Pub Date : 2025-11-01DOI: 10.1016/j.yjmcc.2025.10.009
David Sánchez-López , David García-Vega , J.E. Viñuela , Isabel Ferreirós-Vidal , Diego Iglesias-Álvarez , José Manuel Martínez-Cereijo , Laura Reija-López , Ángel L. Fernández-González , José R. González-Juanatey , Sonia Eiras
Dysfunctional epicardial adiposity is a risk factor for coronary artery disease (CAD). Its genesis is associated with an upregulation of fatty acid binding protein 4 (FABP4) levels, which might exert paracrine inflammatory and atherogenic mechanisms on the cardiovascular system. We aimed to study the prognosis of patients with high systemic FABP4, its association with a neutrophil proatherogenic phenotype, involved mechanisms and its modulation by semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1ra). Higher plasma FABP4 levels than 50 ng/mL were associated with heart failure (HF) onset during follow-up. In patients with CAD, these levels were associated with pro-inflammatory and pro-atherogenic neutrophil profile markers as MPO, NGAL and CD11b, analysed by real-time PCR. The group of patients with the highest FABP4 levels exhibited higher levels of MMP9, CXCR2, and CD11b in neutrophils. A preclinical model, based on neutrophils and coronary endothelial cells, determined the effects of FABP4 on neutrophils' respiratory burst, by flow cytometry, activity of NF-κΒ, by western blot checking IκΒα phosphorylation, CD11b integrin expression levels and adhesion to coronary endothelial cells. A modulation of the neutrophils' transcriptome, analysed by RNA-seq, and plasma chemokine CCL5 levels suggested changes in leukocyte migration and platelet activation pathways in patients who reduced plasma FABP4 levels after semaglutide treatment. Thus, supraphysiological levels of FABP4 induce pro-inflammatory and proatherogenic mechanisms in neutrophils and coronary endothelial cells. Its modulation by semaglutide could explain its benefits on coronary artery disease (CAD).
{"title":"FABP4, marker of worse prognosis in cardiovascular disease, induces neutrophil's proatherogenic phenotype which is modulated by semaglutide","authors":"David Sánchez-López , David García-Vega , J.E. Viñuela , Isabel Ferreirós-Vidal , Diego Iglesias-Álvarez , José Manuel Martínez-Cereijo , Laura Reija-López , Ángel L. Fernández-González , José R. González-Juanatey , Sonia Eiras","doi":"10.1016/j.yjmcc.2025.10.009","DOIUrl":"10.1016/j.yjmcc.2025.10.009","url":null,"abstract":"<div><div>Dysfunctional epicardial adiposity is a risk factor for coronary artery disease (CAD). Its genesis is associated with an upregulation of fatty acid binding protein 4 (FABP4) levels, which might exert paracrine inflammatory and atherogenic mechanisms on the cardiovascular system. We aimed to study the prognosis of patients with high systemic FABP4, its association with a neutrophil proatherogenic phenotype, involved mechanisms and its modulation by semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1ra). Higher plasma FABP4 levels than 50 ng/mL were associated with heart failure (HF) onset during follow-up. In patients with CAD, these levels were associated with pro-inflammatory and pro-atherogenic neutrophil profile markers as MPO, NGAL and CD11b, analysed by real-time PCR. The group of patients with the highest FABP4 levels exhibited higher levels of MMP9, CXCR2, and CD11b in neutrophils. A preclinical model, based on neutrophils and coronary endothelial cells, determined the effects of FABP4 on neutrophils' respiratory burst, by flow cytometry, activity of NF-κΒ, by western blot checking IκΒα phosphorylation, CD11b integrin expression levels and adhesion to coronary endothelial cells. A modulation of the neutrophils' transcriptome, analysed by RNA-seq, and plasma chemokine CCL5 levels suggested changes in leukocyte migration and platelet activation pathways in patients who reduced plasma FABP4 levels after semaglutide treatment. Thus, supraphysiological levels of FABP4 induce pro-inflammatory and proatherogenic mechanisms in neutrophils and coronary endothelial cells. Its modulation by semaglutide could explain its benefits on coronary artery disease (CAD).</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 12-27"},"PeriodicalIF":4.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145438161","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 : 2025-11-01DOI: 10.1016/j.yjmcc.2025.10.015
Nadine Erlenhardt , Franziska Wohlfarth , S. Erfan Moussavi-Torshizi , Angela Koch , Tobias Strasdeit , Katharina Scherschel , Ehsan Amin , Max Anstötz , Christian Meyer , Nikolaj Klöcker
Insulin-like growth factor 1 (IGF-1) controls cardiac growth, metabolism, and contractility. Whereas IGF-1 deficiency is associated with cardiovascular risk, the activation of its signal transduction may be cardioprotective after acute myocardial infarction. Clinical studies evaluate the therapeutic potential of systemic IGF-1 in disease conditions including heart failure, and reported tachycardia as a common side effect. Here, we demonstrate that IGF-1 accelerates cardiac pacemaking in an ex vivo mouse sinoatrial node preparation read out by optical voltage mapping. Heterologous reconstitution experiments in Xenopus laevis oocytes combining extracellular epitope tagging and electrophysiology reveal an increase in cell surface expression of the main cardiac pacemaker channel isoform HCN4 by IGF-1, which stimulates the Rab11-dependent endosomal recycling of the channel protein. In summary, the study not only adds to the modes of HCN channel regulation by growth factor signaling, but may also extend our understanding of arrhythmogenesis, commonly observed in consequence of IGF-1 dysregulation including cardiac hypertrophy.
