Pub Date : 2025-10-01Epub Date: 2025-08-09DOI: 10.1016/j.yjmcc.2025.08.001
Yanyan Zhou , Teng Yang , Suyang Zheng , Tiantian Gan , Fan Yu , Guizhu Liu , Tingting Zhou
Diabetic cardiomyopathy (DCM) is a serious complication associated with diabetes that characterized by the cardiac dysfunction and myocardial fibrosis. Recent studies emphasize the significance of the gut-heart axis in the development of DCM. This current study investigates the effect of systematic-genetical TRPV4 knockout on DCM progression and explores the underlying mechanisms involving gut microbiota modulation and intestinal barrier integrity. The removal of TRPV4 in mice with DCM markedly enhances cardiac performance, decreases myocardial fibrosis, and modifies the composition of gut microbiota, resulting in a significant rise in Bacteroides acidifaciens (BA). TRPV4 deletion also upregulates tight junction proteins (Zonula occludens-1 (ZO-1), Occludin, and Claudin-1) and reduces serum lipopolysaccharide levels. Furthermore, fecal microbiota transplantation from the DCM donors with TRPV4 knockout to the DCM receptors replicates these cardioprotective effects in mice, and administration of BA improves cardiac function and relieves the fibrosis. Our study suggests that the cardioprotective effects of the genetic deletion of TRPV4 are related to changes in the gut microbiome, highlighting the importance of the connection between TRPV4, the gut, and the heart in the disease mechanism and potential therapeutic strategies for DCM.
{"title":"Genetical TRPV4 deletion-associated gut microbiota alleviates cardiac dysfunction in mice with diabetic cardiomyopathy","authors":"Yanyan Zhou , Teng Yang , Suyang Zheng , Tiantian Gan , Fan Yu , Guizhu Liu , Tingting Zhou","doi":"10.1016/j.yjmcc.2025.08.001","DOIUrl":"10.1016/j.yjmcc.2025.08.001","url":null,"abstract":"<div><div>Diabetic cardiomyopathy (DCM) is a serious complication associated with diabetes that characterized by the cardiac dysfunction and myocardial fibrosis. Recent studies emphasize the significance of the gut-heart axis in the development of DCM. This current study investigates the effect of systematic-genetical TRPV4 knockout on DCM progression and explores the underlying mechanisms involving gut microbiota modulation and intestinal barrier integrity. The removal of TRPV4 in mice with DCM markedly enhances cardiac performance, decreases myocardial fibrosis, and modifies the composition of gut microbiota, resulting in a significant rise in <em>Bacteroides acidifaciens</em> (BA). TRPV4 deletion also upregulates tight junction proteins (Zonula occludens-1 (ZO-1), Occludin, and Claudin-1) and reduces serum lipopolysaccharide levels. Furthermore, fecal microbiota transplantation from the DCM donors with TRPV4 knockout to the DCM receptors replicates these cardioprotective effects in mice, and administration of BA improves cardiac function and relieves the fibrosis. Our study suggests that the cardioprotective effects of the genetic deletion of TRPV4 are related to changes in the gut microbiome, highlighting the importance of the connection between TRPV4, the gut, and the heart in the disease mechanism and potential therapeutic strategies for DCM.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 37-50"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821605","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 : 2025-09-01Epub Date: 2025-07-10DOI: 10.1016/j.yjmcc.2025.07.007
Girish C. Melkani
Circadian rhythm is critical in maintaining metabolic homeostasis, including cardiac health, with disruptions often leading to adverse cardiac outcomes. Time-restricted feeding/eating (TRF/TRE) is a dietary approach that limits food intake to specific hours during an organism's active phase, daytime for diurnal animals and nighttime for nocturnal ones. This strategy has shown promise in realigning circadian rhythms and reducing the negative effects of circadian disruption on heart function. This review examines the intricate relationship between circadian rhythms and cardiac health, highlighting the molecular mechanisms governed by central and peripheral clocks. We discuss how circadian misalignment contributes to cardiovascular disease and explore how TRF/TRE can restore circadian synchronization, particularly in the context of lipid metabolism, gene expression, and other physiological processes essential for heart function. The review also examines the impact of TRF/TRE on cardiac renovation, particularly under conditions of circadian disruption associated with cardiovascular and cardiometabolic disorders. We further explore potential molecular mechanisms, including the modulation of clock genes and lipid metabolic pathways, such as diacylglycerol O-acyltransferase 2 (DGAT2), that underpin the cardioprotective effects of TRF. By consolidating findings from genetic and translational animal models and human studies, we underscore the promise of TRF/TRE in improving cardiac outcomes and propose areas for future research. The potential of TRF/TRE as a therapeutic intervention for cardiovascular disease warrants further investigation, particularly in understanding its long-term effects on cardiac health and its integration into clinical practice.
