Journal of molecular and cellular cardiology最新文献

Corrigendum to “MFN2-mediated decrease in mitochondria-associated endoplasmic reticulum membranes contributes to sunitinib-induced endothelial dysfunction and hypertension/JMCC 10006”. “mfn2介导的线粒体相关内质网膜减少有助于舒尼替尼诱导的内皮功能障碍和高血压/JMCC 10006”的更正。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-01-28 DOI: 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

引用次数: 0

Coronary artery disease risk gene PRDM16 regulates smooth muscle homeostasis 冠心病风险基因PRDM16调控平滑肌稳态

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-02-08 DOI: 10.1016/j.yjmcc.2026.02.002

Kunzhe Dong , Yingbing Zuo , Yali Yao , Xiangqin He , Guoqing Hu , Xiaoping Peng , Jiliang Zhou

Objective

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.

Approach and results

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 Prdm16 in vivo, we generated both inducible and constitutive Prdm16 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 Prdm16 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, Prdm16 negatively regulates the expression of Tgfb2 that encodes an upstream ligand of the TGF-β signaling pathway, by suppressing its promoter activity.

Conclusions

Our results suggest that the CAD risk gene PRDM16 is highly expressed in VSMCs and is a novel regulator of VSMC homeostasis and neointima formation.

目的：血管平滑肌细胞（VSMCs）是血管的主要收缩成分，在冠状动脉疾病（CAD）和再狭窄等血管疾病中可以经历从收缩表型到合成表型的表型转换。这一过程导致SMC谱系基因表达减少，增殖、迁移和分泌能力增强，从而推动疾病进展。超级增强子（SE）和谱系特异性转录因子被认为驱动维持细胞身份和稳态的基因表达。本研究的目的是通过筛选动脉组织中se调节的转录因子来确定VSMC稳态的新调节因子。方法和结果：我们通过分析多动脉组织的增强子组蛋白标记H3K27ac ChIP-seq数据来表征人动脉SEs。我们意外地发现转录因子PRDM16富含动脉特异性SEs，这是一种gwas鉴定的CAD风险基因，先前在棕色脂肪细胞中具有良好的作用，但在血管疾病进展中具有未知的功能。对公开的大量RNA-seq和scRNA-seq数据集以及qRT-PCR和Western blotting分析的进一步分析表明，PRDM16在动脉组织和收缩性VSMCs中高表达，而在内脏SMCs中不表达，并且在表型调节的VSMCs中下调。为了探索Prdm16在体内的功能，我们制造了诱导型和组成型Prdm16 smc特异性敲除小鼠，并对主动脉组织和左颈动脉结扎进行了大量RNA-Seq分析，以评估新内膜的形成。smc缺乏Prdm16并不影响基线时的主动脉形态，但显著改变了许多参与VSMC稳态和心血管疾病的基因的表达，并抑制雄性小鼠VSMC增殖和新内膜形成。具体来说，Prdm16通过抑制TGF-β信号通路上游配体Tgfb2的启动子活性，负向调节Tgfb2的表达。结论：我们的研究结果表明CAD风险基因PRDM16在VSMC中高表达，是VSMC稳态和新生内膜形成的新调控因子。

{"title":"Coronary artery disease risk gene PRDM16 regulates smooth muscle homeostasis","authors":"Kunzhe Dong , Yingbing Zuo , Yali Yao , Xiangqin He , Guoqing Hu , Xiaoping Peng , 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}

引用次数: 0

Left and right myocardial ventricular energetics during cardioplegic ischemic arrest and reperfusion in patients undergoing cardiac surgery 心脏手术患者心脏停跳缺血停搏和再灌注时左、右心肌室能量。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-02-15 DOI: 10.1016/j.yjmcc.2026.02.006

Marco Moscarelli , Katie L. Skeffington , Daniel Fudulu , Prakash Punjabi , Costanza Emanueli , Francesca Fiorentino , M-Saadeh Suleiman , Gianni D. Angelini

Background

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.

