Pub Date : 2026-02-05DOI: 10.1016/j.yjmcc.2026.02.001
Ming-Min Zhou, Liao Xu, Di-Zhe Huang, Xi Wang, Jin-Qiang Peng, Yu Liu
Aims: Ventricular arrhythmias (VAs) are a leading cause of sudden cardiac death (SCD) following myocardial infarction (MI), with cardiac sympathetic hyperexcitability serving as a critical trigger. While β-blockers provide partial protection, residual arrhythmic risk persists. Neuronal M-channels (KCNQ2/3) function as critical "brakes" limiting sympathetic hyperexcitability, yet their role in post-MI ventricular arrhythmogenesis remains undefined. In this study, we investigated whether KCNQ2 downregulation in sympathetic ganglia contributes to heightened arrhythmic susceptibility following MI.
Methods and results: Male Sprague-Dawley rats (n = 104) were randomized into four groups: sham, MI, shCtrl+MI, and shKCNQ2 + MI. Adeno-associated viral vectors targeting KCNQ2 or scrambled controls were injected into the left stellate ganglion (LSG) 3 weeks before permanent left anterior descending coronary artery ligation. KCNQ2 expression was significantly reduced in LSG neurons following MI. Targeted KCNQ2 knockdown markedly exacerbated VAs burden during both acute (0-8 h) and chronic phases (4 weeks) post-MI, with increased ventricular fibrillation incidence (93% vs. 43% in shCtrl, P < 0.05). The basal firing activity of LSG neurons was significantly greater in shKCNQ2 + MI rats compared with shCtrl+MI rats. KCNQ2 deficiency exacerbated sympatho-vagal imbalance (elevated LF/HF ratio) and increased ventricular repolarization heterogeneity. Ex vivo studies confirmed enhanced arrhythmia inducibility and reduced ventricular fibrillation threshold in the KCNQ2 knockdown group.
Conclusion: Knockdown of KCNQ2 in LSG neurons exacerbates cardiac sympathetic discharge activity and heightens arrhythmic vulnerability post-MI; however, the absence of direct M-current measurements and gain-of-function validation limits causal conclusions.
{"title":"KCNQ2 downregulation in left stellate ganglion neurons exacerbates malignant ventricular arrhythmias after myocardial infarction.","authors":"Ming-Min Zhou, Liao Xu, Di-Zhe Huang, Xi Wang, Jin-Qiang Peng, Yu Liu","doi":"10.1016/j.yjmcc.2026.02.001","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2026.02.001","url":null,"abstract":"<p><strong>Aims: </strong>Ventricular arrhythmias (VAs) are a leading cause of sudden cardiac death (SCD) following myocardial infarction (MI), with cardiac sympathetic hyperexcitability serving as a critical trigger. While β-blockers provide partial protection, residual arrhythmic risk persists. Neuronal M-channels (KCNQ2/3) function as critical \"brakes\" limiting sympathetic hyperexcitability, yet their role in post-MI ventricular arrhythmogenesis remains undefined. In this study, we investigated whether KCNQ2 downregulation in sympathetic ganglia contributes to heightened arrhythmic susceptibility following MI.</p><p><strong>Methods and results: </strong>Male Sprague-Dawley rats (n = 104) were randomized into four groups: sham, MI, shCtrl+MI, and shKCNQ2 + MI. Adeno-associated viral vectors targeting KCNQ2 or scrambled controls were injected into the left stellate ganglion (LSG) 3 weeks before permanent left anterior descending coronary artery ligation. KCNQ2 expression was significantly reduced in LSG neurons following MI. Targeted KCNQ2 knockdown markedly exacerbated VAs burden during both acute (0-8 h) and chronic phases (4 weeks) post-MI, with increased ventricular fibrillation incidence (93% vs. 43% in shCtrl, P < 0.05). The basal firing activity of LSG neurons was significantly greater in shKCNQ2 + MI rats compared with shCtrl+MI rats. KCNQ2 deficiency exacerbated sympatho-vagal imbalance (elevated LF/HF ratio) and increased ventricular repolarization heterogeneity. Ex vivo studies confirmed enhanced arrhythmia inducibility and reduced ventricular fibrillation threshold in the KCNQ2 knockdown group.</p><p><strong>Conclusion: </strong>Knockdown of KCNQ2 in LSG neurons exacerbates cardiac sympathetic discharge activity and heightens arrhythmic vulnerability post-MI; however, the absence of direct M-current measurements and gain-of-function validation limits causal conclusions.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137605","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 : 2026-01-28DOI: 10.1016/j.yjmcc.2026.01.005
Yao Qu , Zhi-Xue Liu , Xiao-Xu Zheng , Sheng-Nan Wu , Jun-Qing An , Ming-Hui Zou , Zhi-Ren Zhang
{"title":"Corrigendum to “MFN2-mediated decrease in mitochondria-associated endoplasmic reticulum membranes contributes to sunitinib-induced endothelial dysfunction and hypertension/JMCC 10006”.","authors":"Yao Qu , Zhi-Xue Liu , Xiao-Xu Zheng , Sheng-Nan Wu , Jun-Qing An , Ming-Hui Zou , Zhi-Ren Zhang","doi":"10.1016/j.yjmcc.2026.01.005","DOIUrl":"10.1016/j.yjmcc.2026.01.005","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Page 31"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081020","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 : 2026-01-24DOI: 10.1016/j.yjmcc.2025.12.013