{"title":"Time-restricted feeding mediated synchronization of circadian rhythms to sustain cardiovascular health","authors":"Girish C. Melkani","doi":"10.1016/j.yjmcc.2025.07.007","DOIUrl":"10.1016/j.yjmcc.2025.07.007","url":null,"abstract":"<div><div>Circadian rhythm is critical in maintaining metabolic homeostasis, including cardiac health, with disruptions often leading to adverse cardiac outcomes. Time-restricted feeding/eating (TRF/TRE) is a dietary approach that limits food intake to specific hours during an organism's active phase, daytime for diurnal animals and nighttime for nocturnal ones. This strategy has shown promise in realigning circadian rhythms and reducing the negative effects of circadian disruption on heart function. This review examines the intricate relationship between circadian rhythms and cardiac health, highlighting the molecular mechanisms governed by central and peripheral clocks. We discuss how circadian misalignment contributes to cardiovascular disease and explore how TRF/TRE can restore circadian synchronization, particularly in the context of lipid metabolism, gene expression, and other physiological processes essential for heart function. The review also examines the impact of TRF/TRE on cardiac renovation, particularly under conditions of circadian disruption associated with cardiovascular and cardiometabolic disorders. We further explore potential molecular mechanisms, including the modulation of clock genes and lipid metabolic pathways, such as diacylglycerol O-acyltransferase 2 (DGAT2), that underpin the cardioprotective effects of TRF. By consolidating findings from genetic and translational animal models and human studies, we underscore the promise of TRF/TRE in improving cardiac outcomes and propose areas for future research. The potential of TRF/TRE as a therapeutic intervention for cardiovascular disease warrants further investigation, particularly in understanding its long-term effects on cardiac health and its integration into clinical practice.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 1-10"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614378","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 : 2025-09-01Epub Date: 2025-07-11DOI: 10.1016/j.yjmcc.2025.07.009
Chenying Xiang , Ning Liu , Shijie Sun , Haorui Liu , Yifan Xie , Jie Feng , Miaoqing Hu , Yu Nie , Lina Bai
Matrix metalloproteinase 9 (MMP9) is known to modulate cardiac remodeling after myocardial infarction, but its role in cardiomyocyte proliferation remains unclear. Here, we showed that MMP9 deficiency enhanced neonatal cardiomyocyte proliferation and mononucleation following apical resection. Integrated transcriptomic and proteomic analyses revealed that MMP9 knockout induces a metabolic shift from oxidative phosphorylation to glycolysis in injured neonatal hearts, coinciding with upregulation of acyl-CoA thioesterase 1 (ACOT1). ACOT1 overexpression enhanced glycolysis and proliferation in primary rat cardiomyocytes, whereas 2-Deoxy-D-glucose inhibition blocked this effect. Collectively, our findings demonstrate that MMP9 deficiency drives a metabolic shift from oxidative phosphorylation to glycolysis via ACOT1 upregulation, thereby promoting cardiomyocyte proliferation.
