyn Brackin-Helmers,Felix Hennig,Ruhi Yeter,Marie Weinhart,Philipp Mertins,Volkmar Falk,Robert Szulcek,Mariya M Kucherenko,Wolfgang M Kuebler,Christoph Knosalla
AIMSHyperplasia of pulmonary arterial smooth muscle cells (SMCs) contributes to the progression of pulmonary hypertension (PH), yet the underlying pathomechanism of this process in PH secondary to left heart disease (PH-LHD) is poorly understood. We aimed to investigate the role of the endothelial extracellular matrix (ECM), specifically the pulmonary arterial basement membrane (BM), in influencing SMC proliferation and phenotypic changes in PH-LHD.METHODS AND RESULTSSMC hyperplasia and endothelial ECM remodelling were characterized histologically on human pulmonary arterial samples, and by mass spectrometry, and atomic force microscopy on decellularized ECM (dECM) produced in vitro by endothelial cells isolated from pulmonary arteries (PA) of LHD patients without pulmonary hypertension (LHD w/o PH), PH-LHD patients, or healthy-heart controls. Proliferation and migration rates of SMC cultured on endothelial dECM were assessed by Ki67 immunostaining and by wound-healing assay, respectively. The role of mechanosensitive YAP1 in SMC hyperplasia was addressed in human cells and in an aortic-banding rat model of PH-LHD by analysing YAP1 activation and the effect of YAP1 inhibition. PA of LHD w/o PH and PH-LHD patients showed extensive remodelling of the BM. This was confirmed in vitro as altered composition and stiffening of dECM generated by respective patient endothelial cells. ECM remodelling was associated with SMC accumulation in the pulmonary arterial intima in patient samples and promoted SMC migration and proliferation in vitro. Conversely, dECM generated by healthy human endothelial cells reduced the hypermigration and hyperproliferation of SMC from LHD w/o PH and PH-LHD patients. Remodelling of the endothelial ECM in LHD w/o PH and PH-LHD patients also activated YAP1 in SMC, inhibition of which reduced SMC migration and proliferation in vitro. These findings were reproduced in vivo in a rat model of PH-LHD induced by aortic-banding.CONCLUSIONHere, we report endothelial ECM remodelling as a key mechanism driving SMC hyperplasia in PH-LHD. Notably, endothelial ECM remodelling is evident in both patients with LHD w/o PH and those with PH-LHD, raising the possibility that it may reflect an early event in LHD-induced pulmonary vascular remodelling. This ECM remodelling is associated with YAP1 in adjacent SMC, promoting their migration and proliferation and contributing to SMC hyperplasia. Consequently, targeting ECM remodelling and YAP1 activation may offer promising therapeutic strategies for preventing of PA remodelling in PH-LHD.
{"title":"Remodelling of the endothelial extracellular matrix promotes smooth muscle cell hyperplasia in pulmonary hypertension due to left heart disease.","authors":"Netra Nambiar Veetil,Tara Gransar,Shao-Fei Liu,Ahed Almalla,Marieluise Kirchner,Robyn Brackin-Helmers,Felix Hennig,Ruhi Yeter,Marie Weinhart,Philipp Mertins,Volkmar Falk,Robert Szulcek,Mariya M Kucherenko,Wolfgang M Kuebler,Christoph Knosalla","doi":"10.1093/cvr/cvaf238","DOIUrl":"https://doi.org/10.1093/cvr/cvaf238","url":null,"abstract":"AIMSHyperplasia of pulmonary arterial smooth muscle cells (SMCs) contributes to the progression of pulmonary hypertension (PH), yet the underlying pathomechanism of this process in PH secondary to left heart disease (PH-LHD) is poorly understood. We aimed to investigate the role of the endothelial extracellular matrix (ECM), specifically the pulmonary arterial basement membrane (BM), in influencing SMC proliferation and phenotypic changes in PH-LHD.METHODS AND RESULTSSMC hyperplasia and endothelial