Deubiquitinase USP25 Alleviates Obesity-Induced Cardiac Remodeling and Dysfunction by Downregulating TAK1 and Reducing TAK1-Mediated Inflammation

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS JACC: Basic to Translational Science Pub Date : 2024-11-01 DOI:10.1016/j.jacbts.2024.06.001

Bozhi Ye MD , Yanghao Chen MS , Xudong Chen MS , Diyun Xu BA , Yucheng Jiang BA , Wante Lin BA , Danhong Fang MS , Jiachen Xu BA , Jibo Han MS , Xue Han MS , Xiaohong Long MS , Wei Wang BA , Hao Zhou MD , Gaojun Wu MD , Guang Liang PhD

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Abstract

Deubiquitinating enzymes play a vital role in cardiovascular diseases. This study found that cardiomyocyte ubiquitin-specific protease 25 (USP25) expression was downregulated both in myocardial tissue of obesity cardiomyopathy and palmitic acid–stimulated cardiomyocytes. USP25 deficiency exacerbated high-fat diet–induced ventricular remodeling in mice, whereas overexpression of USP25 in cardiomyocytes reversed this pathological phenotype. Mechanistically, USP25 directly binds to TAK1 and P62, and the 178-cysteine of USP25 removes the K63 ubiquitin chain from P62, which promotes the degradation of TAK1 through the autophagy-lysosome pathway, thereby ameliorating obesity-induced ventricular remodeling by reducing inflammation through the TAK1-MAPK pathway. This finding identifies USP25 as a potential therapeutic target for obesity cardiomyopathy.

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去泛素化酶USP25通过下调TAK1和减少TAK1介导的炎症缓解肥胖诱导的心脏重塑和功能障碍

去泛素化酶在心血管疾病中发挥着重要作用。这项研究发现，在肥胖性心肌病的心肌组织和棕榈酸刺激的心肌细胞中，心肌细胞泛素特异性蛋白酶25（USP25）的表达均下调。USP25 缺乏会加剧高脂饮食诱导的小鼠心室重塑，而 USP25 在心肌细胞中的过表达则会逆转这种病理表型。从机理上讲，USP25 可直接与 TAK1 和 P62 结合，USP25 的 178-半胱氨酸可去除 P62 上的 K63 泛素链，从而促进 TAK1 通过自噬-溶酶体途径降解，从而通过 TAK1-MAPK 途径减少炎症，改善肥胖诱导的心室重构。这一发现将 USP25 确定为肥胖症心肌病的潜在治疗靶点。

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.

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Editorial Board Deubiquitinase USP25 Alleviates Obesity-Induced Cardiac Remodeling and Dysfunction by Downregulating TAK1 and Reducing TAK1-Mediated Inflammation Targeting USP25 in the Heart Non-Cell-Autonomous Cardiomyocyte Regulation Complicates Gene Supplementation Therapy for Lmna-Associated Cardiac Defects in Mice When Off-Target Is the Target