Pub 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":"2025-07-16","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}
Myocardial infarction (MI), a leading cause of death worldwide, results in cardiac damage mainly due to cardiomyocyte death. Early endogenous protection against cardiomyocyte death is crucial to limit infarct size and improve clinical outcomes. Previous studies have shown that 14-3-3 proteins play a vital role in cardiomyocyte survival. However, the fundamental mechanism remains unclear. Here, we revealed that 14-3-3 recruited HIP-55 forming a complex to suppress MI-induced cardiomyocyte death in response to myocardial infarction injury. The 14-3-3 partner protein-HIP-55 confers protection against MI-induced cardiomyocyte apoptosis. Mechanistically, the kinase RSK1 phosphorylates HIP-55 S269/T291 sites to promote the 14-3-3/HIP-55 complex formation which suppresses the ASK1 apoptotic pathway. Consistent with this mechanism, S269A/T291A-mutated HIP-55, which is defective in RSK1 phosphorylation and 14-3-3/HIP-55 complex formation, failed to protect against MI-induced cardiomyocyte apoptosis in vivo and in vitro. In summary, these findings demonstrate that the 14-3-3/HIP-55 complex plays a key role in cardiomyocyte survival. Targeting 14-3-3/HIP-55 may be a new therapeutic approach in the setting of acute myocardial damage.
心肌梗死（MI）是世界范围内死亡的主要原因之一，主要由心肌细胞死亡导致心脏损伤。早期内源性心肌细胞死亡保护对限制梗死面积和改善临床结果至关重要。先前的研究表明，14-3-3蛋白在心肌细胞存活中起着至关重要的作用。然而，其基本机制尚不清楚。在这里，我们发现14-3-3招募HIP-55形成一个复合物来抑制心肌梗死损伤后心肌细胞死亡。14-3-3伴侣蛋白- hip -55对心肌细胞凋亡具有保护作用。机制上，RSK1激酶磷酸化HIP-55 S269/T291位点，促进14-3-3/HIP-55复合物的形成，从而抑制ASK1凋亡途径。与这一机制一致的是，S269A/ t291a突变的HIP-55在RSK1磷酸化和14-3-3/HIP-55复合物形成方面存在缺陷，在体内和体外均未能保护mi诱导的心肌细胞凋亡。综上所述，这些发现表明14-3-3/HIP-55复合物在心肌细胞存活中起关键作用。靶向14-3-3/HIP-55可能是治疗急性心肌损伤的新途径。
{"title":"14-3-3/HIP-55 complex attenuates cardiomyocyte apoptosis","authors":"Yunqi Jiang , Dannya Estau , Yuhui Qiao , Zijian Li","doi":"10.1016/j.yjmcc.2025.07.012","DOIUrl":"10.1016/j.yjmcc.2025.07.012","url":null,"abstract":"<div><div>Myocardial infarction (MI), a leading cause of death worldwide, results in cardiac damage mainly due to cardiomyocyte death. Early endogenous protection against cardiomyocyte death is crucial to limit infarct size and improve clinical outcomes. Previous studies have shown that 14-3-3 proteins play a vital role in cardiomyocyte survival. However, the fundamental mechanism remains unclear. Here, we revealed that 14-3-3 recruited HIP-55 forming a complex to suppress MI-induced cardiomyocyte death in response to myocardial infarction injury. The 14-3-3 partner protein-HIP-55 confers protection against MI-induced cardiomyocyte apoptosis. Mechanistically, the kinase RSK1 phosphorylates HIP-55 S269/T291 sites to promote the 14-3-3/HIP-55 complex formation which suppresses the ASK1 apoptotic pathway. Consistent with this mechanism, S269A/T291A-mutated HIP-55, which is defective in RSK1 phosphorylation and 14-3-3/HIP-55 complex formation, failed to protect against MI-induced cardiomyocyte apoptosis in vivo and in vitro. In summary, these findings demonstrate that the 14-3-3/HIP-55 complex plays a key role in cardiomyocyte survival. Targeting 14-3-3/HIP-55 may be a new therapeutic approach in the setting of acute myocardial damage.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 91-101"},"PeriodicalIF":4.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659446","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 : 2025-07-14DOI: 10.1016/j.yjmcc.2025.07.010
Sijia Zhao , Pin Sun , Chao Wang , Xiaolu Li , Zhenyang Xiu , Yu Tian , Xiaoxia Song , Xiangqin He , Tao Yu , Zhirong Jiang
