Journal of molecular and cellular cardiology最新文献

{"title":"Systems analysis reveals neuregulin-1 control of cardiomyocyte size and shape mediated by distinct PI3K and p38 pathways.","authors":"Pichayathida Luanpaisanon, Karen A Ryall, Philip M Tan, James O'Hearn, Laura A Woo, Bryana N Harris, Bethany Wissmann, Alexander Paap, Matthew Rhoads, Mohammad Fallahi-Sichani, Jeffrey J Saucerman","doi":"10.1016/j.yjmcc.2026.10.007","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2026.10.007","url":null,"abstract":"<p><p>Pathological and physiological stresses induce diverse forms of cardiac hypertrophy, with distinct manifestations in cardiomyocyte size and shape regulated by still poorly understood signaling networks. Here, we combined high-content morphological profiling, phospho-protein arrays, and systems modeling to characterize the diverse forms of hypertrophy induced by angiotensin II, endothelin-1, insulin growth factor-1, and neuregulin-1. Reverse-phase protein array profiling of neonatal rat cardiomyocytes and partial least squares regression modeling revealed that Akt, GSK3, and MAPK signaling are differentially regulated by hypertrophic agonists and are predictive of distinct phenotypic outcomes. Among these agonists, neuregulin-1 uniquely induced cardiomyocyte elongation in both neonatal rat and human iPSC-derived cardiomyocytes, in addition to increasing cell area. Pharmacological perturbations in neonatal rat cardiomyocytes demonstrated that neuregulin1-induced elongation and area expansion both require PI3K activity, whereas p38 selectively mediates cell area. A logic-based network model incorporating dual-specificity phosphatases were sufficient to capture the amplifying PI3K and transient p38 signaling dynamics driving phenotypic changes. Together, these results identify distinct signaling cascades by which neuregulin-1 coordinates cardiomyocyte size and shape, providing mechanistic insight into how hypertrophic remodeling can be differentially regulated. This systems approach provides new insight into the pathways that drive distinct forms of cardiomyocyte hypertrophy, highlighting opportunities to selectively target maladaptive remodeling in heart failure.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193909","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}

{"title":"Inhibition of CDK1 attenuates cardiac remodeling via suppression of fibroblast-derived TGF-β1.","authors":"Taishi Yamamoto, Shouji Matsushima, Eri Noda, Kosuke Okabe, Masashi Sada, Nobuyuki Enzan, Yoshitomo Tsutsui, Ryo Miyake, Ryohei Nishimura, Takayuki Toyohara, Hiroko Deguchi Miyamoto, Akihito Ishikita, Soichiro Ikeda, Tomonori Tadokoro, Masataka Ikeda, Keisuke Shinohara, Toru Hashimoto, Daiki Setoyama, Yuya Kunisaki, Shintaro Kinugawa, Hiroyuki Tsutsui, Kohtaro Abe","doi":"10.1016/j.yjmcc.2026.10.006","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2026.10.006","url":null,"abstract":"<p><p>Activation of cyclin-dependent kinase 1 (CDK1) is implicated in fibrosis in liver and skin. However, the role of CDK1 in cardiac remodeling remains unclear. We investigated whether CDK1 inhibition suppresses cardiac remodeling and explored the underlying mechanisms. Angiotensin II (Ang II) was continuously infused into C57BL/6 mice with or without intraperitoneal administration of a selective CDK1 inhibitor (Ro-3306) for 1 week. Ro-3306 attenuated Ang II-induced increases in left ventricular wall thickness and heart weight without affecting blood pressure. Ro-3306 also ameliorated interstitial fibrosis and cardiomyocyte hypertrophy in Ang II-treated hearts, accompanied by reduced Col1a1 and Col3a1 mRNA expression. Ang II increased phosphorylation of CDK1 substrate motifs and transforming growth factor-β1 (TGF-β1) precursor protein levels, a key mediator of cardiac fibrosis and hypertrophy, and these were suppressed by Ro-3306. Ro-3306 also attenuated pressure overload-induced cardiac fibrosis and hypertrophy, accompanied by reduced TGF-β1 precursor protein levels. In cultured cardiac fibroblasts, inhibition of CDK1 by Ro-3306 or small interfering RNA suppressed Ang II-induced increases in TGF-β1 precursor protein levels, whereas no such effect was observed in cultured cardiomyocytes. In contrast, CDK2 knockdown or CDK4/6 inhibitors did not affect TGF-β1 precursor protein levels in cardiac fibroblasts. Comprehensive secretome analysis identified TGF-β1 as a major growth factor secreted from fibroblasts in response to Ang II. Conditioned medium from fibroblasts treated with Ang II induced cardiomyocyte hypertrophy. CDK1 knockdown in fibroblasts suppressed TGF-β1 secretion. Neutralizing TGF-β1 antibodies attenuated hypertrophic effects of conditioned medium from fibroblasts treated with Ang II. In conclusion, CDK1 inhibition attenuates cardiac fibrosis and hypertrophy in vivo, accompanied by reduced cardiac TGF-β1 precursor protein levels. Our in vitro findings further suggest that CDK1 in cardiac fibroblasts regulates TGF-β1 production and secretion, thereby contributing to cardiomyocyte hypertrophy. KEYWORDS: CDK1 Cardiac fibrosis Cardiac hypertrophy TGF-β1.</p>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182043","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}