Methods

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.

Results

Eighty-nine patients were included (CABG: n = 49; AVR: n = 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, p = 0.0032) and glutamate (−4.22 vs −1.33 μmol/mg, p = 0.0009), alongside ADP (−0.53 vs −0.20 μmol/mg, p = 0.0196), GTP (−0.04 vs −0.01 μmol/mg, p = 0.0160), and B-NAD (−0.15 vs −0.04 μmol/mg, p = 0.0137). Computed energy charge decreased significantly in both ventricles (LV: p = 0.0002; RV: p = 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.

Conclusions

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.

背景：在心脏手术期间有效的心肌保护是必不可少的，然而左（LV）和右心室（RV）对缺血-再灌注的差异代谢应激仍然缺乏特征。方法：在英国进行的一项多中心随机试验（ISRCTN33084113）的预先亚研究评估了冠状动脉旁路移植术（CABG）或主动脉瓣置换术（AVR）患者的远程缺血预处理。缺血前和再灌注后分别行左室和右室配对活检。高效液相色谱法定量代谢产物浓度，计算能量学标记物。记录交叉钳夹时间和术后肌钙蛋白水平。结果：纳入89例患者（CABG: n = 49;AVR: n = 40）。缺血再灌注后，左室代谢物下降幅度大于右室。在冠脉搭桥,这包括大ATP持续下降(-0.90 vs -0.13 μ摩尔/毫克,p = 0.0032)和谷氨酸(-4.22 vs -1.33 μ摩尔/毫克,p = 0.0009),与ADP (-0.53 vs -0.20 μ摩尔/毫克,p = 0.0196),三磷酸鸟苷(-0.04 vs -0.01 μ摩尔/毫克,p = 0.0160),和B-NAD (-0.15 vs -0.04 μ摩尔/毫克,p = 0.0137)。计算能量电荷在两心室均显著下降（LV: p = 0.0002;RV: p = 0.010），但在AVR保持稳定。ATP/AMP和ATP/ADP比值在左心室下降更多，表明能量缓冲功能受损。交叉夹持时间与左、右心室能量电荷变化无显著相关性。肌钙蛋白释放量与冠脉搭桥缺血时间相关，但EC下降与冠脉搭桥缺血时间无关。结论：缺血-再灌注后，左室比右室表现出更大的心肌代谢物消耗，特别是在CABG患者中。这些发现支持心室特异性策略来优化心肌保护。

{"title":"Left and right myocardial ventricular energetics during cardioplegic ischemic arrest and reperfusion in patients undergoing cardiac surgery","authors":"Marco Moscarelli , Katie L. Skeffington , Daniel Fudulu , Prakash Punjabi , Costanza Emanueli , Francesca Fiorentino , M-Saadeh Suleiman , 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}

引用次数: 0

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 脑多巴胺神经营养因子（CDNF）的c结构域通过与内质网应激条件下迁移到质膜的KDEL受体结合，负责其心脏保护活性。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-01-24 DOI: 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.

脑多巴胺神经营养因子（CDNF）已成为一种关键的细胞保护分子，在帕金森病模型中具有充分证明的神经保护作用，最近又证明了其心脏保护特性。在这项研究中，我们研究了CDNF及其分离结构域（CDNF- n和CDNF- c）在缺血/再灌注（I/R）损伤的离体心脏中的保护作用。我们的数据显示，在存在CDNF或CDNF- c而非CDNF- n的情况下，未治疗心脏的危险梗死面积从约40%下降至约20%，这表明CDNF- c是CDNF心脏保护活性的主要介质。这种作用是通过激活PI3K/AKT信号通路介导的，因为CDNF-C的心脏保护作用被PI3K/AKT抑制剂wortmannin所消除。该研究还利用心肌细胞（H9c2细胞、新生儿原代心肌细胞和人诱导多能干细胞来源的心肌细胞- hiPSC-dCM）暴露于由thapsigargin诱导的内质网（ER）应激下，检测了CDNF与质膜上KDEL受体（KDEL- r）之间的相互作用。共聚焦显微镜显示，在内质网胁迫下，KDEL-R转运到质膜上，并与全长CDNF和CDNF- c结合。然而，只有全长蛋白被心肌细胞内化，这表明n结构域对CDNF内吞作用至关重要。内化后，CDNF主要转运至溶酶体，少部分转运至线粒体和内质网。总的来说，这些发现确定了外源性CDNF -通过其c结构域-作为一种新的心肌因子，并强调了其通过kdel -r介导的PI3K/AKT激活在心脏损伤和内质网应激相关疾病中的治疗潜力。

