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}
Pub Date : 2025-10-10DOI: 10.1016/j.yjmcc.2025.10.002
Yuhan Wang , Yujing Li , Yanan Zhou , Hao Zhang , Jingyi Zang , Chaofan Yang , Zeyu Gao , Yu Hou , Moshi Song
Acute myocardial infarction (AMI) is a leading cause of cardiovascular disease-related death. Reperfusion therapies, although essential, can exacerbate damage through myocardial ischemia/reperfusion (I/R) injury. Cyclophilin D (CypD) and mitochondrial permeability transition pore (mPTP) opening have been identified as potential therapeutic targets for I/R injury. However, clinical trials with cyclosporin A (CsA) have shown mixed results, highlighting the urgent need for alternative strategies to suppress CypD expression or activity. In this study, we explored the role of Nynrin, a newly identified transcriptional repressor of peptidylprolyl isomerase F (Ppif) that encodes CypD, in mitigating I/R injury by regulating mPTP opening. We first observed that Nynrin was downregulated in adult mouse hearts subjected to I/R and in primary adult mouse cardiomyocytes upon oxygen-glucose deprivation/reperfusion (OGD/R). Subsequently, we generated a tamoxifen-inducible cardiomyocyte-specific Nynrin-knockout (Nynrin-cKO) mouse model, which was well-tolerated in otherwise normal adult mouse hearts. Notably, Nynrin-cKO mice exhibited exacerbated contractile dysfunction and cardiac injury, characterized by enhanced Ppif transcription, CypD expression, mPTP opening, and cardiomyocyte death when subjected to I/R. Furthermore, the exacerbated I/R-induced cardiac dysfunction in Nynrin-cKO mice was significantly reversed by CsA, an mPTP inhibitor that targets CypD, indicating that the intensified pathological manifestations in Nynrin-cKO mice during I/R injury were dependent on CypD and mPTP. Conversely, Nynrin overexpression in primary adult mouse cardiomyocytes blunted Ppif/CypD upregulation and restrained mPTP opening, thus reducing cardiomyocyte damage upon OGD/R. Taken together, our findings highlight the critical role of Nynrin in regulating CypD and mPTP in I/R injury and suggest that targeting Nynrin may be a promising therapeutic strategy for mitigating cardiac dysfunction in managing I/R injury.
{"title":"Nynrin enhances cardiac function by inhibiting mitochondrial permeability transition pore opening upon myocardial ischemia/reperfusion injury","authors":"Yuhan Wang , Yujing Li , Yanan Zhou , Hao Zhang , Jingyi Zang , Chaofan Yang , Zeyu Gao , Yu Hou , Moshi Song","doi":"10.1016/j.yjmcc.2025.10.002","DOIUrl":"10.1016/j.yjmcc.2025.10.002","url":null,"abstract":"<div><div>Acute myocardial infarction (AMI) is a leading cause of cardiovascular disease-related death. Reperfusion therapies, although essential, can exacerbate damage through myocardial ischemia/reperfusion (I/R) injury. Cyclophilin D (CypD) and mitochondrial permeability transition pore (mPTP) opening have been identified as potential therapeutic targets for I/R injury. However, clinical trials with cyclosporin A (CsA) have shown mixed results, highlighting the urgent need for alternative strategies to suppress CypD expression or activity. In this study, we explored the role of Nynrin, a newly identified transcriptional repressor of peptidylprolyl isomerase F (<em>Ppif</em>) that encodes CypD, in mitigating I/R injury by regulating mPTP opening. We first observed that <em>Nynrin</em> was downregulated in adult mouse hearts subjected to I/R and in primary adult mouse cardiomyocytes upon oxygen-glucose deprivation/reperfusion (OGD/R). Subsequently, we generated a tamoxifen-inducible cardiomyocyte-specific <em>Nynrin</em>-knockout (<em>Nynrin</em>-cKO) mouse model, which was well-tolerated in otherwise normal adult mouse hearts. Notably, <em>Nynrin</em>-cKO mice exhibited exacerbated contractile dysfunction and cardiac injury, characterized by enhanced <em>Ppif</em> transcription, CypD expression, mPTP opening, and cardiomyocyte death when subjected to I/R. Furthermore, the exacerbated I/R-induced cardiac dysfunction in <em>Nynrin</em>-cKO mice was significantly reversed by CsA, an mPTP inhibitor that targets CypD, indicating that the intensified pathological manifestations in <em>Nynrin</em>-cKO mice during I/R injury were dependent on CypD and mPTP. Conversely, Nynrin overexpression in primary adult mouse cardiomyocytes blunted <em>Ppif</em>/CypD upregulation and restrained mPTP opening, thus reducing cardiomyocyte damage upon OGD/R. Taken together, our findings highlight the critical role of Nynrin in regulating CypD and mPTP in I/R injury and suggest that targeting Nynrin may be a promising therapeutic strategy for mitigating cardiac dysfunction in managing I/R injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 93-103"},"PeriodicalIF":4.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280335","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 : 2025-10-03DOI: 10.1016/j.yjmcc.2025.10.001