{"title":"Retraction notice to 'Sam68 impedes the recovery of arterial injury by augmenting inflammatory response' [Journal of Molecular and Cellular Cardiology 137 (2019) 82-92].","authors":"Shuling Han, Shiyue Xu, Junlan Zhou, Aijun Qiao, Chan Boriboun, Wenxia Ma, Huadong Li, Dauren Biyashev, Liu Yang, Eric Zhang, Qinghua Liu, Shayi Jiang, Ting C Zhao, Prasanna Krishnamurthy, Chunxiang Zhang, Stéphane Richard, Hongyu Qiu, Jianyi Zhang, Gangjian Qin","doi":"10.1016/j.yjmcc.2026.06.006","DOIUrl":"10.1016/j.yjmcc.2026.06.006","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":" ","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264855","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}

{"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 ,&nbsp;Zhi-Xue Liu ,&nbsp;Xiao-Xu Zheng ,&nbsp;Sheng-Nan Wu ,&nbsp;Jun-Qing An ,&nbsp;Ming-Hui Zou ,&nbsp;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":"2026-04-01","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}

{"title":"Left and right myocardial ventricular energetics during cardioplegic ischemic arrest and reperfusion in patients undergoing cardiac surgery","authors":"Marco Moscarelli ,&nbsp;Katie L. Skeffington ,&nbsp;Daniel Fudulu ,&nbsp;Prakash Punjabi ,&nbsp;Costanza Emanueli ,&nbsp;Francesca Fiorentino ,&nbsp;M-Saadeh Suleiman ,&nbsp;Gianni D. Angelini","doi":"10.1016/j.yjmcc.2026.02.006","DOIUrl":"10.1016/j.yjmcc.2026.02.006","url":null,"abstract":"<div><h3>Background</h3><div>Effective myocardial protection during cardiac surgery is essential, yet the differential metabolic stress of the left (LV) and right ventricles (RV) to ischemia–reperfusion remains poorly characterized.</div></div><div><h3>Methods</h3><div>This predefined substudy of a multicenter randomized trial conducted in the United Kingdom (ISRCTN33084113) evaluated remote ischemic preconditioning in patients undergoing coronary artery bypass grafting (CABG) or aortic valve replacement (AVR). Paired LV and RV biopsies were obtained before ischemia and after reperfusion. High-performance liquid chromatography was used to quantify metabolite concentrations and calculate markers of energetics. Cross-clamp time and postoperative troponin levels were recorded.</div></div><div><h3>Results</h3><div>Eighty-nine patients were included (CABG: <em>n</em> = 49; AVR: <em>n</em> = 40). Following ischemia–reperfusion, LV exhibited greater decline in metabolites than the RV. In CABG, this included larger sustained fall in ATP (−0.90 vs −0.13 μmol/mg, <em>p</em> = 0.0032) and glutamate (−4.22 vs −1.33 μmol/mg, <em>p</em> = 0.0009), alongside ADP (−0.53 vs −0.20 μmol/mg, <em>p</em> = 0.0196), GTP (−0.04 vs −0.01 μmol/mg, <em>p</em> = 0.0160), and B-NAD (−0.15 vs −0.04 μmol/mg, <em>p</em> = 0.0137). Computed energy charge decreased significantly in both ventricles (LV: <em>p</em> = 0.0002; RV: <em>p</em> = 0.010), but remained stable in AVR. ATP/AMP and ATP/ADP ratios declined more in the LV, suggesting impaired energy buffering. There was no significant correlation between cross-clamp time and changes in energy charge in either the LV or RV. Troponin release correlated with ischemic time in CABG, but EC decline did not.</div></div><div><h3>Conclusions</h3><div>The LV shows greater depletion of myocardial metabolites than the RV following ischemia–reperfusion, particularly in CABG patients. These findings support ventricle-specific strategies to optimize myocardial protection.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 84-92"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213393","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}