{"title":"IGF-1 promotes cell surface expression of HCN4 pacemaker channels contributing to tachycardia","authors":"Nadine Erlenhardt , Franziska Wohlfarth , S. Erfan Moussavi-Torshizi , Angela Koch , Tobias Strasdeit , Katharina Scherschel , Ehsan Amin , Max Anstötz , Christian Meyer , Nikolaj Klöcker","doi":"10.1016/j.yjmcc.2025.10.015","DOIUrl":"10.1016/j.yjmcc.2025.10.015","url":null,"abstract":"<div><div>Insulin-like growth factor 1 (IGF-1) controls cardiac growth, metabolism, and contractility. Whereas IGF-1 deficiency is associated with cardiovascular risk, the activation of its signal transduction may be cardioprotective after acute myocardial infarction. Clinical studies evaluate the therapeutic potential of systemic IGF-1 in disease conditions including heart failure, and reported tachycardia as a common side effect. Here, we demonstrate that IGF-1 accelerates cardiac pacemaking in an <em>ex vivo</em> mouse sinoatrial node preparation read out by optical voltage mapping. Heterologous reconstitution experiments in <em>Xenopus laevis</em> oocytes combining extracellular epitope tagging and electrophysiology reveal an increase in cell surface expression of the main cardiac pacemaker channel isoform HCN4 by IGF-1, which stimulates the Rab11-dependent endosomal recycling of the channel protein. In summary, the study not only adds to the modes of HCN channel regulation by growth factor signaling, but may also extend our understanding of arrhythmogenesis, commonly observed in consequence of IGF-1 dysregulation including cardiac hypertrophy.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 165-174"},"PeriodicalIF":4.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431685","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 : 2025-10-28DOI: 10.1016/j.yjmcc.2025.10.008
Sonette Steczina , Saffie Mohran , Matthew C. Childers , Timothy S. McMillen , Ateeqa Naim , Matvey Pilagov , Marica Dente , Kristina B. Kooiker , Christian Mandrycky , Khushi Tawde , Jennifer Hesson , Jing Zhao , Julie Mathieu , J. Manuel Pioner , Michael A. Geeves , Weikang Ma , Farid Moussavi-Harami , Neil M. Kad , Michael Regnier
The R403Q mutation in the sarcomere protein beta-myosin heavy chain (β-MHC) is a known genetic cause of hypertrophic cardiomyopathy (HCM), associated with ventricular hypercontractility, impaired relaxation, and cardiac arrhythmias. Despite extensive research, the mutations impact on myosin contractile properties remains unclear partly due to discrepancies across different model systems. In this study, we used a multidisciplinary approach to explore mutational effects using two distinct heterozygous R403Q systems: a Yucatan minipig model and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). X-ray diffraction of R403Q minipig ventricular muscle demonstrated reduced order of the thick filament, suggesting destabilization of the inhibited OFF (vs. ON) state of myosin in relaxed muscle, which correlated with elevated force at submaximal calcium. Super-resolution, single-molecule fluorescence microscopy indicated elevated ATPase activity in thick filament zones lacking cardiac myosin binding protein-C (cMyBP-C). Furthermore, R403Q myofibrils exhibited slower activation and relaxation kinetics, with reduced sensitivity to ADP. Molecular dynamics simulations suggested that altered interactions at the actomyosin interface contribute to these effects, rather than changes at the nucleotide binding pocket, typically associated with ADP release. Human engineered heterozygous R403Q hiPSC-CMs exhibited reduced maximal myofibril force, slowed relaxation kinetics, and hypercontraction in engineered heart tissue constructs-consistent with HCM phenotypes observed in the heterozygous porcine model. Our results demonstrate that the R403Q mutation induces contractile dysfunction within the early stages of stem cell derived cardiomyocyte development and in juvenile minipigs, and that hypercontractility and slower contractile kinetics may result from a combination of an increased population of activated (ON) myosin heads and delayed detachment during cross-bridge cycling, respectively.