Dahienne Ferreira de Oliveira, Leonardo Maciel, Antonio Dos Santos Silva, Keyla Cristiny Da Coutinho, Fernando Lucas Palhano, Marcelo F Santiago, Debora Foguel
Cerebral dopamine neurotrophic factor (CDNF) has emerged as a key cytoprotective molecule, with well-documented neuroprotective effects in Parkinson's disease models and, more recently, demonstrated cardioprotective properties. In this study, we investigated the protective role of CDNF and its isolated domains (CDNF-N and CDNF-C) in isolated hearts subjected to ischemia/reperfusion (I/R) injury. Our data showed that the infarct area at risk decreased from approximately 40% in untreated hearts to about 20% in the presence of CDNF or CDNF-C, but not CDNF-N, indicating that CDNF-C is the principal mediator of CDNF's cardioprotective activity. This effect is mediated by activation of the PI3K/AKT signaling pathway, as the cardioprotective action of CDNF-C was abolished by wortmannin, a PI3K/AKT inhibitor. The study also examined the interaction between CDNF and the KDEL receptor (KDEL-R) at the plasma membrane using cardiomyocytes (H9c2 cells, neonatal primary cardiomyocytes, and human induced pluripotent stem cell-derived cardiomyocytes - hiPSC-dCM) exposed to endoplasmic reticulum (ER) stress induced by thapsigargin. Confocal microscopy revealed that KDEL-R translocates to the plasma membrane under ER stress, where it binds to both full-length CDNF and CDNF-C. However, only the full-length protein undergoes internalization by cardiomyocytes, suggesting that the N-domain is critical for CDNF endocytosis. Following internalization, CDNF traffics primarily to lysosomes, with a minor fraction localizing to mitochondria and the ER. Collectively, these findings identify exogenous CDNF - through its C-domain - as a novel cardiomyokine and highlight its therapeutic potential in cardiac injury and ER stress-related disorders via KDEL-R-mediated PI3K/AKT activation.
{"title":"The C-domain of the cerebral dopamine neurotrophic factor (CDNF) is responsible for its cardioprotective activity by binding to the KDEL receptor relocated to the plasma membrane under endoplasmic reticulum stress conditions.","authors":"Dahienne Ferreira de Oliveira, Leonardo Maciel, Antonio Dos Santos Silva, Keyla Cristiny Da Coutinho, Fernando Lucas Palhano, Marcelo F Santiago, Debora Foguel","doi":"10.1016/j.yjmcc.2025.12.013","DOIUrl":"10.1016/j.yjmcc.2025.12.013","url":null,"abstract":"<p><p>Cerebral dopamine neurotrophic factor (CDNF) has emerged as a key cytoprotective molecule, with well-documented neuroprotective effects in Parkinson's disease models and, more recently, demonstrated cardioprotective properties. In this study, we investigated the protective role of CDNF and its isolated domains (CDNF-N and CDNF-C) in isolated hearts subjected to ischemia/reperfusion (I/R) injury. Our data showed that the infarct area at risk decreased from approximately 40% in untreated hearts to about 20% in the presence of CDNF or CDNF-C, but not CDNF-N, indicating that CDNF-C is the principal mediator of CDNF's cardioprotective activity. This effect is mediated by activation of the PI3K/AKT signaling pathway, as the cardioprotective action of CDNF-C was abolished by wortmannin, a PI3K/AKT inhibitor. The study also examined the interaction between CDNF and the KDEL receptor (KDEL-R) at the plasma membrane using cardiomyocytes (H9c2 cells, neonatal primary cardiomyocytes, and human induced pluripotent stem cell-derived cardiomyocytes - hiPSC-dCM) exposed to endoplasmic reticulum (ER) stress induced by thapsigargin. Confocal microscopy revealed that KDEL-R translocates to the plasma membrane under ER stress, where it binds to both full-length CDNF and CDNF-C. However, only the full-length protein undergoes internalization by cardiomyocytes, suggesting that the N-domain is critical for CDNF endocytosis. Following internalization, CDNF traffics primarily to lysosomes, with a minor fraction localizing to mitochondria and the ER. Collectively, these findings identify exogenous CDNF - through its C-domain - as a novel cardiomyokine and highlight its therapeutic potential in cardiac injury and ER stress-related disorders via KDEL-R-mediated PI3K/AKT activation.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":" ","pages":"32-47"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146052461","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 : 2026-01-19DOI: 10.1016/j.yjmcc.2026.01.006
Lanzhuoying Zheng , Ke Liang , Yuanyuan Peng , Mengying Jin , Xiao Chen , Xinran Liu , Hua Shao , Tao Zhang , Jiawei Duan , Feifei Yan , Baozhu Wei , Jing Wan
Background
Atherosclerosis (AS), the primary pathophysiological foundation of coronary artery disease (CAD), initiates through endothelial dysfunction that facilitates lipid deposition and plaque formation. Emerging evidence implicates dipeptidyl peptidase IV (DPP4) in vascular pathologies, yet its mechanistic role in AS-associated endothelial ferroptosis remains undefined.