{"title":"Coronary artery disease risk gene PRDM16 regulates smooth muscle homeostasis","authors":"Kunzhe Dong ,&nbsp;Yingbing Zuo ,&nbsp;Yali Yao ,&nbsp;Xiangqin He ,&nbsp;Guoqing Hu ,&nbsp;Xiaoping Peng ,&nbsp;Jiliang Zhou","doi":"10.1016/j.yjmcc.2026.02.002","DOIUrl":"10.1016/j.yjmcc.2026.02.002","url":null,"abstract":"<div><h3>Objective</h3><div>Vascular smooth muscle cells (VSMCs) are the primary contractile component of blood vessels and can undergo phenotypic switching from a contractile to a synthetic phenotype in vascular diseases such as coronary artery disease (CAD) and restenosis. This process leads to decreased expression of SMC lineage genes and increased proliferative, migratory and secretory abilities that drive disease progression. Super-enhancers (SE) and lineage-specific transcription factors are believed to drive expression of genes that maintain cell identity and homeostasis. The goal of this study is to identify novel regulators of VSMC homeostasis by screening for SE-regulated transcription factors in arterial tissues.</div></div><div><h3>Approach and results</h3><div>We characterized human artery SEs by analyzing the enhancer histone mark H3K27ac ChIP-seq data of multiple arterial tissues. We unexpectedly discovered the transcription factor PRDM16, a GWAS-identified CAD risk gene with previously well-documented roles in brown adipocytes but with an unknown function in vascular disease progression, is enriched with artery-specific SEs. Further analysis of public bulk RNA-seq and scRNA-seq datasets, as well as qRT-PCR and Western blotting analysis, demonstrated that PRDM16 is highly expressed in arterial tissues and in contractile VSMCs but not in visceral SMCs, and down-regulated in phenotypically modulated VSMCs. To explore the function of <em>Prdm16</em> in vivo, we generated both inducible and constitutive <em>Prdm16</em> SMC-specific knockout mice and performed bulk RNA-Seq analysis of aortic tissues and left carotid artery ligation to assess neointima formation. SMC-deficiency of <em>Prdm16</em> does not affect the aortic morphology at baseline but significantly alters expression of many genes involved in VSMC homeostasis and cardiovascular disease, and suppresses VSMC proliferation and neointima formation in male mice. Specifically, <em>Prdm16</em> negatively regulates the expression of <em>Tgfb2</em> that encodes an upstream ligand of the TGF-β signaling pathway, by suppressing its promoter activity.</div></div><div><h3>Conclusions</h3><div>Our results suggest that the CAD risk gene <em>PRDM16</em> is highly expressed in VSMCs and is a novel regulator of VSMC homeostasis and neointima formation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 74-83"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157383","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}

{"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 ,&nbsp;Leonardo Maciel ,&nbsp;Antonio dos Santos Silva ,&nbsp;Keyla Cristiny Da Coutinho ,&nbsp;Fernando Lucas Palhano ,&nbsp;Marcelo F. Santiago ,&nbsp;Debora Foguel","doi":"10.1016/j.yjmcc.2025.12.013","DOIUrl":"10.1016/j.yjmcc.2025.12.013","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 32-47"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","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}