Congenital heart disease (CHD) are the predominant cause of neonatal mortality and the most prevalent congenital malformation. Additionally, CHD can impact cardiovascular health in adulthood and exacerbate cardiovascular conditions in the elderly. Emerging studies indicate that both genetic predispositions and environmental factors may contribute to the development of this condition. Notably, formaldehyde (FA), a ubiquitous environmental toxin, has been increasingly implicated in the pathophysiology of CHD through recent investigations. Earlier, we identified long noncoding RNAs (lncRNAs) that exhibited significant differential expression in rats with cardiac developmental impairments associated with FA exposure. Here our study aims to elucidate the role of lncRNA in pathological mechanisms by subjecting H9C2 cells to 24-h formaldehyde exposure or administering formaldehyde (2.0 mg/kg) to female rats and examining their offspring. We indicate that lncRNA 91,234.1 (lnc91234) plays a role in FA-induced CHD by facilitating ferroptosis via PRMT1/ASCL4/GPX4 axis, which influences the methylation of H4R3, leading to lipid peroxidation and malondialdehyde (MDA) accumulation. This research is the first to demonstrate that exposure to FA disrupts cardiac function through ferroptosis and identifies lnc91234 as a novel lncRNA that may serve as a potential therapeutic target for cardiac dysplasia and CHD by modulating myocardial function both in vivo and in vitro.
{"title":"LncRNA 91234.1 targets PRMT1/ASCL4/GPX4 axis to regulate formaldehyde-induced cardiomyocyte ferroptosis and congenital heart disease","authors":"Sijia Zhao , Pin Sun , Chao Wang , Xiaolu Li , Zhenyang Xiu , Yu Tian , Xiaoxia Song , Xiangqin He , Tao Yu , Zhirong Jiang","doi":"10.1016/j.yjmcc.2025.07.010","DOIUrl":"10.1016/j.yjmcc.2025.07.010","url":null,"abstract":"<div><div>Congenital heart disease (CHD) are the predominant cause of neonatal mortality and the most prevalent congenital malformation. Additionally, CHD can impact cardiovascular health in adulthood and exacerbate cardiovascular conditions in the elderly. Emerging studies indicate that both genetic predispositions and environmental factors may contribute to the development of this condition. Notably, formaldehyde (FA), a ubiquitous environmental toxin, has been increasingly implicated in the pathophysiology of CHD through recent investigations. Earlier, we identified long noncoding RNAs (lncRNAs) that exhibited significant differential expression in rats with cardiac developmental impairments associated with FA exposure. Here our study aims to elucidate the role of lncRNA in pathological mechanisms by subjecting H9C2 cells to 24-h formaldehyde exposure or administering formaldehyde (2.0 mg/kg) to female rats and examining their offspring. We indicate that lncRNA 91,234.1 (lnc91234) plays a role in FA-induced CHD by facilitating ferroptosis via PRMT1/ASCL4/GPX4 axis, which influences the methylation of H4R3, leading to lipid peroxidation and malondialdehyde (MDA) accumulation. This research is the first to demonstrate that exposure to FA disrupts cardiac function through ferroptosis and identifies lnc91234 as a novel lncRNA that may serve as a potential therapeutic target for cardiac dysplasia and CHD by modulating myocardial function both in vivo and in vitro.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 76-90"},"PeriodicalIF":4.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649630","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 : 2025-07-12DOI: 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":"2025-07-12","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 : 2025-07-11DOI: 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":"2025-07-11","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 : 2025-07-11DOI: 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":"2025-07-11","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 : 2025-07-11DOI: 10.1016/j.yjmcc.2025.07.008
Daphne Diloretto , Gaurav Sarode , Phung N. Thai , Jeong Han Lee , Evelyn Navar , Jeong eun Park , Chaitali Khadilkar , Ning Zong , Yu Jia Dong , Avni Duda , Erick Romero , Pablo E. Acevedo , Xiao-Dong Zhang , David A. Liem , Imo Ebong , Javier E. Lopez , Heejung Bang , Chao-Yin Chen , Leighton Izu , Martin Cadeiras , Padmini Sirish
Psychosocial stress (PSS) affects all humans with different intensities and is known to significantly increase inflammation and cardiovascular disease [1,2]. An amplifier of inflammation is an intracellular multiprotein complex, the inflammasome, activation of which leads to pro-inflammatory cytokines production. However, the mechanisms leading to the inflammasome activation in the heart by PSS are not well understood. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum (ER) stress and JAK/STAT pathway. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to PSS.