{"title":"Matrix metalloproteinase 9 deficiency promotes endogenous cardiomyocyte proliferation","authors":"Chenying Xiang , Ning Liu , Shijie Sun , Haorui Liu , Yifan Xie , Jie Feng , Miaoqing Hu , Yu Nie , Lina Bai","doi":"10.1016/j.yjmcc.2025.07.009","DOIUrl":"10.1016/j.yjmcc.2025.07.009","url":null,"abstract":"<div><div>Matrix metalloproteinase 9 (MMP9) is known to modulate cardiac remodeling after myocardial infarction, but its role in cardiomyocyte proliferation remains unclear. Here, we showed that MMP9 deficiency enhanced neonatal cardiomyocyte proliferation and mononucleation following apical resection. Integrated transcriptomic and proteomic analyses revealed that MMP9 knockout induces a metabolic shift from oxidative phosphorylation to glycolysis in injured neonatal hearts, coinciding with upregulation of acyl-CoA thioesterase 1 (ACOT1). ACOT1 overexpression enhanced glycolysis and proliferation in primary rat cardiomyocytes, whereas 2-Deoxy-D-glucose inhibition blocked this effect. Collectively, our findings demonstrate that MMP9 deficiency drives a metabolic shift from oxidative phosphorylation to glycolysis via ACOT1 upregulation, thereby promoting cardiomyocyte proliferation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 70-75"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626572","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 : 2025-09-01Epub Date: 2025-07-05DOI: 10.1016/j.yjmcc.2025.06.013
David Chen , Andrew Sindone , Michael L.H. Huang , Karlheinz Peter , Alicia J. Jenkins
Diabetes mellitus is associated with significant morbidity and premature mortality for which heart failure (HF) is a major cause. HF may be due to ischaemia, hypertension, valvular disease, uraemia, or a specific diabetic cardiomyopathy, and multiple causes may co-exist. A recent systematic review suggests that >40 % of people with type 2 diabetes have diastolic dysfunction without a reduction of cardiac systolic function. In people with type 1 diabetes without known cardiovascular disease, 16 % had systolic or diastolic dysfunction. Early diabetic cardiomyopathy is asymptomatic and can progress to symptomatic HF via increasing cardiomyocyte hypertrophy and death as well as cardiac fibrosis. The 5-year mortality rate for HF is similar or worse than many common cancers. There have been significant recent advances in HF treatment including sodium-glucose co-transport 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi), and promising therapies such as finerenone and glucagon-like peptide-1 receptor agonists (GLP-1RA). SGLT2i, finerenone, and GLP-1RA may also have a role in HF prevention in asymptomatic diabetic cardiomyopathy. While there is currently no specific treatment for diabetic cardiomyopathy that goes beyond general HF treatment, there is promising research into innovative technologies such as gene and stem cell therapies. Also, digital technologies will likely have an increasing role in diabetic cardiomyopathy treatment. Herein we review the pathophysiology, diagnosis, and treatment of diabetic cardiomyopathy, with a focus on existing, emerging, and potentially promising novel therapies. We provide practical tables that summarise treatments at each stage as well as important practice points for commonly prescribed drugs.