Severin Haider , Dragana Stefanovska , Eliza Sassu , Claudia Domisch , Madelon Hossfeld , Pia Iaconianni , Stefanie Perez-Feliz , Franziska Schneider-Warme , Peter Kohl , Sebastian Preissl , Luis Hortells
Schwann cells (SC) are crucial for physiological impulse conduction in peripheral nerves. They produce myelin, provide axonal metabolic support, and contribute to reparatory processes after nerve injury. During aging, peripheral nerves acquire myelin structural anomalies and are characterized by a lower fraction of SC and a higher fraction of senescent cells. All these changes correlate with impaired electrical conduction and consequently altered function of target tissues including skeletal muscle weakness and cardiac arrhythmia. To characterize and compare cardiac and sciatic nerve SC, as well as to explore age-related differences in SC abundance and their properties, we analyzed two TdTomato reporter mouse strains to isolate Sox10 or Plp1 expressing SC. We performed RNA-sequencing on sorted TdTomato-positive cells from the heart and sciatic nerve and validated transcriptomic findings at the protein level using immunofluorescence. Our data reveal a pro-angiogenic profile in cardiac SC when compared to sciatic SC. In addition, higher levels of neural-death associated genes and lower gene and protein expression levels of the fatty acid co-transporter Fabp4/FABP4 are detected in cardiac SC from old compared to young mice, suggesting an aging-related impairment of fatty acid transport. Finally, sciatic SC activate collagen remodeling and increased pro-inflammatory signaling including TNFα. Thus, cardiac and musculoskeletal SC have different expression profiles, and undergo different changes during aging, which may contribute to impaired nerve function in both organ systems.
{"title":"Multi-level expression profiling of cardiac and musculoskeletal Schwann cells in young and old mice","authors":"Severin Haider , Dragana Stefanovska , Eliza Sassu , Claudia Domisch , Madelon Hossfeld , Pia Iaconianni , Stefanie Perez-Feliz , Franziska Schneider-Warme , Peter Kohl , Sebastian Preissl , Luis Hortells","doi":"10.1016/j.yjmcc.2025.10.001","DOIUrl":"10.1016/j.yjmcc.2025.10.001","url":null,"abstract":"<div><div>Schwann cells (SC) are crucial for physiological impulse conduction in peripheral nerves. They produce myelin, provide axonal metabolic support, and contribute to reparatory processes after nerve injury. During aging, peripheral nerves acquire myelin structural anomalies and are characterized by a lower fraction of SC and a higher fraction of senescent cells. All these changes correlate with impaired electrical conduction and consequently altered function of target tissues including skeletal muscle weakness and cardiac arrhythmia. To characterize and compare cardiac and sciatic nerve SC, as well as to explore age-related differences in SC abundance and their properties, we analyzed two TdTomato reporter mouse strains to isolate <em>Sox10</em> or <em>Plp1</em> expressing SC. We performed RNA-sequencing on sorted TdTomato-positive cells from the heart and sciatic nerve and validated transcriptomic findings at the protein level using immunofluorescence. Our data reveal a pro-angiogenic profile in cardiac SC when compared to sciatic SC. In addition, higher levels of neural-death associated genes and lower gene and protein expression levels of the fatty acid co-transporter <em>Fabp4</em>/FABP4 are detected in cardiac SC from old compared to young mice, suggesting an aging-related impairment of fatty acid transport. Finally, sciatic SC activate collagen remodeling and increased pro-inflammatory signaling including TNFα. Thus, cardiac and musculoskeletal SC have different expression profiles, and undergo different changes during aging, which may contribute to impaired nerve function in both organ systems.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 51-65"},"PeriodicalIF":4.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232688","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 : 2025-10-02DOI: 10.1016/j.yjmcc.2025.09.009
Zhiyong Sun , Na Li , Min Huang , Ying Li , Changhao Wang , Zhezhe Qu , Shuting Yu , Zhongting Mei , Bo Wu , Shunkang Dou , Jianhao Jiang , Yaozhi Zhang , Chuanhao Huang , Jiaqi Han , Yufei Yue , Xin Li , Yuechao Dong , Weijie Du