Methods
Multidisciplinary approaches were employed: 1) Bioinformatic analysis of public databases identified DPP4-ferroptosis-AS associations; 2) Clinical samples measured plasma DPP4 levels across CAD severity strata; 3) Atherogenic progression was compared between DPP4−/−ApoE−/− and ApoE−/− mice under a high-fat diet; 4) Ox-LDL-induced endothelial injury models assessed DPP4-mediated ferroptosis mechanisms combining proteomics, cycloheximide chase assays, and pharmacological modulation of autophagy.
Results
Clinical samples analysis revealed a significant increase in plasma DPP4 levels in patients with severe coronary artery stenosis, with DPP4 enrichment observed at plaque. Animal studies demonstrated that DPP4 deficiency attenuated progression of AS and ferroptosis in murine models. Cellular experiments revealed ox-LDL upregulated DPP4 expression, concomitant with increased ferroptosis susceptibility and endothelial dysfunction. DPP4 inhibition preserved endothelial viability by blocking lipid peroxide accumulation. Mechanistically, mouse proteomics revealed that ferroptosis and autophagy pathways were associated with DPP4 in AS. DPP4 destabilized FTH1 via NCOA4-mediated ferritinophagy, proven by concordant rescue effects of chloroquine (autophagy inhibition) and saxagliptin (DPP4 inhibition) on FTH1 preservation.
Conclusions
This study establishes endothelial DPP4 as a regulator of ferritinophagy-driven ferroptosis, inducing endothelial dysfunction in AS. Our findings propose targeting the DPP4-NCOA4-FTH1 axis as a promising strategy to preserve endothelial viability and halt early AS progression, with translational implications for repurposing DPP4 inhibitors in cardiovascular therapeutics.
{"title":"DPP4-regulated endothelial cell ferroptosis modulates atherosclerosis progression by ferritinophagy","authors":"Lanzhuoying Zheng , Ke Liang , Yuanyuan Peng , Mengying Jin , Xiao Chen , Xinran Liu , Hua Shao , Tao Zhang , Jiawei Duan , Feifei Yan , Baozhu Wei , Jing Wan","doi":"10.1016/j.yjmcc.2026.01.006","DOIUrl":"10.1016/j.yjmcc.2026.01.006","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis (AS), the primary pathophysiological foundation of coronary artery disease (CAD), initiates through endothelial dysfunction that facilitates lipid deposition and plaque formation. Emerging evidence implicates dipeptidyl peptidase IV (DPP4) in vascular pathologies, yet its mechanistic role in AS-associated endothelial ferroptosis remains undefined.</div></div><div><h3>Methods</h3><div>Multidisciplinary approaches were employed: 1) Bioinformatic analysis of public databases identified DPP4-ferroptosis-AS associations; 2) Clinical samples measured plasma DPP4 levels across CAD severity strata; 3) Atherogenic progression was compared between DPP4<sup>−/−</sup>ApoE<sup>−/−</sup> and ApoE<sup>−/−</sup> mice under a high-fat diet; 4) Ox-LDL-induced endothelial injury models assessed DPP4-mediated ferroptosis mechanisms combining proteomics, cycloheximide chase assays, and pharmacological modulation of autophagy.</div></div><div><h3>Results</h3><div>Clinical samples analysis revealed a significant increase in plasma DPP4 levels in patients with severe coronary artery stenosis, with DPP4 enrichment observed at plaque. Animal studies demonstrated that DPP4 deficiency attenuated progression of AS and ferroptosis in murine models. Cellular experiments revealed ox-LDL upregulated DPP4 expression, concomitant with increased ferroptosis susceptibility and endothelial dysfunction. DPP4 inhibition preserved endothelial viability by blocking lipid peroxide accumulation. Mechanistically, mouse proteomics revealed that ferroptosis and autophagy pathways were associated with DPP4 in AS. DPP4 destabilized FTH1 via NCOA4-mediated ferritinophagy, proven by concordant rescue effects of chloroquine (autophagy inhibition) and saxagliptin (DPP4 inhibition) on FTH1 preservation.</div></div><div><h3>Conclusions</h3><div>This study establishes endothelial DPP4 as a regulator of ferritinophagy-driven ferroptosis, inducing endothelial dysfunction in AS. Our findings propose targeting the DPP4-NCOA4-FTH1 axis as a promising strategy to preserve endothelial viability and halt early AS progression, with translational implications for repurposing DPP4 inhibitors in cardiovascular therapeutics.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 14-30"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018895","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 : 2026-01-14DOI: 10.1016/j.yjmcc.2026.01.004
Monica Kanki , Morag J. Young