{"title":"Diabetic cardiomyopathy: insights into pathophysiology, diagnosis and clinical management","authors":"David Chen , Andrew Sindone , Michael L.H. Huang , Karlheinz Peter , Alicia J. Jenkins","doi":"10.1016/j.yjmcc.2025.06.013","DOIUrl":"10.1016/j.yjmcc.2025.06.013","url":null,"abstract":"<div><div>Diabetes mellitus is associated with significant morbidity and premature mortality for which heart failure (HF) is a major cause. HF may be due to ischaemia, hypertension, valvular disease, uraemia, or a specific diabetic cardiomyopathy, and multiple causes may co-exist. A recent systematic review suggests that >40 % of people with type 2 diabetes have diastolic dysfunction without a reduction of cardiac systolic function. In people with type 1 diabetes without known cardiovascular disease, 16 % had systolic or diastolic dysfunction. Early diabetic cardiomyopathy is asymptomatic and can progress to symptomatic HF via increasing cardiomyocyte hypertrophy and death as well as cardiac fibrosis. The 5-year mortality rate for HF is similar or worse than many common cancers. There have been significant recent advances in HF treatment including sodium-glucose co-transport 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi), and promising therapies such as finerenone and glucagon-like peptide-1 receptor agonists (GLP-1RA). SGLT2i, finerenone, and GLP-1RA may also have a role in HF prevention in asymptomatic diabetic cardiomyopathy. While there is currently no specific treatment for diabetic cardiomyopathy that goes beyond general HF treatment, there is promising research into innovative technologies such as gene and stem cell therapies. Also, digital technologies will likely have an increasing role in diabetic cardiomyopathy treatment. Herein we review the pathophysiology, diagnosis, and treatment of diabetic cardiomyopathy, with a focus on existing, emerging, and potentially promising novel therapies. We provide practical tables that summarise treatments at each stage as well as important practice points for commonly prescribed drugs.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 55-69"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584173","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 : 2025-09-01Epub Date: 2025-07-23DOI: 10.1016/j.yjmcc.2025.07.015
Dongqing Chen , Amanda J. Croft , Tatt Jhong Haw , Conagh Kelly , Lohis Balachandran , Aaron L. Sverdlov , Doan T.M. Ngo
Inhibition of poly (ADP-ribose) polymerase (PARP) has shown cardioprotective effects in myocardial injury, and PARP activation has been implicated in Doxorubicin-induced cardiotoxicity (DIC). Thus, PARP inhibition may be a potential preventive therapy for DIC. The present study aims to determine the cardioprotective effects of Olaparib in preventing DIC in in vitro and in vivo models. In vitro: Human cardiomyocytes (HCM) were treated with Doxorubicin at 1 μM (EC50) +/− 80 μM of Olaparib for 48 and 72 h, assessing cell viability (CellTiter-Glo®) and conducted gene expression analysis; Concomitant Olaparib treatment prevented Doxorubicin-induced impairment of HCM viability. Doxorubicin induced upregulation of mRNA expressions of genes involved in apoptosis: CASP3; DNA damage: BBC3; and cardiac remodeling: TGF-β; −all were reversed by Olaparib. In vivo: Female C57BL/6 mice were administered intraperitoneally either: A) vehicle of 0.9 % saline and 8 % DMSO in PBS; B) Doxorubicin at 5 mg/kg/wk. for 5 weeks; C) Olaparib at a dose of 50 mg/kg in 8 % DMSO, administered 3 times/week; D) Olaparib at 50 mg/kg, administered 3 times/week, started one week prior to commencement of Doxorubicin treatments at 5 mg/kg/week. Serial echocardiography was performed. mRNA, protein expressions and RNA sequencing were performed in the cardiac tissues; Doxorubicin induced significant LV dysfunction after 6 weeks of treatment; whereas the mice treated with Olaparib in combination with Doxorubicin showed preservation of cardiac function. Analysis of RNA-seq and Western blot data suggested that Olaparib's cardioprotective effects in DIC may involve regulating innate immune responses by lowering cGAS-STING levels, elevated by Doxorubicin. Olaparib protects HCM against DIC both in vitro and in vivo. This is mediated in part via cGAS-STING pathway.