Cardiac fibrosis, a common pathological process characterized by excessive deposition of extracellular matrix components in the myocardium, poses a critical challenge in the field of cardiovascular research and clinical practice. 5-Methylcytosine (m5C) is an extensive post-transcriptional RNA modification known to participate in various cellular responses and biological processes by regulating RNA metabolism. However, it remains unclear whether m5C RNA modifications exert regulatory effects on cardiovascular diseases, particularly cardiac fibrosis. Here, we report that NSUN2, a typical m5C methyltransferase, affects the RNA stability of HuR through m5C modification, promoting the development of cardiac fibrosis. Upon the conditional knockdown of NSUN2 specifically in myofibroblasts, the extent of cardiac fibrosis was suppressed. In conclusion, we specifically knocked down NSUN2 in cardiac myofibroblasts, which further reduced the RNA stability of HuR and thus ameliorated cardiac fibrosis caused by myocardial ischemia, offering a new therapeutic target for the clinical treatment of cardiac fibrosis.
{"title":"Myofibroblast specific knockdown of NSUN2 suppresses cardiac fibrosis post-myocardial infarction","authors":"Zhiyong Sun , Na Li , Min Huang , Ying Li , Changhao Wang , Zhezhe Qu , Shuting Yu , Zhongting Mei , Bo Wu , Shunkang Dou , Jianhao Jiang , Yaozhi Zhang , Chuanhao Huang , Jiaqi Han , Yufei Yue , Xin Li , Yuechao Dong , Weijie Du","doi":"10.1016/j.yjmcc.2025.09.009","DOIUrl":"10.1016/j.yjmcc.2025.09.009","url":null,"abstract":"<div><div>Cardiac fibrosis, a common pathological process characterized by excessive deposition of extracellular matrix components in the myocardium, poses a critical challenge in the field of cardiovascular research and clinical practice. 5-Methylcytosine (m5C) is an extensive post-transcriptional RNA modification known to participate in various cellular responses and biological processes by regulating RNA metabolism. However, it remains unclear whether m5C RNA modifications exert regulatory effects on cardiovascular diseases, particularly cardiac fibrosis. Here, we report that NSUN2, a typical m5C methyltransferase, affects the RNA stability of HuR through m5C modification, promoting the development of cardiac fibrosis. Upon the conditional knockdown of NSUN2 specifically in myofibroblasts, the extent of cardiac fibrosis was suppressed. In conclusion, we specifically knocked down NSUN2 in cardiac myofibroblasts, which further reduced the RNA stability of HuR and thus ameliorated cardiac fibrosis caused by myocardial ischemia, offering a new therapeutic target for the clinical treatment of cardiac fibrosis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 27-36"},"PeriodicalIF":4.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228419","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 : 2025-09-30DOI: 10.1016/j.yjmcc.2025.09.007
Yong Peng , Linlin Shang , Gan Chen , Simeng Zhao , Mengyun Mao , Danxi Zhu , Di Qin
Acute sympathetic stress, which causes hyperactivation of β-adrenergic receptors (β-AR) in the heart, is a key pathological factor in the development of cardiac disease. Isoproterenol (ISO) is a non-selective β-AR agonist, which was utilized to develop an experimental animal model of pathological cardiac remodeling, simulating the acute sympathetic stress-induced cardiac injury. Current research evidences support the potential role of exercise in preventing or treating heart injury caused by β-adrenergic overactivation. The mechanisms of exercise against ISO-induced cardiac injury include of inhibiting cardiac inflammation and oxidative stress, suppressing apoptosis, pyroptosis, and necroptosis in cardiomyocytes, activating Adenosine 5′ -monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, reducing reactive oxygen species (ROS) to regulate the inflammatory response. Despite the protective effects of exercise in attenuating ISO-induced cardiac injury, further studies are necessary to explore the optimal combination of exercise intensity and duration. Additionally, comparative research is required to evaluate the protective effects of different exercise types, investigate the relationship between exercise-induced protection and ISO dosage, and reveal new mechanism underlying the protective effects of exercise against ISO-induced heart injury. This study will improve our understanding of the mechanisms by which exercise protects against cardiac injury induced by β-adrenergic overload, and establish a stronger foundation for studying the effects of exercise against β-adrenergic overload-induced cardiac injury.