{"title":"LARP7 promotes postnatal cardiac regeneration by facilitating G2/M phase transition","authors":"Shasha Zhang ,&nbsp;Kang Cheng ,&nbsp;Junhao Xiong ,&nbsp;Xing Liu ,&nbsp;Juntao Lin ,&nbsp;Huan Hu ,&nbsp;Zilong Geng ,&nbsp;Weimin Xu ,&nbsp;Shizhan Xu ,&nbsp;Ao Tan ,&nbsp;Jin Zhang ,&nbsp;Wenjuan Li ,&nbsp;Zhizhao Guo ,&nbsp;Ping Yang ,&nbsp;Xiao Cheng ,&nbsp;Tao Zhong ,&nbsp;Xiaoling Guo ,&nbsp;Lijun Fu ,&nbsp;Min Zhang ,&nbsp;Jinghai Chen ,&nbsp;Bing Zhang","doi":"10.1016/j.yjmcc.2026.02.003","DOIUrl":"10.1016/j.yjmcc.2026.02.003","url":null,"abstract":"<div><div>The limited regenerative potential of adult mammalian cardiomyocyte is the biggest hurdle for the heart repair after injury. La Ribonucleoprotein 7 (LARP7), a member of La ribonucleoprotein domain family, is the key regulator of transcription and DNA damage response, but it's role in heart regeneration remains elusive. In this study, the authors discover LARP7 expression level is correlated with myocardial regeneration. Overexpressing LARP7 in the cardiomyocytes moderately promote the cardiomyocyte proliferation and extend the neonatal heart's regenerative window. The mechanism uncovers that LARP7 enhances G₂/M phase transition of cardiomyocyte by suppressing p21 via the SIRT1/p53 pathway and thereby elevating the activity of CDK1/CCNB. To further boost regenerative capacity, The authors co-express CCND1 and CDK4 together with LARP7 using a dual AAV9 system that markedly boosts the cardiac regeneration and facilitates recovery post cardiac damage. In sum, our study unveils LARP7 as a novel molecular switch of cell cycle. LARP7 ectopic expression, especially combining with G₁/S regulators effectively enhances the cardiac regeneration, which underscores LARP7 as a perspective target in cardiac regeneration.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 48-58"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157370","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}

{"title":"DPP4-regulated endothelial cell ferroptosis modulates atherosclerosis progression by ferritinophagy","authors":"Lanzhuoying Zheng ,&nbsp;Ke Liang ,&nbsp;Yuanyuan Peng ,&nbsp;Mengying Jin ,&nbsp;Xiao Chen ,&nbsp;Xinran Liu ,&nbsp;Hua Shao ,&nbsp;Tao Zhang ,&nbsp;Jiawei Duan ,&nbsp;Feifei Yan ,&nbsp;Baozhu Wei ,&nbsp;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^−/−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.</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":"2026-04-01","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}

{"title":"Tgfbr2 deficiency promotes mitochondrial dysfunction of vascular smooth muscle cells in thoracic aortic aneurysms and dissections","authors":"Zhenqing Teng ,&nbsp;Qi Wang ,&nbsp;Yang Zhang ,&nbsp;Quan Zhang ,&nbsp;Li Shen ,&nbsp;Xiang Ma","doi":"10.1016/j.yjmcc.2026.02.004","DOIUrl":"10.1016/j.yjmcc.2026.02.004","url":null,"abstract":"<div><div>Mitochondrial dysregulation promotes vascular destabilization through modulation of the phenotypic plasticity of vascular smooth muscle cells (VSMCs) in thoracic aortic aneurysms and dissections (TAADs). Canonical transforming growth factor-β (TGF-β) signaling, another pivotal pathway in TAADs, also controls VSMC homeostasis, yet the mechanistic interplay between these two axes is unclear. We aimed to determine whether, and how, dysregulated TGF-β signaling directly precipitates mitochondrial injury that drives TAADs progression. Herein, we systematically characterized the regulatory nexus between TGF-β signaling and mitochondrial function during TAADs progression. Single-cell transcriptomic profiling revealed significant correlation between mitochondrial dysfunction and TGF-β pathway dysregulation in TAADs specimens. Using conditional <em>Tgfbr2</em> knockout mice with VSMC-specific targeting, we provide compelling evidence that dysregulated TGF-β signaling mediates mitochondrial impairment through intricate molecular crosstalk. Bulk RNA sequencing and untargeted metabolomics established a definitive causal relationship between mitochondrial dysfunction and aortic degeneration severity in VSMC-specific <em>Tgfbr2</em>-deficient mice. Pseudo-temporal trajectory analysis identified mitochondrial respiratory complex IV as a critical downstream effector of TGF-β-mediated mitochondrial regulation. Western blot analyses demonstrated that VSMC-specific <em>Tgfbr2</em> ablation significantly diminished the expression of complex IV regulatory proteins, exhibiting linear correlation with vascular injury severity. Our findings establish a paradigmatic shift in TAADs pathophysiology from unidirectional mechanisms toward integrated multi-pathway networks, providing a robust theoretical framework for developing synergistic therapeutic interventions targeting the mitochondrial–TGF-β regulatory axis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 93-109"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227149","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}