{"title":"Anti-cancer agent Olaparib ameliorates doxorubicin-induced cardiotoxicity in vitro and in vivo","authors":"Dongqing Chen , Amanda J. Croft , Tatt Jhong Haw , Conagh Kelly , Lohis Balachandran , Aaron L. Sverdlov , Doan T.M. Ngo","doi":"10.1016/j.yjmcc.2025.07.015","DOIUrl":"10.1016/j.yjmcc.2025.07.015","url":null,"abstract":"<div><div>Inhibition of poly (ADP-ribose) polymerase (PARP) has shown cardioprotective effects in myocardial injury, and PARP activation has been implicated in Doxorubicin-induced cardiotoxicity (DIC). Thus, PARP inhibition may be a potential preventive therapy for DIC. The present study aims to determine the cardioprotective effects of Olaparib in preventing DIC in in vitro and in vivo models. In vitro<em>:</em> Human cardiomyocytes (HCM) were treated with Doxorubicin at 1 μM (EC50) +/− 80 μM of Olaparib for 48 and 72 h, assessing cell viability (CellTiter-Glo®) and conducted gene expression analysis; Concomitant Olaparib treatment prevented Doxorubicin-induced impairment of HCM viability. Doxorubicin induced upregulation of mRNA expressions of genes involved in apoptosis: <em>CASP3</em>; DNA damage: <em>BBC3</em>; and cardiac remodeling: <em>TGF-β</em>; −all were reversed by Olaparib. In vivo<em>:</em> Female C57BL/6 mice were administered intraperitoneally either: A) vehicle of 0.9 % saline and 8 % DMSO in PBS; B) Doxorubicin at 5 mg/kg/wk. for 5 weeks; C) Olaparib at a dose of 50 mg/kg in 8 % DMSO, administered 3 times/week; D) Olaparib at 50 mg/kg, administered 3 times/week, started one week prior to commencement of Doxorubicin treatments at 5 mg/kg/week. Serial echocardiography was performed. mRNA, protein expressions and RNA sequencing were performed in the cardiac tissues; Doxorubicin induced significant LV dysfunction after 6 weeks of treatment; whereas the mice treated with Olaparib in combination with Doxorubicin showed preservation of cardiac function. Analysis of RNA-seq and Western blot data suggested that Olaparib's cardioprotective effects in DIC may involve regulating innate immune responses by lowering cGAS-STING levels, elevated by Doxorubicin. Olaparib protects HCM against DIC both in vitro and in vivo. This is mediated in part via cGAS-STING pathway.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 114-126"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713407","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 : 2025-09-01Epub Date: 2025-07-16DOI: 10.1016/j.yjmcc.2025.07.004
Chelsea E. Gibbs , Patrick M. Boyle
{"title":"Corrigendum to “Population-based computational simulations elucidate mechanisms of focal arrhythmia following stem cell injection” [Journal of Molecular and Cellular Cardiology 204 (2025) 5–16]","authors":"Chelsea E. Gibbs , Patrick M. Boyle","doi":"10.1016/j.yjmcc.2025.07.004","DOIUrl":"10.1016/j.yjmcc.2025.07.004","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Page 54"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144656497","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 : 2025-09-01Epub Date: 2025-07-11DOI: 10.1016/j.yjmcc.2025.07.006
Feixiang Yan , Weiyue Wang , Maryam Moossavi , Ping Zhu , Noa Odell , Xiaolei Xu
Background
Truncating TITIN variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM); however, key pathological signaling pathways remain elusive. We recently established a zebrafish model of TTNtv DCM and developed a F0-based genome editing technology for the rapid screening of genetic modifiers.
Methods
We screened multiple known cardiomyopathy signaling pathways through a F0-based genetic assay using a zebrafish ttntv DCM model. Because ERK signaling was identified from the screen, which was also independently identified as an altered signaling pathway during a cardiac transcriptomic study of the ttntv DCM model, we then assessed modifying effects of differentially expressed genes (DEGs) in ERK signaling.
Results
erk1 and mek1 have been identified as therapeutic modifiers for ttntv DCM. Consistent with their modifying effects, we observed increased levels of phosphorylated Erk1 protein in ttntv adult zebrafish. Mechanistically, we showed that enhanced ERK signaling results in deregulated nutrient response, as indicated by the muted response of phosphorylated ribosomal protein S6 (pS6) expression in the heart during the fasting-refeeding cycle. The inhibition of ERK signaling is sufficient to rescue deregulated nutrient response and mitigate cardiac dysfunction. Further genetic screens of DEGs in ERK signaling identified ppp1r10, encoding a protein phosphatase 1 (PP1) regulatory subunit that regulates Mek1/Erk1 phosphorylation, as another therapeutic modifier gene that also rescues deregulated nutrient response.
Conclusions
An Erk - nutrient response signaling axis is disrupted in ttntv cardiomyopathy, which can be repaired by the inhibition of erk1, mek1 or ppp1r10, suggesting a new therapeutic avenue for TTNtv DCM.