ECM remodelling were characterized histologically on human pulmonary arterial samples, and by mass spectrometry, and atomic force microscopy on decellularized ECM (dECM) produced in vitro by endothelial cells isolated from pulmonary arteries (PA) of LHD patients without pulmonary hypertension (LHD w/o PH), PH-LHD patients, or healthy-heart controls. Proliferation and migration rates of SMC cultured on endothelial dECM were assessed by Ki67 immunostaining and by wound-healing assay, respectively. The role of mechanosensitive YAP1 in SMC hyperplasia was addressed in human cells and in an aortic-banding rat model of PH-LHD by analysing YAP1 activation and the effect of YAP1 inhibition. PA of LHD w/o PH and PH-LHD patients showed extensive remodelling of the BM. This was confirmed in vitro as altered composition and stiffening of dECM generated by respective patient endothelial cells. ECM remodelling was associated with SMC accumulation in the pulmonary arterial intima in patient samples and promoted SMC migration and proliferation in vitro. Conversely, dECM generated by healthy human endothelial cells reduced the hypermigration and hyperproliferation of SMC from LHD w/o PH and PH-LHD patients. Remodelling of the endothelial ECM in LHD w/o PH and PH-LHD patients also activated YAP1 in SMC, inhibition of which reduced SMC migration and proliferation in vitro. These findings were reproduced in vivo in a rat model of PH-LHD induced by aortic-banding.CONCLUSIONHere, we report endothelial ECM remodelling as a key mechanism driving SMC hyperplasia in PH-LHD. Notably, endothelial ECM remodelling is evident in both patients with LHD w/o PH and those with PH-LHD, raising the possibility that it may reflect an early event in LHD-induced pulmonary vascular remodelling. This ECM remodelling is associated with YAP1 in adjacent SMC, promoting their migration and proliferation and contributing to SMC hyperplasia. Consequently, targeting ECM remodelling and YAP1 activation may offer promising therapeutic strategies for preventing of PA remodelling in PH-LHD.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"198200 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lu Wang,Zeyu Chen,Aiden Tang,Zhe Yu,Bin Zhou,Sylvia M Evans,Ju Chen,Paul Grossfeld
AIMSThinning of the compact myocardium is a major contributor to adverse outcomes in ventricular non-compaction, the third most common form of cardiomyopathy. Endothelial-specific deletion of Ets1, a gene associated with Jacobsen syndrome, causes ventricular non-compaction with reduced compact myocardium. However, the mechanisms by which pathological cardiac endothelium impairs compact myocardium growth remain poorly understood.METHODS AND RESULTSTo uncover the mechanisms underlying compact myocardium thinning and identify therapeutic endothelial-secreted factors, we performed single-cell RNA sequencing. Aberrant cardiomyocyte and endothelial cell states were observed in non-compacted ventricles. Conditional deletion of Ets1 in either the endocardium or coronary endothelium impaired compact myocardial growth. In endocardium, Ets1 deficiency suppressed Notch1 signaling by upregulating Dlk1 and downregulating Dll4, both direct Ets1 targets. In coronary endothelium, Ets1 deficiency reduced the expression of its direct targets Hmcn1, Slit2, and Col18a1, three extracellular matrix (ECM) components that promote compact myocardial proliferation. Notably, treatment with these ECM proteins or the Notch1 effector Nrg1 restored the impaired compact myocardial proliferation.CONCLUSIONSThese findings highlight Ets1-regulated endothelial-secreted factors as essential for compact myocardium development and suggest novel therapeutic targets for ventricular non-compaction.