{"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":"<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}

引用次数: 0

LARP7 promotes postnatal cardiac regeneration by facilitating G2/M phase transition LARP7通过促进G2/M相变促进出生后心脏再生。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-02-08 DOI: 10.1016/j.yjmcc.2026.02.003

Shasha Zhang , Kang Cheng , Junhao Xiong , Xing Liu , Juntao Lin , Huan Hu , Zilong Geng , Weimin Xu , Shizhan Xu , Ao Tan , Jin Zhang , Wenjuan Li , Zhizhao Guo , Ping Yang , Xiao Cheng , Tao Zhong , Xiaoling Guo , Lijun Fu , Min Zhang , Jinghai Chen , Bing Zhang

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.

成年哺乳动物心肌细胞有限的再生潜能是心脏损伤后修复的最大障碍。La核糖核蛋白7 （LARP7）是La核糖核蛋白结构域家族的成员，是转录和DNA损伤反应的关键调节因子，但其在心脏再生中的作用尚不清楚。在本研究中，作者发现LARP7表达水平与心肌再生相关。心肌细胞过表达LARP7可适度促进心肌细胞增殖，延长新生儿心脏再生窗口期。其机制揭示了LARP7通过SIRT1/p53通路抑制p21，从而提高CDK1/CCNB活性，从而促进心肌细胞G2/M期转变。为了进一步提高再生能力，作者使用双AAV9系统共同表达CCND1和CDK4以及LARP7，显著促进心脏再生并促进心脏损伤后的恢复。总之，我们的研究揭示了LARP7作为细胞周期的一个新的分子开关。LARP7异位表达，特别是与G1/S调节因子结合，可有效促进心脏再生，这凸显了LARP7作为心脏再生靶点的前景。

{"title":"LARP7 promotes postnatal cardiac regeneration by facilitating G2/M phase transition","authors":"Shasha Zhang , Kang Cheng , Junhao Xiong , Xing Liu , Juntao Lin , Huan Hu , Zilong Geng , Weimin Xu , Shizhan Xu , Ao Tan , Jin Zhang , Wenjuan Li , Zhizhao Guo , Ping Yang , Xiao Cheng , Tao Zhong , Xiaoling Guo , Lijun Fu , Min Zhang , Jinghai Chen , 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 G<sub>2</sub>/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 G<sub>1</sub>/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}

引用次数: 0

DPP4-regulated endothelial cell ferroptosis modulates atherosclerosis progression by ferritinophagy dpp4调控的内皮细胞铁凋亡通过铁蛋白吞噬调节动脉粥样硬化的进展。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-01-19 DOI: 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.