{"title":"Deregulated nutrient response in ttntv cardiomyopathy can be repaired via Erk inhibition for cardioprotective effects","authors":"Feixiang Yan , Weiyue Wang , Maryam Moossavi , Ping Zhu , Noa Odell , Xiaolei Xu","doi":"10.1016/j.yjmcc.2025.07.006","DOIUrl":"10.1016/j.yjmcc.2025.07.006","url":null,"abstract":"<div><h3>Background</h3><div>Truncating TITIN variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM); however, key pathological signaling pathways remain elusive. We recently established a zebrafish model of TTNtv DCM and developed a F0-based genome editing technology for the rapid screening of genetic modifiers.</div></div><div><h3>Methods</h3><div>We screened multiple known cardiomyopathy signaling pathways through a F0-based genetic assay using a zebrafish <em>ttntv</em> DCM model. Because ERK signaling was identified from the screen, which was also independently identified as an altered signaling pathway during a cardiac transcriptomic study of the <em>ttntv</em> DCM model, we then assessed modifying effects of differentially expressed genes (DEGs) in ERK signaling.</div></div><div><h3>Results</h3><div><em>erk1</em> and <em>mek1</em> have been identified as therapeutic modifiers for <em>ttntv</em> DCM. Consistent with their modifying effects, we observed increased levels of phosphorylated Erk1 protein in <em>ttntv</em> adult zebrafish. Mechanistically, we showed that enhanced ERK signaling results in deregulated nutrient response, as indicated by the muted response of phosphorylated ribosomal protein S6 (pS6) expression in the heart during the fasting-refeeding cycle. The inhibition of ERK signaling is sufficient to rescue deregulated nutrient response and mitigate cardiac dysfunction. Further genetic screens of DEGs in ERK signaling identified <em>ppp1r10</em>, encoding a protein phosphatase 1 (PP1) regulatory subunit that regulates Mek1/Erk1 phosphorylation, as another therapeutic modifier gene that also rescues deregulated nutrient response.</div></div><div><h3>Conclusions</h3><div>An Erk - nutrient response signaling axis is disrupted in <em>ttntv</em> cardiomyopathy, which can be repaired by the inhibition of <em>erk1, mek1</em> or <em>ppp1r10,</em> suggesting a new therapeutic avenue for <em>TTNtv</em> DCM.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 27-38"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626571","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 : 2025-09-01Epub Date: 2025-07-12DOI: 10.1016/j.yjmcc.2025.07.011
Jinzhao Yang , Jiang-Yun Luo , Hongyin Chen , Wai San Cheang , Juan Huang , Li Wang , Wing Tak Wong , Litao Sun , Yu Huang , Xiao Yu Tian , Yang Zhang
Objective
Endothelial dysfunction is a key contributor to hypertension, and dysregulation of TGF-β/BMP signaling pathways exacerbates vascular pathogenesis. However, the precise role of SMAD4 in the development of vascular inflammation and dysfunction in hypertension remains poorly understood.
Methods
Tie2-Cre/ERT2 system was used to generate an endothelial-specific Smad4 knockout mouse. Hypertension was induced by infusion of angiotensin II (Ang II) via implanting an osmotic pump subcutaneously. Endothelium-dependent relaxations (EDRs) of various blood vessels were assessed using a wire myograph system. Gene expression in vivo and in vitro was evaluated through RNA-seq, qPCR, immunofluorescence staining, and western blotting. Nitric oxide (NO) and reactive oxygen species (ROS) production were measured using fluorescent probes under confocal microscopy.
Results
EC-Smad4 KO mice showed a significant reduction in Ang II-induced blood pressure elevation compared to control EC-Smad4 WT mice. EDRs in the aorta, mesenteric, and carotid arteries were markedly improved in EC-Smad4 KO mice. In the aortic endothelium, excess ROS generation and VCAM1 expression induced by Ang II were suppressed in EC-Smad4 KO mice. SMAD4 knockdown also led to diminished phosphorylation of p38 MAPK in response to Ang II, increased phosphorylated eNOS (p-eNOS) at Ser1177. Additionally, Smad4 downregulation resulted in reduced mRNA and protein levels of GRP78, ATF6, and PERK, key markers of tunicamycin-induced endoplasmic reticulum (ER) stress.