{"title":"Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model","authors":"Sonette Steczina , Saffie Mohran , Matthew C. Childers , Timothy S. McMillen , Ateeqa Naim , Matvey Pilagov , Marica Dente , Kristina B. Kooiker , Christian Mandrycky , Khushi Tawde , Jennifer Hesson , Jing Zhao , Julie Mathieu , J. Manuel Pioner , Michael A. Geeves , Weikang Ma , Farid Moussavi-Harami , Neil M. Kad , Michael Regnier","doi":"10.1016/j.yjmcc.2025.10.008","DOIUrl":"10.1016/j.yjmcc.2025.10.008","url":null,"abstract":"<div><div>The R403Q mutation in the sarcomere protein beta-myosin heavy chain (β-MHC) is a known genetic cause of hypertrophic cardiomyopathy (HCM), associated with ventricular hypercontractility, impaired relaxation, and cardiac arrhythmias. Despite extensive research, the mutations impact on myosin contractile properties remains unclear partly due to discrepancies across different model systems. In this study, we used a multidisciplinary approach to explore mutational effects using two distinct heterozygous R403Q systems: a Yucatan minipig model and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). X-ray diffraction of R403Q minipig ventricular muscle demonstrated reduced order of the thick filament, suggesting destabilization of the inhibited OFF (vs. ON) state of myosin in relaxed muscle, which correlated with elevated force at submaximal calcium. Super-resolution, single-molecule fluorescence microscopy indicated elevated ATPase activity in thick filament zones lacking cardiac myosin binding protein-C (cMyBP-C). Furthermore, R403Q myofibrils exhibited slower activation and relaxation kinetics, with reduced sensitivity to ADP. Molecular dynamics simulations suggested that altered interactions at the actomyosin interface contribute to these effects, rather than changes at the nucleotide binding pocket, typically associated with ADP release. Human engineered heterozygous R403Q hiPSC-CMs exhibited reduced maximal myofibril force, slowed relaxation kinetics, and hypercontraction in engineered heart tissue constructs-consistent with HCM phenotypes observed in the heterozygous porcine model. Our results demonstrate that the R403Q mutation induces contractile dysfunction within the early stages of stem cell derived cardiomyocyte development and in juvenile minipigs, and that hypercontractility and slower contractile kinetics may result from a combination of an increased population of activated (ON) myosin heads and delayed detachment during cross-bridge cycling, respectively.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 143-160"},"PeriodicalIF":4.7,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409289","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 : 2025-10-27DOI: 10.1016/j.yjmcc.2025.10.011
Mariana Shumliakivska , Ariane Fischer , Marion Muhly-Reinholz , Vincent Elvin Leonard , Tina Rasper , Galip S. Aslan , Yosif Manavski , Julian U.G. Wagner , Benjamin Meder , Susanne S. Hille , Oliver J. Müller , Guillermo Luxán , Stefanie Dimmeler
Cardiomyocytes are postmitotic cells that do not proliferate in the heart. In order to maintain the structural integrity of the heart, cardiomyocyte loss due to cell death after myocardial infarction is compensated with a non-contractile fibrotic scar that compromises cardiac function. Here, we have combined heart failure transcriptomics with in vitro assays to determine the molecular mechanisms that govern cell death in heart failure. Our data identified the reduced gene expression of the long non-coding RNA (lncRNA) small nucleolar RNA host gene 15 (Snhg15) as a hallmark of ischemic and dilated heart failure. Furthermore, loss-of-function studies in HL-1-cardiomyocyte-like cells revealed that Snhg15 depletion induces nucleolar disruption and cell death in a p53-dependent mechanism. Finally, adeno-associated virus delivery of Snhg15 prior to a myocardial infarction partially protected cardiac function in the acute and chronic phases after myocardial infarction. In conclusion, our studies identify Snhg15 as a regulator of cardiomyocyte cell death in the context of heart failure and suggest that delivery of the lncRNA may represent a potential therapeutic tool to reduce cardiomyocyte death.