Diabetes mellitus is a global health burden and represents a major cause of cardiovascular disease-related morbidity and mortality. Diabetic cardiomyopathy continues to predispose individuals to overt heart failure despite significant advances in the development of anti-hyperglycaemic medications. Currently, there is a lack of biomarkers for the detection of myocardial injury in the early stages of diabetic cardiomyopathy, which underscores the urgent need to identify early disease processes and develop novel therapeutic strategies. The mineralocorticoid receptor (MR) has proven to be a valuable therapeutic target in heart failure, which may translate to a promising option to reduce the risk of cardiovascular complications in mid-to-late stages of diabetic cardiomyopathy. This narrative review discusses the role of inappropriate MR activation in common pathogenic mechanisms underlying diabetic cardiomyopathy, as well as highlighting the circadian clock as an emerging target in diabetes that has been linked to modulation of MR activation. It will also outline the cardiovascular protection yielded from anti-diabetic agents and MR antagonists (MRA) in preclinical and clinical settings of diabetes. Although our knowledge of the mechanisms of myocardial injury in diabetes is expanding quickly, current therapeutic strategies do not mitigate the high risks of cardiovascular disease in this vulnerable population. Further investment in understanding the consequences of adverse MR signalling and potentially the early introduction of MR blockade in management plans may be critical for combating the burden of cardiomyopathy in the diabetic population.
{"title":"The mineralocorticoid receptor: a new chapter for therapeutic regulation of diabetic cardiomyopathy","authors":"Monica Kanki , Morag J. Young","doi":"10.1016/j.yjmcc.2026.01.004","DOIUrl":"10.1016/j.yjmcc.2026.01.004","url":null,"abstract":"<div><div>Diabetes mellitus is a global health burden and represents a major cause of cardiovascular disease-related morbidity and mortality. Diabetic cardiomyopathy continues to predispose individuals to overt heart failure despite significant advances in the development of anti-hyperglycaemic medications. Currently, there is a lack of biomarkers for the detection of myocardial injury in the early stages of diabetic cardiomyopathy, which underscores the urgent need to identify early disease processes and develop novel therapeutic strategies. The mineralocorticoid receptor (MR) has proven to be a valuable therapeutic target in heart failure, which may translate to a promising option to reduce the risk of cardiovascular complications in mid-to-late stages of diabetic cardiomyopathy. This narrative review discusses the role of inappropriate MR activation in common pathogenic mechanisms underlying diabetic cardiomyopathy, as well as highlighting the circadian clock as an emerging target in diabetes that has been linked to modulation of MR activation. It will also outline the cardiovascular protection yielded from anti-diabetic agents and MR antagonists (MRA) in preclinical and clinical settings of diabetes. Although our knowledge of the mechanisms of myocardial injury in diabetes is expanding quickly, current therapeutic strategies do not mitigate the high risks of cardiovascular disease in this vulnerable population. Further investment in understanding the consequences of adverse MR signalling and potentially the early introduction of MR blockade in management plans may be critical for combating the burden of cardiomyopathy in the diabetic population.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 1-13"},"PeriodicalIF":4.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989709","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 : 2026-01-06DOI: 10.1016/j.yjmcc.2026.01.003
Yang He , Kaisheng Jiang , Junhong Sun , Qianhao Zhao , Jiacheng Yue , Wenzhao Wei , Jie Cao , Da Zheng , Hui Yao , Shuquan Zhao , Hu Zhao , Erwen Huang
N6-methyladenosine (m6A) modification plays important roles in various biological processes, yet its function in macrophages and its potential link to ferroptosis in promoting atherosclerosis (AS) remain unclear. In this study, elevated levels of m6A modification and methyltransferase-like 3 (METTL3) expression were observed in AS arteries of mice. The number of METTL3-positive macrophages increased in both mouse and human AS arteries. Systemic inhibition or macrophage-specific knockdown of METTL3 attenuated AS plaque formation in mice. RNA-sequencing revealed that ferroptosis-associated genes were enriched following METTL3 knockdown in bone marrow-derived macrophages (BMDM). Consistent with this, inhibition of ferroptosis also reduced AS plaques. Further analysis showed increased m6A modification and expression of legumain (LGMN) in mouse AS arteries. Elevated LGMN expression was also detected in oxidized low-density lipoprotein (ox-LDL)-treated BMDM and in macrophages within AS lesions. Knockdown of LGMN in BMDM attenuated ox-LDL-induced ferroptosis, lipid deposition, and inflammatory responses. Macrophage-specific knockdown of LGMN in mice reduced plaque formation and ferroptosis in AS arteries. Additionally, macrophage-specific METTL3 knockdown suppressed the upregulation of LGMN expression in AS arteries. The effects of ox-LDL on BMDM were abolished by METTL3 knockdown but rescued by LGMN overexpression. Mechanistically, YTHDF1 bound to m6A-methylated LGMN mRNA and enhanced its translation. Together, The in vivo and in vitro results demonstrate that LGMN acts as a novel mediator of AS by linking METTL3-dependent m6A modification to macrophage ferroptosis.