Conclusion
Smad4 signaling is a critical mediator of endothelial dysfunction and vascular inflammation in hypertension. Endothelial-specific deletion of Smad4 ameliorates vascular dysfunction by reducing oxidative stress, suppressing ER stress, and alleviating vascular inflammation.
{"title":"Targeting endothelial SMAD4 ameliorates endothelial dysfunction in hypertensive mice","authors":"Jinzhao Yang , Jiang-Yun Luo , Hongyin Chen , Wai San Cheang , Juan Huang , Li Wang , Wing Tak Wong , Litao Sun , Yu Huang , Xiao Yu Tian , Yang Zhang","doi":"10.1016/j.yjmcc.2025.07.011","DOIUrl":"10.1016/j.yjmcc.2025.07.011","url":null,"abstract":"<div><h3>Objective</h3><div>Endothelial dysfunction is a key contributor to hypertension, and dysregulation of TGF-β/BMP signaling pathways exacerbates vascular pathogenesis. However, the precise role of SMAD4 in the development of vascular inflammation and dysfunction in hypertension remains poorly understood.</div></div><div><h3>Methods</h3><div>Tie2-Cre/ERT2 system was used to generate an endothelial-specific Smad4 knockout mouse. Hypertension was induced by infusion of angiotensin II (Ang II) via implanting an osmotic pump subcutaneously. Endothelium-dependent relaxations (EDRs) of various blood vessels were assessed using a wire myograph system. Gene expression in vivo and in vitro was evaluated through RNA-seq, qPCR, immunofluorescence staining, and western blotting. Nitric oxide (NO) and reactive oxygen species (ROS) production were measured using fluorescent probes under confocal microscopy.</div></div><div><h3>Results</h3><div>EC-Smad4 KO mice showed a significant reduction in Ang II-induced blood pressure elevation compared to control EC-Smad4 WT mice. EDRs in the aorta, mesenteric, and carotid arteries were markedly improved in EC-Smad4 KO mice. In the aortic endothelium, excess ROS generation and VCAM1 expression induced by Ang II were suppressed in EC-Smad4 KO mice. SMAD4 knockdown also led to diminished phosphorylation of p38 MAPK in response to Ang II, increased phosphorylated eNOS (p-eNOS) at Ser1177. Additionally, Smad4 downregulation resulted in reduced mRNA and protein levels of GRP78, ATF6, and PERK, key markers of tunicamycin-induced endoplasmic reticulum (ER) stress.</div></div><div><h3>Conclusion</h3><div>Smad4 signaling is a critical mediator of endothelial dysfunction and vascular inflammation in hypertension. Endothelial-specific deletion of Smad4 ameliorates vascular dysfunction by reducing oxidative stress, suppressing ER stress, and alleviating vascular inflammation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 44-53"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637275","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 : 2025-09-01Epub Date: 2025-07-24DOI: 10.1016/j.yjmcc.2025.07.014
Spyros Zissimopoulos , Pavel Kirilenko , Aitana Braza-Boïls , Esther Zorio , Yueyi Wang , Ana Maria Gomez , Mark B. Cannell , Branko Latinkic , Ewan D. Fowler
Background
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca2+ cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca2+ leak during systole disrupts repolarization in a transgenic mouse model of CPVT.
Methods
Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes.
Results
R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca2+ leak during the Ca2+ transient decay, in the form of late Ca2+ sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs.
Conclusions
Ca2+-mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.