{"title":"The long non-coding RNA Snhg15 protects the heart after myocardial infarction","authors":"Mariana Shumliakivska , Ariane Fischer , Marion Muhly-Reinholz , Vincent Elvin Leonard , Tina Rasper , Galip S. Aslan , Yosif Manavski , Julian U.G. Wagner , Benjamin Meder , Susanne S. Hille , Oliver J. Müller , Guillermo Luxán , Stefanie Dimmeler","doi":"10.1016/j.yjmcc.2025.10.011","DOIUrl":"10.1016/j.yjmcc.2025.10.011","url":null,"abstract":"<div><div>Cardiomyocytes are postmitotic cells that do not proliferate in the heart. In order to maintain the structural integrity of the heart, cardiomyocyte loss due to cell death after myocardial infarction is compensated with a non-contractile fibrotic scar that compromises cardiac function. Here, we have combined heart failure transcriptomics with <em>in vitro</em> assays to determine the molecular mechanisms that govern cell death in heart failure. Our data identified the reduced gene expression of the long non-coding RNA (lncRNA) small nucleolar RNA host gene 15 (<em>Snhg15</em>) as a hallmark of ischemic and dilated heart failure. Furthermore, loss-of-function studies in HL-1-cardiomyocyte-like cells revealed that <em>Snhg15</em> depletion induces nucleolar disruption and cell death in a p53-dependent mechanism. Finally, adeno-associated virus delivery of <em>Snhg15</em> prior to a myocardial infarction partially protected cardiac function in the acute and chronic phases after myocardial infarction. In conclusion, our studies identify <em>Snhg15</em> as a regulator of cardiomyocyte cell death in the context of heart failure and suggest that delivery of the lncRNA may represent a potential therapeutic tool to reduce cardiomyocyte death.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 72-82"},"PeriodicalIF":4.7,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401074","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 : 2025-10-25DOI: 10.1016/j.yjmcc.2025.10.010
Xinyu Nie , Xingyue Feng , Can Xu
{"title":"Fibroblast metabolic reprogramming determines scar quality and sex-specific remodeling after infarction","authors":"Xinyu Nie , Xingyue Feng , Can Xu","doi":"10.1016/j.yjmcc.2025.10.010","DOIUrl":"10.1016/j.yjmcc.2025.10.010","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 161-162"},"PeriodicalIF":4.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145474494","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 : 2025-10-24DOI: 10.1016/j.yjmcc.2025.10.005
Jianfei Xiong , Guoxiang Liu , Tianyuan Jia , Qian Yang , Changqing Zhu , Shiwei Wang
Background
Sepsis-induced myocardial dysfunction (SIMD) is a critical complication of sepsis, and ferroptosis has been identified as a key contributor to its pathogenesis. Emerging evidence suggests that sepsis profoundly disrupts the gut microbiota composition, leading to dysbiosis. Butyrate, a short-chain fatty acid produced by gut microbiota, has been implicated in ferroptosis regulation; however, its role in SIMD remains controversial. This study aims to elucidate the protective effects of gut microbiota-derived butyrate against SIMD through ferroptosis modulation.
Methods
This study assessed cardiac function using echocardiography and quantified myocardial injury biomarkers via ELISA. Myocardial iron deposition was evaluated using Prussian blue staining. The gut microbiota composition was analyzed using 16S rRNA gene sequencing. Ferroptosis-related protein expression in SIMD heart tissues and H9C2 cardiomyocytes was examined via western blotting to determine the regulatory role of butyrate.
Results
Sepsis-induced gut microbiota dysbiosis was characterized by a significant reduction in butyrate-producing bacteria. Echocardiographic assessments (CO, EF), myocardial injury markers (BNP, cTnI), histopathological analysis (H&E staining), and cardiomyocyte ultrastructure (TEM) demonstrated that butyrate administration significantly alleviated myocardial injury in SIMD. Mechanistically, butyrate mitigated oxidative stress by increasing GSH levels and reducing MDA levels. Furthermore, butyrate treatment reversed the sepsis-induced downregulation of GPX4 and suppressed the upregulation of ACSL4 and PTGS2, thereby inhibiting ferroptosis.
Conclusion
These findings highlight the protective role of butyrate in SIMD, with ferroptosis inhibition serving as a key cardioprotective mechanism. Targeting gut microbiota-derived butyrate may represent a promising therapeutic strategy for sepsis-induced myocardial injury.