{"title":"METTL3-dependent N6-methyladenosine modification on LGMN mRNA promotes macrophage ferroptosis and atherosclerosis","authors":"Yang He , Kaisheng Jiang , Junhong Sun , Qianhao Zhao , Jiacheng Yue , Wenzhao Wei , Jie Cao , Da Zheng , Hui Yao , Shuquan Zhao , Hu Zhao , Erwen Huang","doi":"10.1016/j.yjmcc.2026.01.003","DOIUrl":"10.1016/j.yjmcc.2026.01.003","url":null,"abstract":"<div><div>N6-methyladenosine (m6A) modification plays important roles in various biological processes, yet its function in macrophages and its potential link to ferroptosis in promoting atherosclerosis (AS) remain unclear. In this study, elevated levels of m6A modification and methyltransferase-like 3 (METTL3) expression were observed in AS arteries of mice. The number of METTL3-positive macrophages increased in both mouse and human AS arteries. Systemic inhibition or macrophage-specific knockdown of METTL3 attenuated AS plaque formation in mice. RNA-sequencing revealed that ferroptosis-associated genes were enriched following METTL3 knockdown in bone marrow-derived macrophages (BMDM). Consistent with this, inhibition of ferroptosis also reduced AS plaques. Further analysis showed increased m6A modification and expression of legumain (LGMN) in mouse AS arteries. Elevated LGMN expression was also detected in oxidized low-density lipoprotein (ox-LDL)-treated BMDM and in macrophages within AS lesions. Knockdown of LGMN in BMDM attenuated ox-LDL-induced ferroptosis, lipid deposition, and inflammatory responses. Macrophage-specific knockdown of LGMN in mice reduced plaque formation and ferroptosis in AS arteries. Additionally, macrophage-specific METTL3 knockdown suppressed the upregulation of LGMN expression in AS arteries. The effects of ox-LDL on BMDM were abolished by METTL3 knockdown but rescued by LGMN overexpression. Mechanistically, YTHDF1 bound to m6A-methylated LGMN mRNA and enhanced its translation. Together, The in vivo and in vitro results demonstrate that LGMN acts as a novel mediator of AS by linking METTL3-dependent m6A modification to macrophage ferroptosis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 89-103"},"PeriodicalIF":4.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933712","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 : 2026-01-05DOI: 10.1016/j.yjmcc.2026.01.002
Xiaolin Yue , Yawei Wang , Zhinan Wu , Hanlin Lu , Fan Jiang , Wencheng Zhang , Yan Liu
Hypertension is a complex condition influenced by many factors. RNA polymerase I (pol I)-specific transcription initiation factor-1A (TIF-1A) regulates ribosome biosynthesis by participating in the formation of a competent pre-initiation complex. However, limited information is available regarding the role of TIF-1A in vascular smooth muscle cells (VSMCs) and its impact on blood pressure. This study investigated the biological function of TIF-1A in the modulation of smooth muscle contraction and explored the potential therapeutic targets of hypertension. Vascular smooth muscle-specific Tif-1a-knockout (Tif-1aSMKO) mice were generated by crossbreeding Tif-1aflox/flox and SMMHC-CreERT2 mice. The angiotensin II (Ang II)-infused mice and spontaneously hypertensive rats were used as animal models of hypertension. The primary mouse smooth muscle cell model induced by Ang II was used for in vitro observations. Compared to that of the control, the phenotype of the Tif-1aSMKO mice exhibited lower blood pressure. The contractile response to vasoconstrictors was also lower in mesenteric artery segments isolated from Tif-1aSMKO mice. Functional abnormalities in Tif-1aSMKO mice have been attributed to ribosomal dysfunction, which results in decreased ribosomal biosynthesis. Consistently, the expression of proteins associated with smooth muscle contraction decreased in Tif-1a-deficient smooth muscle cells. Finally, the smooth muscle-specific deletion of Tif-1a attenuated Angiotensin II-induced hypertension and vascular remodeling in mice. Administration of RNA pol I transcription inhibitor BMH-21 ameliorates hypertension in spontaneously hypertensive rats. TIF-1A regulated vascular smooth muscle contraction and maintained blood pressure by modulating ribosomal biosynthesis. Thus, TIF-1A inhibition may represent a new research orientation for the treatment of hypertension.
