The role of CARMA3 in regulating fibrosis to prevent hypertrophic cardiomyopathy.

IF 7 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-10-06 DOI:10.1038/s41420-025-02645-z

Yafeng Liu, Ganyi Chen, Yiwei Yao, Yunfei Jiang, Chenghao Wen, Wuwei Wang, Quan Liu, Yide Cao, Fuhua Huang, Wen Chen, Zhibing Qiu

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Abstract

Hypertrophic cardiomyopathy (HCM) is characterized by cardiac hypertrophy and fibrosis. To investigate the impact of CARMA3 on fibroblast phenotypic transformation in hypertrophic cardiomyopathy (HCM), the correlation between CARMA3 expression and fibrosis was analyzed in HCM patients. Cardiac function and fibroblast phenotypic transformation were assessed in wild-type and CARMA3-knockout mice subjected to transverse aortic constriction (TAC) or angiotensin II treatment. Additionally, cardiac fibroblasts were screened using flow cytometry and proteomic analysis to identify potential targets. Significant cardiac functional impairment and fibrosis were observed in CARMA3-knockout mice following TAC or angiotensin II treatment. Primary fibroblasts isolated from these mice exhibited increased myofibroblast differentiation, extracellular collagen production, mitochondrial damage, and macrophage inflammation. Elevated STAT1 expression was identified in cardiac fibroblasts from CARMA3-knockout mice through proteomic analysis. Additionally, STAT1 phosphorylation was regulated by CARMA3, and an interaction between CARMA3 and STAT1 was detected in response to pressure overload. In conclusion, CARMA3 may suppress myofibroblast activation by inhibiting STAT1 phosphorylation, thereby improving myocardial fibrosis in pressure overload-induced HCM.

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CARMA3在调节纤维化预防肥厚性心肌病中的作用。

肥厚性心肌病（HCM）以心脏肥大和纤维化为特征。为了研究CARMA3对肥厚性心肌病（HCM）成纤维细胞表型转化的影响，我们分析了肥厚性心肌病患者中CARMA3表达与纤维化的相关性。在横断主动脉收缩（TAC）或血管紧张素II治疗下，评估野生型和carma3基因敲除小鼠的心功能和成纤维细胞表型转化。此外，使用流式细胞术和蛋白质组学分析筛选心脏成纤维细胞以确定潜在靶点。在TAC或血管紧张素II治疗后，carma3基因敲除小鼠观察到明显的心功能损伤和纤维化。从这些小鼠中分离的原代成纤维细胞表现出肌成纤维细胞分化、细胞外胶原生成、线粒体损伤和巨噬细胞炎症增加。通过蛋白质组学分析，在carma3基因敲除小鼠的心脏成纤维细胞中发现STAT1表达升高。此外，STAT1的磷酸化受到CARMA3的调控，并且在压力过载的响应中检测到CARMA3和STAT1之间的相互作用。综上所述，CARMA3可能通过抑制STAT1磷酸化来抑制肌成纤维细胞的激活，从而改善压力过载诱导的HCM的心肌纤维化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.