{"title":"Targeting gut microbiotasu-derived butyrate for Ferroptosis inhibition in Sepsis-induced myocardial dysfunction","authors":"Jianfei Xiong , Guoxiang Liu , Tianyuan Jia , Qian Yang , Changqing Zhu , Shiwei Wang","doi":"10.1016/j.yjmcc.2025.10.005","DOIUrl":"10.1016/j.yjmcc.2025.10.005","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis-induced myocardial dysfunction (SIMD) is a critical complication of sepsis, and ferroptosis has been identified as a key contributor to its pathogenesis. Emerging evidence suggests that sepsis profoundly disrupts the gut microbiota composition, leading to dysbiosis. Butyrate, a short-chain fatty acid produced by gut microbiota, has been implicated in ferroptosis regulation; however, its role in SIMD remains controversial. This study aims to elucidate the protective effects of gut microbiota-derived butyrate against SIMD through ferroptosis modulation.</div></div><div><h3>Methods</h3><div>This study assessed cardiac function using echocardiography and quantified myocardial injury biomarkers via ELISA. Myocardial iron deposition was evaluated using Prussian blue staining. The gut microbiota composition was analyzed using 16S rRNA gene sequencing. Ferroptosis-related protein expression in SIMD heart tissues and H9C2 cardiomyocytes was examined via western blotting to determine the regulatory role of butyrate.</div></div><div><h3>Results</h3><div>Sepsis-induced gut microbiota dysbiosis was characterized by a significant reduction in butyrate-producing bacteria. Echocardiographic assessments (CO, EF), myocardial injury markers (BNP, cTnI), histopathological analysis (H&E staining), and cardiomyocyte ultrastructure (TEM) demonstrated that butyrate administration significantly alleviated myocardial injury in SIMD. Mechanistically, butyrate mitigated oxidative stress by increasing GSH levels and reducing MDA levels. Furthermore, butyrate treatment reversed the sepsis-induced downregulation of GPX4 and suppressed the upregulation of ACSL4 and PTGS2, thereby inhibiting ferroptosis.</div></div><div><h3>Conclusion</h3><div>These findings highlight the protective role of butyrate in SIMD, with ferroptosis inhibition serving as a key cardioprotective mechanism. Targeting gut microbiota-derived butyrate may represent a promising therapeutic strategy for sepsis-induced myocardial injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 119-127"},"PeriodicalIF":4.7,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370262","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 : 2025-10-23DOI: 10.1016/j.yjmcc.2025.10.007
Xiaosu Yuan , Lin Song , Peiyan Wang , Dandan Xiao , Yi Jia , Lin Ye , Kangwei Jia , Jianxun Wang , Wei Ding
As air pollution intensifies, the health risks associated with PM2.5 have gained increasing global attention. Previous research has established a link between PM2.5 exposure and increased risk of cardiovascular diseases (CVDs), yet the underlying mechanisms remain unclear. In this study, we demonstrate that PM2.5 induces ferroptosis in myocardial cells both in vitro and in vivo. We also show that PM2.5 exposure increases lipid peroxidation levels and cellular iron content while depleting glutathione (GSH). Notable alterations in the expression of transferrin receptor protein 1 (TfR1), ferritin light chain (FTL), and ferritin heavy chain (FTH) suggest that the dysfunction in iron uptake and storage plays a pivotal role in ferroptosis. Moreover, we observed that PM2.5 exposure upregulates p53 expression, which transcriptionally regulates TfR1 synthesis. This leads to increased iron influx into cells, causing iron overload and ultimately contributing to ferroptosis and myocardial injury. In conclusion, our findings suggest that PM2.5 promotes ferroptosis in the myocardium via the p53/TfR1 pathway.
{"title":"p53 mediates iron overload and ferroptosis via transcriptional regulation of TfR1 in PM2.5-exposed cardiomyocytes","authors":"Xiaosu Yuan , Lin Song , Peiyan Wang , Dandan Xiao , Yi Jia , Lin Ye , Kangwei Jia , Jianxun Wang , Wei Ding","doi":"10.1016/j.yjmcc.2025.10.007","DOIUrl":"10.1016/j.yjmcc.2025.10.007","url":null,"abstract":"<div><div>As air pollution intensifies, the health risks associated with PM2.5 have gained increasing global attention. Previous research has established a link between PM2.5 exposure and increased risk of cardiovascular diseases (CVDs), yet the underlying mechanisms remain unclear. In this study, we demonstrate that PM2.5 induces ferroptosis in myocardial cells both in vitro and in vivo. We also show that PM2.5 exposure increases lipid peroxidation levels and cellular iron content while depleting glutathione (GSH). Notable alterations in the expression of transferrin receptor protein 1 (TfR1), ferritin light chain (FTL), and ferritin heavy chain (FTH) suggest that the dysfunction in iron uptake and storage plays a pivotal role in ferroptosis. Moreover, we observed that PM2.5 exposure upregulates p53 expression, which transcriptionally regulates TfR1 synthesis. This leads to increased iron influx into cells, causing iron overload and ultimately contributing to ferroptosis and myocardial injury. In conclusion, our findings suggest that PM2.5 promotes ferroptosis in the myocardium via the p53/TfR1 pathway.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 128-142"},"PeriodicalIF":4.7,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370307","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}
Post-infarction metabolism changes, inflammatory responses, and fibrosis are crucial contributors to adverse cardiac remodeling. 2-(1′H-indole-3′‑carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), the aryl hydrocarbon receptor (AHR) ligand, has demonstrated effective AHR activation, yet its impact and mechanisms in myocardial infarction (MI) remain unclear.