{"title":"Transcription initiation factor-1A regulates the contraction of vascular smooth muscle and maintains blood pressure","authors":"Xiaolin Yue , Yawei Wang , Zhinan Wu , Hanlin Lu , Fan Jiang , Wencheng Zhang , Yan Liu","doi":"10.1016/j.yjmcc.2026.01.002","DOIUrl":"10.1016/j.yjmcc.2026.01.002","url":null,"abstract":"<div><div>Hypertension is a complex condition influenced by many factors. RNA polymerase I (pol I)-specific transcription initiation factor-1A (TIF-1A) regulates ribosome biosynthesis by participating in the formation of a competent pre-initiation complex. However, limited information is available regarding the role of TIF-1A in vascular smooth muscle cells (VSMCs) and its impact on blood pressure. This study investigated the biological function of TIF-1A in the modulation of smooth muscle contraction and explored the potential therapeutic targets of hypertension. Vascular smooth muscle-specific <em>Tif-1a</em>-knockout (<em>Tif-1a</em><sup>SMKO</sup>) mice were generated by crossbreeding <em>Tif-1a</em><sup>flox/flox</sup> and SMMHC-CreER<sup>T2</sup> mice. The angiotensin II (Ang II)-infused mice and spontaneously hypertensive rats were used as animal models of hypertension. The primary mouse smooth muscle cell model induced by Ang II was used for <em>in vitro</em> observations. Compared to that of the control, the phenotype of the <em>Tif-1a</em><sup>SMKO</sup> mice exhibited lower blood pressure. The contractile response to vasoconstrictors was also lower in mesenteric artery segments isolated from <em>Tif-1a</em><sup>SMKO</sup> mice. Functional abnormalities in <em>Tif-1a</em><sup>SMKO</sup> mice have been attributed to ribosomal dysfunction, which results in decreased ribosomal biosynthesis. Consistently, the expression of proteins associated with smooth muscle contraction decreased in <em>Tif-1a</em>-deficient smooth muscle cells. Finally, the smooth muscle-specific deletion of <em>Tif-1a</em> attenuated Angiotensin II-induced hypertension and vascular remodeling in mice. Administration of RNA pol I transcription inhibitor BMH-21 ameliorates hypertension in spontaneously hypertensive rats. TIF-1A regulated vascular smooth muscle contraction and maintained blood pressure by modulating ribosomal biosynthesis. Thus, TIF-1A inhibition may represent a new research orientation for the treatment of hypertension.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 38-50"},"PeriodicalIF":4.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917693","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 : 2026-01-04DOI: 10.1016/j.yjmcc.2026.01.001
Paul J. Bushway , Wei Feng , Marina Sampaio De Menezes Cruz , Sofie Maisel , Aysen Shathaya , Pranita Rao , Umang Patel , Jinsun Park , Chao Chen , Zhiyuan Tang , Betul Gunes , Eren Gunes , Mao Ye , Yusu Gu , Eric Adler
Cardiac thin filament mutations in TNNI3 are associated with up to 3 % of hypertrophic (HCM) cardiomyopathy cases and contribute to severe restrictive (RCM) and dilated (DCM) cardiomyopathy caseloads. As such, thin filament cardiomyopathy mediated by TNNI3 mutations is an orphan disease with unmet therapeutic need. Gene therapy is one approach to addressing orphan disease but has been restricted to the repletion of protein deficiency. Based on the best available knowledge, TNNI3 gene therapy has never been applied in the context of a functional mutant protein. Described here is the viral gene therapy rescue at a 4-month endpoint of an experimental murine Tnni3 mutation resulting in slow-onset dilated cardiomyopathy (DCM) with cardiac failure at 12–18 months. Mutant mice treated with AAV encoding wild-type (WT) human TNNI3 at 1.0E+14 vg/kG prevented the onset of DCM pathology. This work describes the first adeno-associated virus (AAV) gene therapy replacement of functional mutated Tnni3 protein. The results suggest a broader application of gene therapy for gene replacement.