背景：动脉粥样硬化（AS）是冠状动脉疾病（CAD）的主要病理生理基础，起源于内皮功能障碍，促进脂质沉积和斑块形成。新出现的证据表明二肽基肽酶IV （DPP4）与血管病理有关，但其在as相关的内皮性铁下垂中的机制作用仍不明确。方法：采用多学科方法：1)对公共数据库进行生物信息学分析，确定dpp4 -死铁- as相关性；2)临床样本测量不同冠心病严重程度的血浆DPP4水平；3)比较高脂饮食下DPP4-/-ApoE-/-和ApoE-/-小鼠的动脉粥样硬化进展；4) ox - ldl诱导的内皮损伤模型结合蛋白质组学、环己亚胺追踪法和自噬的药理调节来评估dpp4介导的铁凋亡机制。结果：临床样本分析显示，严重冠状动脉狭窄患者血浆DPP4水平显著升高，在斑块处观察到DPP4富集。动物研究表明，DPP4缺乏可减轻小鼠AS和铁下垂的进展。细胞实验显示ox-LDL上调DPP4表达，同时伴有铁下垂易感性增加和内皮功能障碍。DPP4抑制通过阻断脂质过氧化积累来维持内皮细胞的活力。机制上，小鼠蛋白质组学显示，AS中的铁下垂和自噬途径与DPP4相关。DPP4通过ncoa4介导的铁蛋白自噬破坏FTH1的稳定，氯喹（自噬抑制）和沙格列汀（DPP4抑制）对FTH1保存的一致拯救作用证明了这一点。结论：本研究证实内皮细胞DPP4在as中作为铁蛋白吞噬驱动的铁上睑垂的调节因子，诱导内皮功能障碍。我们的研究结果表明，靶向DPP4- ncoa4 - fth1轴是一种很有希望的策略，可以保护内皮细胞的活力，阻止早期as的进展，并具有在心血管治疗中重新利用DPP4抑制剂的翻译意义。

{"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":"2026-04-01","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}

引用次数: 0

KCNQ2 downregulation in left stellate ganglion neurons exacerbates malignant ventricular arrhythmias after myocardial infarction 左星状神经节神经元KCNQ2下调加重心肌梗死后恶性室性心律失常。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-02-05 DOI: 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.

目的：室性心律失常（VAs）是心肌梗死（MI）后心源性猝死（SCD）的主要原因，心脏交感神经兴奋性亢进是一个关键触发因素。虽然β受体阻滞剂提供部分保护，但残余的心律失常风险仍然存在。神经元m通道（KCNQ2/3）作为限制交感神经亢进的关键“制动器”，但其在心肌梗死后室性心律失常中的作用仍不明确。在这项研究中，我们研究了交感神经节中KCNQ2的下调是否有助于心肌梗死后心律失常易感性的增加。方法和结果：雄性Sprague-Dawley大鼠（n = 104）随机分为4组：sham， MI， shCtrl+MI和shKCNQ2 + MI。在永久性左冠状动脉前降支结扎术前3 周，将靶向KCNQ2或重组对照的腺相关病毒载体注射到左星状神经节（LSG）。心肌梗死后LSG神经元中KCNQ2的表达显著降低。靶向KCNQ2敲低显著加重了心肌梗死后急性期（0-8 h）和慢性期（4 周）的VAs负担，心室颤动发生率增加（93% vs. shCtrl, P: 43%） 结论：LSG神经元中KCNQ2敲低加剧了心肌梗死后心脏交感放电活动，增加了心律失常易感性；然而，缺乏直接的m电流测量和功能获得验证限制了因果结论。

{"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":"10.1016/j.yjmcc.2026.02.001","url":null,"abstract":"<div><h3>Aims</h3><div>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.</div></div><div><h3>Methods and results</h3><div>Male Sprague-Dawley rats (<em>n</em> = 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, <em>P</em> < 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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 59-73"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","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}

引用次数: 0

Tgfbr2 deficiency promotes mitochondrial dysfunction of vascular smooth muscle cells in thoracic aortic aneurysms and dissections Tgfbr2缺乏促进胸主动脉瘤和夹层血管平滑肌细胞线粒体功能障碍。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-02-17 DOI: 10.1016/j.yjmcc.2026.02.004

Zhenqing Teng , Qi Wang , Yang Zhang , Quan Zhang , Li Shen , Xiang Ma

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 Tgfbr2 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 Tgfbr2-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 Tgfbr2 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.