Methods
The MI model was established by ligating left anterior coronary artery, and ITE was administered for 4 weeks. Echocardiography and hemodynamic monitoring were used to assess cardiac structure and function. Hematoxylin-eosin and Masson's trichrome were used to examine morphology and collagen deposition. Transmission electron microscopy was employed to examine mitochondrial morphology. The transcriptome and metabolome were used to screen for key targets and pathways. Hypoxic neonatal rat cardiomyocytes and fibroblasts models combined with adenoviral AHR knockdown were used to verify key targets and pathways.
Results
ITE intervention significantly improved cardiac structure and function, mitochondrial morphology, fibrosis and inflammation in MI rats. Multi-omics revealed that differentially expressed genes and metabolites were enriched in glucose metabolism related pathways and identified a key target, HK2. Compared to MI group, ITE significantly improved the expression of key enzymes in glucose metabolism after MI. In vitro, AHR activation by ITE and tapinarof significantly ameliorated hypoxia-induced abnormalities in HK2, CISY, OGDH, fibrosis, and inflammatory markers, while hexokinase inhibitor eliminated the beneficial effects of ITE. Moreover, AHR knockdown impairs glucose metabolism and promotes inflammation and fibrosis.
Conclusion
The AHR activation by ITE mitigates inflammation and fibrosis, improves cardiac structure and function by promoting HK2 and glucose metabolism after MI.
背景：梗死后代谢改变、炎症反应和纤维化是不良心脏重构的关键因素。2-（1‘ h -吲哚-3’羰基）-噻唑-4-羧酸甲酯（ITE）是芳烃受体（AHR）的配体，已被证明能有效激活AHR，但其在心肌梗死（MI）中的作用和机制尚不清楚。方法：结扎左冠状动脉前支，建立心肌梗死模型，给药4 周。超声心动图和血流动力学监测评估心脏结构和功能。苏木精-伊红和马松三色法检测形态学和胶原沉积。透射电镜观察线粒体形态。转录组和代谢组用于筛选关键靶点和途径。使用缺氧新生大鼠心肌细胞和成纤维细胞模型联合腺病毒AHR敲低来验证关键靶点和途径。结果：ITE干预显著改善心肌梗死大鼠心脏结构和功能、线粒体形态、纤维化和炎症。多组学显示，差异表达的基因和代谢物在糖代谢相关途径中富集，并确定了一个关键靶点HK2。与心肌梗死组相比，ITE可显著改善心肌梗死后糖代谢关键酶的表达。体外实验中，ITE和tapinarof激活AHR可显著改善缺氧诱导的HK2、CISY、OGDH、纤维化和炎症标志物异常，而己糖激酶抑制剂可消除ITE的有益作用。此外，AHR敲低会损害葡萄糖代谢，促进炎症和纤维化。结论：ITE激活AHR可减轻心肌梗死后的炎症和纤维化，通过促进HK2和糖代谢改善心肌结构和功能。
{"title":"Beneficial effects of aryl hydrocarbon receptor activation on post-infarction myocardial metabolism, inflammation and fibrosis: implications from multi-omics","authors":"Yong Chu , Jiang Zhu , Shuaijie Chen , Xiaoyan Lin , Zhongxing Zhou , Ruming Shen , Hongzhuang Wang , Longqing Chen , Jinxiu Lin , Hailin Zhang , Dajun Chai","doi":"10.1016/j.yjmcc.2025.10.006","DOIUrl":"10.1016/j.yjmcc.2025.10.006","url":null,"abstract":"<div><h3>Background</h3><div>Post-infarction metabolism changes, inflammatory responses, and fibrosis are crucial contributors to adverse cardiac remodeling. 2-(1′H-indole-3′‑carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), the aryl hydrocarbon receptor (AHR) ligand, has demonstrated effective AHR activation, yet its impact and mechanisms in myocardial infarction (MI) remain unclear.</div></div><div><h3>Methods</h3><div>The MI model was established by ligating left anterior coronary artery, and ITE was administered for 4 weeks. Echocardiography and hemodynamic monitoring were used to assess cardiac structure and function. Hematoxylin-eosin and Masson's trichrome were used to examine morphology and collagen deposition. Transmission electron microscopy was employed to examine mitochondrial morphology. The transcriptome and metabolome were used to screen for key targets and pathways. Hypoxic neonatal rat cardiomyocytes and fibroblasts models combined with adenoviral AHR knockdown were used to verify key targets and pathways.</div></div><div><h3>Results</h3><div>ITE intervention significantly improved cardiac structure and function, mitochondrial morphology, fibrosis and inflammation in MI rats. Multi-omics revealed that differentially expressed genes and metabolites were enriched in glucose metabolism related pathways and identified a key target, HK2. Compared to MI group, ITE significantly improved the expression of key enzymes in glucose metabolism after MI. In vitro, AHR activation by ITE and tapinarof significantly ameliorated hypoxia-induced abnormalities in HK2, CISY, OGDH, fibrosis, and inflammatory markers, while hexokinase inhibitor eliminated the beneficial effects of ITE. Moreover, AHR knockdown impairs glucose metabolism and promotes inflammation and fibrosis.</div></div><div><h3>Conclusion</h3><div>The AHR activation by ITE mitigates inflammation and fibrosis, improves cardiac structure and function by promoting HK2 and glucose metabolism after MI.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 104-118"},"PeriodicalIF":4.7,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355092","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 : 2025-10-14DOI: 10.1016/j.yjmcc.2025.10.004
Ren Jie Phang , Nan Su , Anne M. Kong , Shiang Y. Lim , Jarmon G. Lees