{"title":"Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation","authors":"Spyros Zissimopoulos , Pavel Kirilenko , Aitana Braza-Boïls , Esther Zorio , Yueyi Wang , Ana Maria Gomez , Mark B. Cannell , Branko Latinkic , Ewan D. Fowler","doi":"10.1016/j.yjmcc.2025.07.014","DOIUrl":"10.1016/j.yjmcc.2025.07.014","url":null,"abstract":"<div><h3>Background</h3><div>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca<sup>2+</sup> cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca<sup>2+</sup> leak during systole disrupts repolarization in a transgenic mouse model of CPVT.</div></div><div><h3>Methods</h3><div>Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes.</div></div><div><h3>Results</h3><div>R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca<sup>2+</sup> leak during the Ca<sup>2+</sup> transient decay, in the form of late Ca<sup>2+</sup> sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs.</div></div><div><h3>Conclusions</h3><div>Ca<sup>2+</sup>-mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 127-140"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717966","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 : 2025-09-01Epub Date: 2025-07-17DOI: 10.1016/j.yjmcc.2025.07.013
E.V. Minnebaeva , M.A. Gonotkov , A.V. Durkina , E.A. Lebedeva , A.V. Fedorov , M.A. Chelombitko , O.B. Pustovit , T.S. Filatova , J.E. Azarov , O.G. Bernikova
Introduction
The aging myocardium undergoes significant electrophysiological and structural remodeling. These complex alterations may affect conduction velocity (CV), whose age-related changes remain unclear. This study aims at evaluation of the CV changes in the rats of different ages and assessment of the contribution of cellular and tissue factors into CV.
Methods
The CV was determined in 3-, 12- and 24-month-old anesthetized rats using epicardial mapping under ventricular stimulation. The contribution of gap junction functionality to CV was assessed using carbenoxolone, an uncoupling agent for Cx43. The measurement of sodium ion current (INa) was performed in isolated ventricular cardiomyocytes using the patch-clamp technique. Expression of gene transcripts encoding Cx43 (GJA1a) and sodium currents (SCN5a) were assessed using RT-PCR analysis.
Results
The baseline longitudinal conduction velocity (CVL) did not differ between 3-, 12- and 24-month-old groups. Intravenous administration of carbenoxolone decreased the CVL only in the 3-month-old animals. The density of sodium current (INa) of 24-month-old rats was greater as compared to 3-month-old rats. The extent of fibrosis was less prominent in 3-month-old rats than in the older animals. The expression of SCN5a gene transcripts was increased and expression of GJA1a was decreased in the 24-month-old rats.
Conclusions
The enhancement of sodium current preserves conduction velocity despite impaired connexin function and increased fibrosis in the aging myocardium.
{"title":"Enhancement of sodium current contributes to the maintenance of conduction velocity in the aging myocardium","authors":"E.V. Minnebaeva , M.A. Gonotkov , A.V. Durkina , E.A. Lebedeva , A.V. Fedorov , M.A. Chelombitko , O.B. Pustovit , T.S. Filatova , J.E. Azarov , O.G. Bernikova","doi":"10.1016/j.yjmcc.2025.07.013","DOIUrl":"10.1016/j.yjmcc.2025.07.013","url":null,"abstract":"<div><h3>Introduction</h3><div>The aging myocardium undergoes significant electrophysiological and structural remodeling. These complex alterations may affect conduction velocity (CV), whose age-related changes remain unclear. This study aims at evaluation of the CV changes in the rats of different ages and assessment of the contribution of cellular and tissue factors into CV.</div></div><div><h3>Methods</h3><div>The CV was determined in 3-, 12- and 24-month-old anesthetized rats using epicardial mapping under ventricular stimulation. The contribution of gap junction functionality to CV was assessed using carbenoxolone, an uncoupling agent for Cx43. The measurement of sodium ion current (I<sub>Na</sub>) was performed in isolated ventricular cardiomyocytes using the patch-clamp technique. Expression of gene transcripts encoding Cx43 (GJA1a) and sodium currents (SCN5a) were assessed using RT-PCR analysis.</div></div><div><h3>Results</h3><div>The baseline longitudinal conduction velocity (CV<sub>L</sub>) did not differ between 3-, 12- and 24-month-old groups. Intravenous administration of carbenoxolone decreased the CV<sub>L</sub> only in the 3-month-old animals. The density of sodium current (I<sub>Na</sub>) of 24-month-old rats was greater as compared to 3-month-old rats. The extent of fibrosis was less prominent in 3-month-old rats than in the older animals. The expression of SCN5a gene transcripts was increased and expression of GJA1a was decreased in the 24-month-old rats.</div></div><div><h3>Conclusions</h3><div>The enhancement of sodium current preserves conduction velocity despite impaired connexin function and increased fibrosis in the aging myocardium.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 102-112"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667765","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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