{"title":"Psychosocial stress amplifies inflammation through NLRP3 Inflammasome activated by endoplasmic reticulum stress in the mouse heart","authors":"Daphne Diloretto , Gaurav Sarode , Phung N. Thai , Jeong Han Lee , Evelyn Navar , Jeong eun Park , Chaitali Khadilkar , Ning Zong , Yu Jia Dong , Avni Duda , Erick Romero , Pablo E. Acevedo , Xiao-Dong Zhang , David A. Liem , Imo Ebong , Javier E. Lopez , Heejung Bang , Chao-Yin Chen , Leighton Izu , Martin Cadeiras , Padmini Sirish","doi":"10.1016/j.yjmcc.2025.07.008","DOIUrl":"10.1016/j.yjmcc.2025.07.008","url":null,"abstract":"<div><div>Psychosocial stress (PSS) affects all humans with different intensities and is known to significantly increase inflammation and cardiovascular disease [<span><span>1</span></span>,<span><span>2</span></span>]. An amplifier of inflammation is an intracellular multiprotein complex, the inflammasome, activation of which leads to pro-inflammatory cytokines production. However, the mechanisms leading to the inflammasome activation in the heart by PSS are not well understood. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum (ER) stress and JAK/STAT pathway. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to PSS.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 39-43"},"PeriodicalIF":4.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626573","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 : 2025-07-10DOI: 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":"2025-07-10","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 : 2025-07-10DOI: 10.1016/j.yjmcc.2025.07.005
Collin K. Wells , Daniel C. Nguyen , Robert E. Brainard , Lindsey A. McNally , Maleesha De Silva , Kenneth R. Brittian , Lauren Garrett , Madison S. Taylor , Yania Martinez-Ondaro , Caitlin Howard , Snigdha Suluru , Sujith Dassanayaka , Tamer M.A. Mohamed , Richa Singhal , Andrew A. Gibb , Pawel K. Lorkiewicz , Joseph B. Moore IV , Steven P. Jones , Bradford G. Hill
Fibroblasts are crucial for cardiac repair after myocardial infarction (MI). In response to signaling cues, they differentiate to phenotypes with robust capacities to synthesize and secrete extracellular matrix (ECM) and signaling molecules. Although activated fibroblast phenotypes are associated with pronounced changes in metabolism, it remains unclear how the metabolic network upholds the effector functions of fibroblasts in the infarcted heart. We found that two enzymes that could facilitate a phosphoenolpyruvate cycle, i.e. pyruvate kinase muscle isoform 2 (PKM2) and phosphoenolpyruvate carboxykinase 2 (PCK2), are elevated in the heart after MI. Although Pck2 deletion had no effect on post-MI remodeling, fibroblast-specific switching of Pkm2 to Pkm1 (fbPkm2 → 1) mitigated ventricular dilation, wall thinning, and losses in ejection fraction caused by MI. Despite these salutary effects, fbPkm2 → 1 switching did not alter cardiac fibrosis in vivo, nor did it affect collagen production, cytokine or chemokine secretion, myofibroblast differentiation markers, or transcriptional regulation in vitro. Nevertheless, Pkm2 → 1 splice variant switching increased myofibroblast contractile activity as well as influenced the metabolic phenotype of fibroblasts, as shown by increased pyruvate kinase activity, higher mitochondrial respiratory capacity, and elevation in glycolytic intermediate abundance. Despite these changes, Pkm2 → 1 switching had relatively minor effects on glucose carbon fate, as determined by stable isotope-resolved metabolomics. Nevertheless, these metabolic data demonstrate that cardiac fibroblasts exhibit minimal glucose-supported de novo glycine synthesis in vitro, yet possess high hexosamine and glucuronate biosynthetic pathway activity. Collectively, these findings reveal that fibroblast PKM isoforms influence post-MI remodeling, highlighting pyruvate kinase as a potential therapeutic target.