{"title":"Ets1-regulated endothelial-secreted factors promote compact myocardial growth and contribute to the pathogenesis of ventricular non-compaction.","authors":"Lu Wang,Zeyu Chen,Aiden Tang,Zhe Yu,Bin Zhou,Sylvia M Evans,Ju Chen,Paul Grossfeld","doi":"10.1093/cvr/cvaf264","DOIUrl":"https://doi.org/10.1093/cvr/cvaf264","url":null,"abstract":"AIMSThinning of the compact myocardium is a major contributor to adverse outcomes in ventricular non-compaction, the third most common form of cardiomyopathy. Endothelial-specific deletion of Ets1, a gene associated with Jacobsen syndrome, causes ventricular non-compaction with reduced compact myocardium. However, the mechanisms by which pathological cardiac endothelium impairs compact myocardium growth remain poorly understood.METHODS AND RESULTSTo uncover the mechanisms underlying compact myocardium thinning and identify therapeutic endothelial-secreted factors, we performed single-cell RNA sequencing. Aberrant cardiomyocyte and endothelial cell states were observed in non-compacted ventricles. Conditional deletion of Ets1 in either the endocardium or coronary endothelium impaired compact myocardial growth. In endocardium, Ets1 deficiency suppressed Notch1 signaling by upregulating Dlk1 and downregulating Dll4, both direct Ets1 targets. In coronary endothelium, Ets1 deficiency reduced the expression of its direct targets Hmcn1, Slit2, and Col18a1, three extracellular matrix (ECM) components that promote compact myocardial proliferation. Notably, treatment with these ECM proteins or the Notch1 effector Nrg1 restored the impaired compact myocardial proliferation.CONCLUSIONSThese findings highlight Ets1-regulated endothelial-secreted factors as essential for compact myocardium development and suggest novel therapeutic targets for ventricular non-compaction.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"39 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tao Wang, Xin-Zhe Chen, Hong-Fei Xu, Jin-Xi Wang, Jia-Hao Ren, Lu-Yu Zhou, Cui-Yun Liu, Xin-Min Li, Yu-Qin Wang, Su-Min Yang, Mei-Hua Zhang, Yu-Hui Zhang, Kai-Yang Lin, Jin-Wei Tian, Kun Wang
Aims The adult mammalian heart possesses severely limited regenerative capacity. Cardiomyocyte loss during cardiac injury, coupled with this restricted regenerative potential, represents a fundamental cause of heart failure and associated mortality. While PIWI-interacting RNAs (piRNAs) are abundantly expressed in cardiac tissue, their functional roles and molecular mechanisms in cardiomyocyte proliferation and heart regeneration remain largely undefined. In this study, we systematically investigated piRNA-mediated regulation of cardiomyocyte proliferation and cardiac repair processes. Methods and results Using piRNA microarray analysis, we identified a novel piRNA regulating cardiomyocyte proliferation, which we named MCPPIR (myocardial cell proliferation-promoting piRNA). Genetic ablation of MCPPIR in mice attenuated cardiomyocyte proliferation and impaired neonatal heart regeneration, while MCPPIR overexpression enhanced proliferation, reduced fibrosis, and improved cardiac function post-myocardial infarction. Through mass spectrometry and RNA pull-down assays, we identified HNRNPH1 as a key binding partner. Cardiomyocyte-specific HNRNPH1 knockout mice displayed enhanced proliferative capacity. o8G-RNA immunoprecipitation sequencing revealed POC1B as the downstream target, with MCPPIR preventing HNRNPH1-mediated repression of POC1B mRNA. Mechanistically, the MCPPIR-HNRNPH1-POC1B axis maintains centrosome integrity, thereby promoting cardiomyocyte proliferation and cardiac repair. Conclusion Our study reveals a previously unrecognized role of piRNAs in regulating cardiomyocyte proliferation. We demonstrate that MCPPIR drives cardiomyocyte proliferation and promotes cardiac repair in adult hearts through o8G-mediated post-transcriptional regulation of POC1B mRNA. These findings establish the MCPPIR/POC1B axis as a promising therapeutic target for ischemic heart diseases, and a novel paradigm for developing regenerative therapies against myocardial injury.