Type 2 diabetes is a global health crisis, closely associated with an increased risk of heart failure due to the development of diabetic cardiomyopathy. Progress in understanding the underlying mechanisms and identifying effective treatments has been limited by the lack of robust preclinical models that accurately mimic human cardiac physiology. Human induced pluripotent stem cells (iPSCs) offer the unique ability to generate large quantities of both cardiomyocytes and non-myocytes, enabling the development of advanced models for cardiovascular research. In this study, we present engineered 3D multicellular cardiac microtissues, comprising human iPSC-derived cardiomyocytes, endothelial cells, autonomic neurons, and cardiac fibroblasts, designed to provide a more physiologically relevant platform for investigating the effects of diabetogenic conditions on human heart tissue. Under diabetogenic conditions, these multicellular cardiac microtissues exhibited reduced viability, fibrotic marker expression, and prolonged systolic and diastolic phases, closely mirroring the contractile dysfunction observed in late-stage diabetic cardiomyopathy, outcomes not replicated in traditional 2D culture of cardiomyocytes or cardiomyocyte-only microtissues. Metformin treatment prevented the manifestation of diastolic dysfunction induced by diabetogenic conditions, demonstrating the utility of multicellular cardiac microtissues for drug assessment. Our findings emphasize the critical role of non-myocytes in the progression of cardiac dysfunction induced by hyperglycaemia and hyperlipidaemia, underscoring their importance in disease modelling. These iPSC-derived multicellular cardiac microtissues represent a significant advancement in preclinical models for diabetic cardiomyopathy, providing a more accurate platform for mechanistic studies and drug discovery.
{"title":"Modelling diabetes-associated metabolic stress in human multicellular cardiac microtissues","authors":"Ren Jie Phang , Nan Su , Anne M. Kong , Shiang Y. Lim , Jarmon G. Lees","doi":"10.1016/j.yjmcc.2025.10.004","DOIUrl":"10.1016/j.yjmcc.2025.10.004","url":null,"abstract":"<div><div>Type 2 diabetes is a global health crisis, closely associated with an increased risk of heart failure due to the development of diabetic cardiomyopathy. Progress in understanding the underlying mechanisms and identifying effective treatments has been limited by the lack of robust preclinical models that accurately mimic human cardiac physiology. Human induced pluripotent stem cells (iPSCs) offer the unique ability to generate large quantities of both cardiomyocytes and non-myocytes, enabling the development of advanced models for cardiovascular research. In this study, we present engineered 3D multicellular cardiac microtissues, comprising human iPSC-derived cardiomyocytes, endothelial cells, autonomic neurons, and cardiac fibroblasts, designed to provide a more physiologically relevant platform for investigating the effects of diabetogenic conditions on human heart tissue. Under diabetogenic conditions, these multicellular cardiac microtissues exhibited reduced viability, fibrotic marker expression, and prolonged systolic and diastolic phases, closely mirroring the contractile dysfunction observed in late-stage diabetic cardiomyopathy, outcomes not replicated in traditional 2D culture of cardiomyocytes or cardiomyocyte-only microtissues. Metformin treatment prevented the manifestation of diastolic dysfunction induced by diabetogenic conditions, demonstrating the utility of multicellular cardiac microtissues for drug assessment. Our findings emphasize the critical role of non-myocytes in the progression of cardiac dysfunction induced by hyperglycaemia and hyperlipidaemia, underscoring their importance in disease modelling. These iPSC-derived multicellular cardiac microtissues represent a significant advancement in preclinical models for diabetic cardiomyopathy, providing a more accurate platform for mechanistic studies and drug discovery.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 80-92"},"PeriodicalIF":4.7,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308242","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 : 2025-10-12DOI: 10.1016/j.yjmcc.2025.10.003
Paul Pauls , Larissa Fabritz , Julius R. Herting , Amanda Johann , Jule H. König , Jan S. Schulte , Matthias D. Seidl , Carolina E. Soppa , Uwe Kirchhefer
Background
It is unclear whether the increase in protein expression of PP2A regulatory subunit PR72 seen in human heart failure represents a primary compensatory mechanism or the final reaction to contractile decompensation. To address this question, we have explored the effects of chronic catecholaminergic stress in a transgenic (TG) mouse model with heart-specific overexpression of PR72 that exhibits hypercontractility at basal conditions.