{"title":"Pyruvate kinase splice variants in fibroblasts influence cardiac remodeling after myocardial infarction in male mice","authors":"Collin K. Wells , Daniel C. Nguyen , Robert E. Brainard , Lindsey A. McNally , Maleesha De Silva , Kenneth R. Brittian , Lauren Garrett , Madison S. Taylor , Yania Martinez-Ondaro , Caitlin Howard , Snigdha Suluru , Sujith Dassanayaka , Tamer M.A. Mohamed , Richa Singhal , Andrew A. Gibb , Pawel K. Lorkiewicz , Joseph B. Moore IV , Steven P. Jones , Bradford G. Hill","doi":"10.1016/j.yjmcc.2025.07.005","DOIUrl":"10.1016/j.yjmcc.2025.07.005","url":null,"abstract":"<div><div>Fibroblasts are crucial for cardiac repair after myocardial infarction (MI). In response to signaling cues, they differentiate to phenotypes with robust capacities to synthesize and secrete extracellular matrix (ECM) and signaling molecules. Although activated fibroblast phenotypes are associated with pronounced changes in metabolism, it remains unclear how the metabolic network upholds the effector functions of fibroblasts in the infarcted heart. We found that two enzymes that could facilitate a phosphoenolpyruvate cycle, i.e. pyruvate kinase muscle isoform 2 (PKM2) and phosphoenolpyruvate carboxykinase 2 (PCK2), are elevated in the heart after MI. Although <em>Pck2</em> deletion had no effect on post-MI remodeling, fibroblast-specific switching of <em>Pkm2</em> to <em>Pkm1</em> (fb<em>Pkm2 → 1</em>) mitigated ventricular dilation, wall thinning, and losses in ejection fraction caused by MI. Despite these salutary effects, fb<em>Pkm2 → 1</em> switching did not alter cardiac fibrosis in vivo, nor did it affect collagen production, cytokine or chemokine secretion, myofibroblast differentiation markers, or transcriptional regulation in vitro. Nevertheless, <em>Pkm2 → 1</em> splice variant switching increased myofibroblast contractile activity as well as influenced the metabolic phenotype of fibroblasts, as shown by increased pyruvate kinase activity, higher mitochondrial respiratory capacity, and elevation in glycolytic intermediate abundance. Despite these changes, <em>Pkm2 → 1</em> switching had relatively minor effects on glucose carbon fate, as determined by stable isotope-resolved metabolomics. Nevertheless, these metabolic data demonstrate that cardiac fibroblasts exhibit minimal glucose-supported de novo glycine synthesis in vitro, yet possess high hexosamine and glucuronate biosynthetic pathway activity. Collectively, these findings reveal that fibroblast PKM isoforms influence post-MI remodeling, highlighting pyruvate kinase as a potential therapeutic target.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 11-26"},"PeriodicalIF":4.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618600","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}
Recent studies have highlighted the significance of soluble αKlotho in renal dysfunction-associated vascular health, however, the underlying molecular mechanisms by which soluble αKlotho maintains the vascular smooth muscle cells (VSMCs) phenotype and prevents vascular calcification remain unclear. Clinical analyses revealed an inverse correlation between circulating αKlotho levels and vascular calcification severity in early CKD patients. Recombinant protein or lentiviral vector transfection of soluble αKlotho significantly suppressed the osteogenic transdifferentiation of VSMCs in vitro. AAV-mediated overexpression of soluble αKlotho in VSMCs remarkably reduced vascular calcification without altering circulating soluble αKlotho levels or mineral metabolism in mice under a high-phosphate diet after nephrectomy. We also employed a combination of transcriptomics and proteomics approaches, as well as in vitro and in vivo vascular calcification models, and determined that soluble αKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. The Hsp90aa1-specific inhibitor, 17-AAG, acted as an efficient therapeutic approach to attenuate vascular calcification in vivo and in vitro. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1 and blunted the phosphorylation of Hsp90aa1 at Thr5/7, which abolished Hsp90aa1-Hif1α axis activation in response to osteogenic induction. Our findings revealed a crucial pathway that soluble αKlotho interacts with Hsp90aa1 and suppresses the activation of the Hsp90aa1-Hif1α axis, which is involved in the osteogenic transdifferentiation of VSMCs and vascular calcification. Targeting Hsp90 may be a promising strategy for vascular calcification treatment, as various HSP90 inhibitors have been used for a range of clinical conditions.
{"title":"Soluble αKlotho interacts with Hsp90aa1 to inhibit the chaperone machinery-mediated Hif1α stabilization and alleviate CKD-induced vascular calcification","authors":"Fengyang Xu , Jialin Guo , Yunyun Guo , Jiaxin Ma , Wentao Sang , Xiangkai Zhao , Jian Zhang , Tonghui Xu , Feng Xu , Yuguo Chen","doi":"10.1016/j.yjmcc.2025.07.003","DOIUrl":"10.1016/j.yjmcc.2025.07.003","url":null,"abstract":"<div><div>Recent studies have highlighted the significance of soluble αKlotho in renal dysfunction-associated vascular health, however, the underlying molecular mechanisms by which soluble αKlotho maintains the vascular smooth muscle cells (VSMCs) phenotype and prevents vascular calcification remain unclear. Clinical analyses revealed an inverse correlation between circulating αKlotho levels and vascular calcification severity in early CKD patients. Recombinant protein or lentiviral vector transfection of soluble αKlotho significantly suppressed the osteogenic transdifferentiation of VSMCs in vitro. AAV-mediated overexpression of soluble αKlotho in VSMCs remarkably reduced vascular calcification without altering circulating soluble αKlotho levels or mineral metabolism in mice under a high-phosphate diet after nephrectomy. We also employed a combination of transcriptomics and proteomics approaches, as well as in vitro and in vivo vascular calcification models, and determined that soluble αKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. The Hsp90aa1-specific inhibitor, 17-AAG, acted as an efficient therapeutic approach to attenuate vascular calcification in vivo and in vitro. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1 and blunted the phosphorylation of Hsp90aa1 at Thr5/7, which abolished Hsp90aa1-Hif1α axis activation in response to osteogenic induction. Our findings revealed a crucial pathway that soluble αKlotho interacts with Hsp90aa1 and suppresses the activation of the Hsp90aa1-Hif1α axis, which is involved in the osteogenic transdifferentiation of VSMCs and vascular calcification. Targeting Hsp90 may be a promising strategy for vascular calcification treatment, as various HSP90 inhibitors have been used for a range of clinical conditions.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Pages 100-116"},"PeriodicalIF":4.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584174","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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