{"title":"MCPPIR promotes cardiomyocyte proliferation and cardiac repair via o8G oxidation of POC1B mRNA","authors":"Tao Wang, Xin-Zhe Chen, Hong-Fei Xu, Jin-Xi Wang, Jia-Hao Ren, Lu-Yu Zhou, Cui-Yun Liu, Xin-Min Li, Yu-Qin Wang, Su-Min Yang, Mei-Hua Zhang, Yu-Hui Zhang, Kai-Yang Lin, Jin-Wei Tian, Kun Wang","doi":"10.1093/cvr/cvaf265","DOIUrl":"https://doi.org/10.1093/cvr/cvaf265","url":null,"abstract":"Aims The adult mammalian heart possesses severely limited regenerative capacity. Cardiomyocyte loss during cardiac injury, coupled with this restricted regenerative potential, represents a fundamental cause of heart failure and associated mortality. While PIWI-interacting RNAs (piRNAs) are abundantly expressed in cardiac tissue, their functional roles and molecular mechanisms in cardiomyocyte proliferation and heart regeneration remain largely undefined. In this study, we systematically investigated piRNA-mediated regulation of cardiomyocyte proliferation and cardiac repair processes. Methods and results Using piRNA microarray analysis, we identified a novel piRNA regulating cardiomyocyte proliferation, which we named MCPPIR (myocardial cell proliferation-promoting piRNA). Genetic ablation of MCPPIR in mice attenuated cardiomyocyte proliferation and impaired neonatal heart regeneration, while MCPPIR overexpression enhanced proliferation, reduced fibrosis, and improved cardiac function post-myocardial infarction. Through mass spectrometry and RNA pull-down assays, we identified HNRNPH1 as a key binding partner. Cardiomyocyte-specific HNRNPH1 knockout mice displayed enhanced proliferative capacity. o8G-RNA immunoprecipitation sequencing revealed POC1B as the downstream target, with MCPPIR preventing HNRNPH1-mediated repression of POC1B mRNA. Mechanistically, the MCPPIR-HNRNPH1-POC1B axis maintains centrosome integrity, thereby promoting cardiomyocyte proliferation and cardiac repair. Conclusion Our study reveals a previously unrecognized role of piRNAs in regulating cardiomyocyte proliferation. We demonstrate that MCPPIR drives cardiomyocyte proliferation and promotes cardiac repair in adult hearts through o8G-mediated post-transcriptional regulation of POC1B mRNA. These findings establish the MCPPIR/POC1B axis as a promising therapeutic target for ischemic heart diseases, and a novel paradigm for developing regenerative therapies against myocardial injury.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"72 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Florian Bruns, Anke C Fender, Theresa Poppenborg, Samuel C Dudley, Dobromir Dobrev
Type 2 diabetes (T2D) is an established risk factor for multiple cardiovascular diseases including atrial fibrillation (AF). The causal relationship between type 1 diabetes (T1D) and AF is poorly defined. T1D and AF share many underlying risk factors, but how T1D may promote AF independently of obesity and other features typical of T2D is not known. Here we critically review the quality of the available clinical evidence specifically linking AF with the distinct characteristics of T1D and evaluate the mechanistic insights from preclinical models. We provide a conceptual overview of candidate contributing players and highlight important gaps in knowledge, unmet clinical needs, and potential therapeutic perspectives.
{"title":"Type 1 diabetes mellitus and atrial fibrillation – clinical relationships, mechanistic insights and therapeutic implications","authors":"Florian Bruns, Anke C Fender, Theresa Poppenborg, Samuel C Dudley, Dobromir Dobrev","doi":"10.1093/cvr/cvaf252","DOIUrl":"https://doi.org/10.1093/cvr/cvaf252","url":null,"abstract":"Type 2 diabetes (T2D) is an established risk factor for multiple cardiovascular diseases including atrial fibrillation (AF). The causal relationship between type 1 diabetes (T1D) and AF is poorly defined. T1D and AF share many underlying risk factors, but how T1D may promote AF independently of obesity and other features typical of T2D is not known. Here we critically review the quality of the available clinical evidence specifically linking AF with the distinct characteristics of T1D and evaluate the mechanistic insights from preclinical models. We provide a conceptual overview of candidate contributing players and highlight important gaps in knowledge, unmet clinical needs, and potential therapeutic perspectives.