{"title":"Animal models and mechanisms of exercise in attenuating cardiac injury induced by beta-adrenergic hyperactivation","authors":"Yong Peng , Linlin Shang , Gan Chen , Simeng Zhao , Mengyun Mao , Danxi Zhu , Di Qin","doi":"10.1016/j.yjmcc.2025.09.007","DOIUrl":"10.1016/j.yjmcc.2025.09.007","url":null,"abstract":"<div><div>Acute sympathetic stress, which causes hyperactivation of β-adrenergic receptors (β-AR) in the heart, is a key pathological factor in the development of cardiac disease. Isoproterenol (ISO) is a non-selective β-AR agonist, which was utilized to develop an experimental animal model of pathological cardiac remodeling, simulating the acute sympathetic stress-induced cardiac injury. Current research evidences support the potential role of exercise in preventing or treating heart injury caused by β-adrenergic overactivation. The mechanisms of exercise against ISO-induced cardiac injury include of inhibiting cardiac inflammation and oxidative stress, suppressing apoptosis, pyroptosis, and necroptosis in cardiomyocytes, activating Adenosine 5′ -monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, reducing reactive oxygen species (ROS) to regulate the inflammatory response. Despite the protective effects of exercise in attenuating ISO-induced cardiac injury, further studies are necessary to explore the optimal combination of exercise intensity and duration. Additionally, comparative research is required to evaluate the protective effects of different exercise types, investigate the relationship between exercise-induced protection and ISO dosage, and reveal new mechanism underlying the protective effects of exercise against ISO-induced heart injury. This study will improve our understanding of the mechanisms by which exercise protects against cardiac injury induced by β-adrenergic overload, and establish a stronger foundation for studying the effects of exercise against β-adrenergic overload-induced cardiac injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 15-26"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212821","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 : 2025-09-30DOI: 10.1016/j.yjmcc.2025.09.008
Dilip Thomas , Phillip C. Yang , Joseph C. Wu , Nazish Sayed
The COVID-19 pandemic has revealed that the impact of SARS-CoV-2 infection extends well beyond the acute phase, with long-term sequelae affecting multiple organ systems, most notably, the cardiovascular system. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by persistent symptoms such as fatigue, dyspnea, chest pain, and palpitations, which can last for months or even years after initial recovery. Increasing evidence implicates immune dysregulation, endothelial dysfunction, persistent viral antigens, and coagulopathy as central drivers of cardiovascular complications. Mechanistic studies demonstrate that direct viral infection of cardiac and vascular cells, along with autoantibody formation and cytokine-mediated injury, contribute to myocardial inflammation, fibrosis, and arrhythmias. Sex-based immunological differences and underlying comorbidities further influence individual susceptibility and disease trajectory. Large-scale epidemiological studies have confirmed significantly increased risks of pericarditis, cardiomyopathy, dysrhythmias, and heart failure among COVID-19 survivors. In parallel, the emergence of advanced preclinical platforms, including patient-derived induced pluripotent stem cell (iPSC)-based cardiac organoids, engineered heart tissues, and organ-on-a-chip systems has enabled mechanistic dissection of Long COVID pathophysiology. These human-relevant models, when integrated with clinical datasets and artificial intelligence (AI)-driven analytics, offer powerful tools for biomarker discovery, risk stratification, and precision therapeutic development. This review synthesizes the current understanding of cardiovascular involvement in Long COVID, highlights key mechanistic insights from both clinical and preclinical studies, and outlines future directions for diagnostic and therapeutic innovation.