Methods
Mice were treated with isoprenaline (ISO) or NaCl for 7 days using osmotic minipumps. Hearts or isolated cardiomyocytes from the animals were functionally examined.
Results
We could show (i) that PR72 expression is not only increased after chronic ISO stimulation but also in other different stress and insufficiency models. In TG mice, 7 days of ISO treatment led to (ii) increased hypertrophy, pulmonary edema, more fibrosis, and higher ACTA1 gene expression compared to wild-type (WT) mice. These effects were accompanied by (iii) a decrease in myocellular contractility and prolonged relaxation. Ca2+ transients (iv) showed correspondingly delayed decay kinetics in TG versus WT, while (v) the reduction of L-type calcium peak current by ISO treatment was less pronounced in TG cells. The decrease in RyR2 phosphorylation in TG (vi) supports a deterioration in contractility due to chronic ISO treatment in TG.
Conclusion
Our results indicate that the upregulation of PP2A-PR72 in various stress and heart failure models has a long-term effect, perpetuating the molecular and functional detrimental cardiac changes, if it does not have a triggering effect.
{"title":"Catecholaminergic stress results in signs of heart failure in PP2A-PR72 overexpressor mice","authors":"Paul Pauls , Larissa Fabritz , Julius R. Herting , Amanda Johann , Jule H. König , Jan S. Schulte , Matthias D. Seidl , Carolina E. Soppa , Uwe Kirchhefer","doi":"10.1016/j.yjmcc.2025.10.003","DOIUrl":"10.1016/j.yjmcc.2025.10.003","url":null,"abstract":"<div><h3>Background</h3><div>It is unclear whether the increase in protein expression of PP2A regulatory subunit PR72 seen in human heart failure represents a primary compensatory mechanism or the final reaction to contractile decompensation. To address this question, we have explored the effects of chronic catecholaminergic stress in a transgenic (TG) mouse model with heart-specific overexpression of PR72 that exhibits hypercontractility at basal conditions.</div></div><div><h3>Methods</h3><div>Mice were treated with isoprenaline (ISO) or NaCl for 7 days using osmotic minipumps. Hearts or isolated cardiomyocytes from the animals were functionally examined.</div></div><div><h3>Results</h3><div>We could show (i) that PR72 expression is not only increased after chronic ISO stimulation but also in other different stress and insufficiency models. In TG mice, 7 days of ISO treatment led to (ii) increased hypertrophy, pulmonary edema, more fibrosis, and higher <em>ACTA1</em> gene expression compared to wild-type (WT) mice. These effects were accompanied by (iii) a decrease in myocellular contractility and prolonged relaxation. Ca<sup>2+</sup> transients (iv) showed correspondingly delayed decay kinetics in TG versus WT, while (v) the reduction of L-type calcium peak current by ISO treatment was less pronounced in TG cells. The decrease in RyR2 phosphorylation in TG (vi) supports a deterioration in contractility due to chronic ISO treatment in TG.</div></div><div><h3>Conclusion</h3><div>Our results indicate that the upregulation of PP2A-PR72 in various stress and heart failure models has a long-term effect, perpetuating the molecular and functional detrimental cardiac changes, if it does not have a triggering effect.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 66-79"},"PeriodicalIF":4.7,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292429","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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