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"119 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aims Alternative mRNA splicing is a significant part of transcriptome reprogramming during the pathological manifestation of heart diseases. Earlier studies have identified a muscle-specific isoform of RBFox1 (RNA binding fox-1 homolog 1) to be a key RNA splicing regulator in pressure overload induced heart failure. However, the physiological impact of RBFox1 in myocardial infarction (MI), and the downstream mRNA alternative splicing events during MI induced cardiac remodelling remains unknown. Methods and results Here we found RBFox1 expression was significantly decreased in Sprague-Dawley rat hearts post MI. Restoring the expression of RBFox1 prevented cardiac remodelling and dysfunction post MI characterized by improved cardiac function, reduced hypertrophy and fibrosis, associated with attenuated induction of cardiac stress marker genes. In cultured cardiomyocytes, expression of RBFox1 was sufficient to prevent hypoxia induced cell death measured by TUNEL staining and cleaved caspase 3, while inactivation of RBFox1 aggravated cardiac cell death. Mechanistically, we identified RBFox1 expression affected a broad spectrum of gene expression in post-MI hearts. In addition, a hypoxia-sensitive alternative splicing variant of Mbnl1 (Muscleblind-like 1) mRNA was identified to be regulated by RBFox1, resulting in the expression of a cell death related Mbnl1 isoform with 12 amino-acid deletion at the C-terminus (Mbnl1-ΔExon7). Strikingly, the selective inhibition of Mbnl1 Exon7 inclusion using anti-sense oligo protected the heart from myocardial infarction induced injury in vivo. Conclusion In summary, we have established a cardio-protective role of RBFox1 in myocardial infarction induced cardiac remodelling and dysfunction. Restoration of RBFox1 expression, and targeted modulation of its downstream alternative splicing target Mbnl1, is a potential therapeutic approach for cardiac dysfunction and remodelling in MI injured heart.
{"title":"Cardioprotective role of RBFox1 in myocardial infarction-induced heart failure","authors":"Mengying He, Woan Ting Tay, Ningjing Song, Tian Liu, Shuxun (Vincent) Ren, Cansheng Zhu, Nkechi Onubogu, Ozgu Biler, Jia En Tan, Caitlin Keezer, Xingyu He, Anthony Pham, Shuyuan Sheng, Hao Ding, Junxin Lin, Lingjun Wang, Yigang Wang, Xinyang Hu, Yibin Wang, Chen Gao","doi":"10.1093/cvr/cvaf206","DOIUrl":"https://doi.org/10.1093/cvr/cvaf206","url":null,"abstract":"Aims Alternative mRNA splicing is a significant part of transcriptome reprogramming during the pathological manifestation of heart diseases. Earlier studies have identified a muscle-specific isoform of RBFox1 (RNA binding fox-1 homolog 1) to be a key RNA splicing regulator in pressure overload induced heart failure. However, the physiological impact of RBFox1 in myocardial infarction (MI), and the downstream mRNA alternative splicing events during MI induced cardiac remodelling remains unknown. Methods and results Here we found RBFox1 expression was significantly decreased in Sprague-Dawley rat hearts post MI. Restoring the expression of RBFox1 prevented cardiac remodelling and dysfunction post MI characterized by improved cardiac function, reduced hypertrophy and fibrosis, associated with attenuated induction of cardiac stress marker genes. In cultured cardiomyocytes, expression of RBFox1 was sufficient to prevent hypoxia induced cell death measured by TUNEL staining and cleaved caspase 3, while inactivation of RBFox1 aggravated cardiac cell death. Mechanistically, we identified RBFox1 expression affected a broad spectrum of gene expression in post-MI hearts. In addition, a hypoxia-sensitive alternative splicing variant of Mbnl1 (Muscleblind-like 1) mRNA was identified to be regulated by RBFox1, resulting in the expression of a cell death related Mbnl1 isoform with 12 amino-acid deletion at the C-terminus (Mbnl1-ΔExon7). Strikingly, the selective inhibition of Mbnl1 Exon7 inclusion using anti-sense oligo protected the heart from myocardial infarction induced injury in vivo. Conclusion In summary, we have established a cardio-protective role of RBFox1 in myocardial infarction induced cardiac remodelling and dysfunction. Restoration of RBFox1 expression, and targeted modulation of its downstream alternative splicing target Mbnl1, is a potential therapeutic approach for cardiac dysfunction and remodelling in MI injured heart.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"2 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Changing the channel: USP10 unlocks a chaperone-mediated autophagy pathway for NaV1.5.","authors":"Phil Barnett,Carol Ann Remme","doi":"10.1093/cvr/cvaf240","DOIUrl":"https://doi.org/10.1093/cvr/cvaf240","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"147 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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