{"title":"Decoding long COVID-associated cardiovascular dysfunction: Mechanisms, models, and new approach methodologies","authors":"Dilip Thomas , Phillip C. Yang , Joseph C. Wu , Nazish Sayed","doi":"10.1016/j.yjmcc.2025.09.008","DOIUrl":"10.1016/j.yjmcc.2025.09.008","url":null,"abstract":"<div><div>The COVID-19 pandemic has revealed that the impact of SARS-CoV-2 infection extends well beyond the acute phase, with long-term sequelae affecting multiple organ systems, most notably, the cardiovascular system. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by persistent symptoms such as fatigue, dyspnea, chest pain, and palpitations, which can last for months or even years after initial recovery. Increasing evidence implicates immune dysregulation, endothelial dysfunction, persistent viral antigens, and coagulopathy as central drivers of cardiovascular complications. Mechanistic studies demonstrate that direct viral infection of cardiac and vascular cells, along with autoantibody formation and cytokine-mediated injury, contribute to myocardial inflammation, fibrosis, and arrhythmias. Sex-based immunological differences and underlying comorbidities further influence individual susceptibility and disease trajectory. Large-scale epidemiological studies have confirmed significantly increased risks of pericarditis, cardiomyopathy, dysrhythmias, and heart failure among COVID-19 survivors. In parallel, the emergence of advanced preclinical platforms, including patient-derived induced pluripotent stem cell (iPSC)-based cardiac organoids, engineered heart tissues, and organ-on-a-chip systems has enabled mechanistic dissection of Long COVID pathophysiology. These human-relevant models, when integrated with clinical datasets and artificial intelligence (AI)-driven analytics, offer powerful tools for biomarker discovery, risk stratification, and precision therapeutic development. This review synthesizes the current understanding of cardiovascular involvement in Long COVID, highlights key mechanistic insights from both clinical and preclinical studies, and outlines future directions for diagnostic and therapeutic innovation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 37-50"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212785","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 : 2025-09-23DOI: 10.1016/j.yjmcc.2025.09.006
Judy S. Choi , Mehnaz Pervin , James E. Vince , Arpeeta Sharma , Judy B. de Haan
Cardiovascular disease remains a leading global cause of mortality, with inflammation playing a crucial role in driving its pathology. Despite advancements in cardiovascular disease management, current treatment options primarily address risk factors and symptoms rather than underlying disease mechanisms. Among the key mechanistic drivers are the NLRP3 multiprotein inflammasome complexes of the innate immune system, which are activated in response to cellular stress or injury. One of the key downstream effectors of NLRP3 activation is gasdermin D, which forms pores in the plasma membrane to initiate pyroptotic cell death, leading to the release of pro-inflammatory cytokines. This review will highlight the role of NLRP3 inflammasome activation and gasdermin D-mediated pyroptosis in driving cardiovascular diseases, including atherosclerosis, myocardial infarction, ischemic stroke and diabetic cardiomyopathy. It will also identify recent innovative therapeutic approaches that target the NLRP3 inflammasome-gasdermin D axis, which are currently being evaluated in preclinical studies and clinical trials.
{"title":"Targeting the NLRP3 Inflammasome-Gasdermin D Axis to Combat Cardiovascular Diseases","authors":"Judy S. Choi , Mehnaz Pervin , James E. Vince , Arpeeta Sharma , Judy B. de Haan","doi":"10.1016/j.yjmcc.2025.09.006","DOIUrl":"10.1016/j.yjmcc.2025.09.006","url":null,"abstract":"<div><div>Cardiovascular disease remains a leading global cause of mortality, with inflammation playing a crucial role in driving its pathology. Despite advancements in cardiovascular disease management, current treatment options primarily address risk factors and symptoms rather than underlying disease mechanisms. Among the key mechanistic drivers are the NLRP3 multiprotein inflammasome complexes of the innate immune system, which are activated in response to cellular stress or injury. One of the key downstream effectors of NLRP3 activation is gasdermin D, which forms pores in the plasma membrane to initiate pyroptotic cell death, leading to the release of pro-inflammatory cytokines. This review will highlight the role of NLRP3 inflammasome activation and gasdermin D-mediated pyroptosis in driving cardiovascular diseases, including atherosclerosis, myocardial infarction, ischemic stroke and diabetic cardiomyopathy. It will also identify recent innovative therapeutic approaches that target the NLRP3 inflammasome-gasdermin D axis, which are currently being evaluated in preclinical studies and clinical trials.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"209 ","pages":"Pages 1-14"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149344","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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