{"title":"AAV-TNNI3 rescues an experimental murine Tnni3 mutation resulting in thin filament mediated DCM","authors":"Paul J. Bushway , Wei Feng , Marina Sampaio De Menezes Cruz , Sofie Maisel , Aysen Shathaya , Pranita Rao , Umang Patel , Jinsun Park , Chao Chen , Zhiyuan Tang , Betul Gunes , Eren Gunes , Mao Ye , Yusu Gu , Eric Adler","doi":"10.1016/j.yjmcc.2026.01.001","DOIUrl":"10.1016/j.yjmcc.2026.01.001","url":null,"abstract":"<div><div>Cardiac thin filament mutations in <em>TNNI3</em> are associated with up to 3 % of hypertrophic (HCM) cardiomyopathy cases and contribute to severe restrictive (RCM) and dilated (DCM) cardiomyopathy caseloads. As such, thin filament cardiomyopathy mediated by <em>TNNI3</em> mutations is an orphan disease with unmet therapeutic need. Gene therapy is one approach to addressing orphan disease but has been restricted to the repletion of protein deficiency. Based on the best available knowledge, <em>TNNI3</em> gene therapy has never been applied in the context of a functional mutant protein. Described here is the viral gene therapy rescue at a 4-month endpoint of an experimental murine <em>Tnni3</em> mutation resulting in slow-onset dilated cardiomyopathy (DCM) with cardiac failure at 12–18 months. Mutant mice treated with AAV encoding wild-type (WT) human <em>TNNI3</em> at 1.0E+14 vg/kG prevented the onset of DCM pathology. This work describes the first adeno-associated virus (AAV) gene therapy replacement of functional mutated Tnni3 protein. The results suggest a broader application of gene therapy for gene replacement.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 26-37"},"PeriodicalIF":4.7,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911869","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 : 2026-01-04DOI: 10.1016/j.yjmcc.2025.12.012
C.E.R. Smith, C.J. Quinn, J.D. Clarke, Z. Sultan, H. Najem, N.C. Denham, D.C. Hutchings, A.S. Whitley, G.W.P. Madders, J.L. Caldwell, L.K. Toms, D.A. Eisner, C. Pinali, A.W. Trafford, K.M. Dibb
Transverse (t)-tubules ensure a uniform rise in cellular Ca2+ facilitating cardiac contraction. They play a key role in the large mammalian atria (including human) and their loss in heart failure is associated with impaired Ca2+ release. While t-tubule restoration is therefore an ideal therapeutic target, atrial t-tubule development is not well understood. Here we sought to determine how atrial t-tubules develop and the impact on Ca2+ handling. Atrial postnatal development was examined in sheep from newborn through to adulthood. T-tubule development was assessed using confocal microscopy and serial block face Scanning Electron Microscopy. Voltage clamp coupled with Ca2+ epifluorescence was used to assess concomitant functional changes to Ca2+ handling. Atrial t-tubule density increased until 3 months of age when the t-tubule network was disordered. As development continued t-tubules became more ordered but surprisingly the distance of the cell interior to t-tubule membrane increased due to a lack of additional t-tubules coupled with increased cell width. As t-tubules developed, L-type Ca2+ current density (ICa-L) and sarcoplasmic reticulum (SR) Ca2+ content decreased. Although these changes would be expected to decrease Ca2+ transient amplitude, Ca2+ buffering was simultaneously reduced which our data suggests maintains Ca2+ transient amplitude during neonatal development. By understanding how the Ca2+ transient is preserved despite drastic changes in t-tubule density and structure during development, this study may provide insights into adaptive mechanisms in Ca2+ cycling that mitigate the impact of reduced t-tubule density.