线粒体失调通过调节胸主动脉瘤和夹层（TAADs）中血管平滑肌细胞（VSMCs）的表型可塑性来促进血管不稳定。典型转化生长因子-β (TGF-β)信号是TAADs的另一个关键途径，也控制VSMC的稳态，但这两个轴之间的相互作用机制尚不清楚。我们的目的是确定TGF-β信号失调是否以及如何直接导致线粒体损伤，从而驱动TAADs的进展。在此，我们系统地表征了TGF-β信号传导和TAADs进展过程中线粒体功能之间的调节关系。单细胞转录组学分析显示TAADs标本中线粒体功能障碍与TGF-β通路失调有显著相关性。我们使用具有vsmc特异性靶向的条件Tgfbr2敲除小鼠，提供了令人信服的证据，证明TGF-β信号失调通过复杂的分子串扰介导线粒体损伤。大量RNA测序和非靶向代谢组学在vsmc特异性tgfbr2缺陷小鼠中建立了线粒体功能障碍与主动脉变性严重程度之间的明确因果关系。伪时间轨迹分析发现线粒体呼吸复合体IV是TGF-β介导的线粒体调控的关键下游效应物。Western blot分析显示，vsmc特异性Tgfbr2消融术显著降低复合体IV调节蛋白的表达，与血管损伤严重程度呈线性相关。我们的研究结果建立了TAADs病理生理学从单向机制向综合多通路网络的范式转变，为开发针对线粒体- tgf -β调控轴的协同治疗干预提供了强有力的理论框架。

{"title":"Tgfbr2 deficiency promotes mitochondrial dysfunction of vascular smooth muscle cells in thoracic aortic aneurysms and dissections","authors":"Zhenqing Teng , Qi Wang , Yang Zhang , Quan Zhang , Li Shen , 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}

引用次数: 0

The mineralocorticoid receptor: a new chapter for therapeutic regulation of diabetic cardiomyopathy 糖皮质激素受体：糖尿病性心肌病治疗调控的新篇章。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-04-01 Epub Date: 2026-01-14 DOI: 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.

糖尿病是一个全球性的健康负担，是心血管疾病相关发病率和死亡率的主要原因。尽管抗高血糖药物的发展取得了重大进展，但糖尿病性心肌病仍然使个体易患明显的心力衰竭。目前，缺乏用于检测糖尿病性心肌病早期心肌损伤的生物标志物，这强调了迫切需要识别早期疾病过程并开发新的治疗策略。矿物皮质激素受体（MR）已被证明是心力衰竭的一个有价值的治疗靶点，这可能转化为降低中晚期糖尿病心肌病心血管并发症风险的有希望的选择。这篇叙述性综述讨论了不适当的MR激活在糖尿病性心肌病的常见致病机制中的作用，并强调了生物钟作为糖尿病中与MR激活调节有关的新兴靶点。它还将概述抗糖尿病药物和MR拮抗剂（MRA）在糖尿病临床前和临床环境中的心血管保护作用。尽管我们对糖尿病心肌损伤机制的了解正在迅速扩大，但目前的治疗策略并不能降低这一易感人群患心血管疾病的高风险。进一步投资于了解不良MR信号的后果，并可能在管理计划中尽早引入MR阻断，这对于对抗糖尿病人群心肌病的负担至关重要。

{"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":"2026-04-01","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}

引用次数: 0

Corrigendum to 'NADPH oxidase 4 regulates vascular inflammation in aging and atherosclerosis' [Journal of Molecular and Cellular Cardiology 102 (2017) 10-21]. “NADPH氧化酶4调节血管炎症在衰老和动脉粥样硬化中的作用”[j]. Molecular and Cellular Cardiology, 102(2017) 10-21。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-03-21 DOI: 10.1016/j.yjmcc.2026.03.004

Andrey Lozhkin, Aleksandr E Vendrov, Hua Pan, Samuel A Wickline, Nageswara R Madamanchi, Marschall S Runge

引用次数: 0