{"title":"Atrial t-tubules adopt a distinct developmental state as Ca2+ handling matures postnatally","authors":"C.E.R. Smith, C.J. Quinn, J.D. Clarke, Z. Sultan, H. Najem, N.C. Denham, D.C. Hutchings, A.S. Whitley, G.W.P. Madders, J.L. Caldwell, L.K. Toms, D.A. Eisner, C. Pinali, A.W. Trafford, K.M. Dibb","doi":"10.1016/j.yjmcc.2025.12.012","DOIUrl":"10.1016/j.yjmcc.2025.12.012","url":null,"abstract":"<div><div>Transverse (t)-tubules ensure a uniform rise in cellular Ca<sup>2+</sup> facilitating cardiac contraction. They play a key role in the large mammalian atria (including human) and their loss in heart failure is associated with impaired Ca<sup>2+</sup> release. While t-tubule restoration is therefore an ideal therapeutic target, atrial t-tubule development is not well understood. Here we sought to determine how atrial t-tubules develop and the impact on Ca<sup>2+</sup> handling. Atrial postnatal development was examined in sheep from newborn through to adulthood. T-tubule development was assessed using confocal microscopy and serial block face Scanning Electron Microscopy. Voltage clamp coupled with Ca<sup>2+</sup> epifluorescence was used to assess concomitant functional changes to Ca<sup>2+</sup> handling. Atrial t-tubule density increased until 3 months of age when the t-tubule network was disordered. As development continued t-tubules became more ordered but surprisingly the distance of the cell interior to t-tubule membrane increased due to a lack of additional t-tubules coupled with increased cell width. As t-tubules developed, L-type Ca<sup>2+</sup> current density (<em>I</em><sub>Ca-L</sub>) and sarcoplasmic reticulum (SR) Ca<sup>2+</sup> content decreased. Although these changes would be expected to decrease Ca<sup>2+</sup> transient amplitude, Ca<sup>2+</sup> buffering was simultaneously reduced which our data suggests maintains Ca<sup>2+</sup> transient amplitude during neonatal development. By understanding how the Ca<sup>2+</sup> transient is preserved despite drastic changes in t-tubule density and structure during development, this study may provide insights into adaptive mechanisms in Ca<sup>2+</sup> cycling that mitigate the impact of reduced t-tubule density.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 60-74"},"PeriodicalIF":4.7,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911832","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 : 2026-01-02DOI: 10.1016/j.yjmcc.2025.12.010
Sophia A. Eikenberry, Michelle L. Gumz
Circadian rhythms drive cardiovascular health, and when dysfunctional, disease. Circadian biology rules daily rhythms in physiological mechanisms which allow our bodies to coordinate function with the demands of the external environment. However, the machinery underlying circadian rhythms, termed the “molecular clock”, can become altered by both external and internal factors. For instance, breaking the clock through disrupted light exposure can drive high blood pressure, which is detrimental to cardiovascular health. Importantly, cardiovascular disease itself can disrupt the molecular clock, further exacerbating pathology. The focus of this review is this latter aspect of the bi-directional relationship between circadian machinery and cardiovascular function, investigated in preclinical models. First, we describe the importance of blood pressure regulation and relevant systems. We then describe the existence of circadian rhythms in blood pressure, and briefly, how a broken clock can disrupt these rhythms and lead to disease. The focus of this review will be to outline evidence from pre-clinical and translational studies investigating the direct impact of cardiovascular disease on circadian machinery in the brain, heart, aorta, and kidney. This is with the goal of 1) highlighting the potential for harnessing the molecular clock through circadian interventions in combination with other treatment, and 2) aiding pre-clinical cardiovascular researchers in understanding their results which may be impacted by time of day.
{"title":"Watching the clock: Blood pressure and cardiovascular disease influence circadian machinery in pre-clinical models","authors":"Sophia A. Eikenberry, Michelle L. Gumz","doi":"10.1016/j.yjmcc.2025.12.010","DOIUrl":"10.1016/j.yjmcc.2025.12.010","url":null,"abstract":"<div><div>Circadian rhythms drive cardiovascular health, and when dysfunctional, disease. Circadian biology rules daily rhythms in physiological mechanisms which allow our bodies to coordinate function with the demands of the external environment. However, the machinery underlying circadian rhythms, termed the “molecular clock”, can become altered by both external and internal factors. For instance, breaking the clock through disrupted light exposure can drive high blood pressure, which is detrimental to cardiovascular health. Importantly, cardiovascular disease itself can disrupt the molecular clock, further exacerbating pathology. The focus of this review is this latter aspect of the bi-directional relationship between circadian machinery and cardiovascular function, investigated in preclinical models. First, we describe the importance of blood pressure regulation and relevant systems. We then describe the existence of circadian rhythms in blood pressure, and briefly, how a broken clock can disrupt these rhythms and lead to disease. The focus of this review will be to outline evidence from pre-clinical and translational studies investigating the direct impact of cardiovascular disease on circadian machinery in the brain, heart, aorta, and kidney. This is with the goal of 1) highlighting the potential for harnessing the molecular clock through circadian interventions in combination with other treatment, and 2) aiding pre-clinical cardiovascular researchers in understanding their results which may be impacted by time of day.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 51-59"},"PeriodicalIF":4.7,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900581","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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