{"title":"Deubiquitinase USP47 Ameliorates Cardiac Hypertrophy Through Reducing Protein O-GlcNAcylation.","authors":"Yu Jiang, Wenyao Cai, Guangtao Lei, Guorong Cai, Qinghua Wu, Peng Lu","doi":"10.1097/FJC.0000000000001640","DOIUrl":null,"url":null,"abstract":"<p><strong>Abstract: </strong>Cardiac hypertrophy is a crucial risk factor for heart failure when the heart is confronted with physiologic or pathologic stimuli. The ubiquitin-proteasome system plays a critical role in the pathogenesis of cardiac hypertrophy. However, as a key component of the ubiquitin-proteasome system, the role of deubiquitinating enzymes in cardiac hypertrophy is not well understood. In this study, we observed that the expression level of deubiquitinase USP47 was increased in hypertrophic hearts and angiotensin II (Ang II)-stimulated neonatal rat cardiomyocytes. Adenovirus-mediated gain- and loss-of-function approaches indicated that USP47 overexpression significantly attenuated Ang II-induced cardiac hypertrophy in vitro and in vivo, whereas endogenous USP47 deficiency promoted the prohypertrophic effect of Ang II. Further investigation demonstrated that USP47 inhibited O-GlcNAcylation in cardiomyocytes by controlling the expression of O-GlcNAcase. Mechanistically, USP47 bound, deubiquitinated, and stabilized protein arginine methyltransferase 5 (PRMT5), thus upregulating O-GlcNAcase expression. We found that the restoration of PRMT5 abolished the prohypertrophic effects of USP47 silence in vitro. Therefore, our results provide the first evidence of the involvement of USP47 in cardiac hypertrophy and identify USP47 as a potential target for hypertrophic therapy.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"54-62"},"PeriodicalIF":2.6000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cardiovascular Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/FJC.0000000000001640","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Abstract: Cardiac hypertrophy is a crucial risk factor for heart failure when the heart is confronted with physiologic or pathologic stimuli. The ubiquitin-proteasome system plays a critical role in the pathogenesis of cardiac hypertrophy. However, as a key component of the ubiquitin-proteasome system, the role of deubiquitinating enzymes in cardiac hypertrophy is not well understood. In this study, we observed that the expression level of deubiquitinase USP47 was increased in hypertrophic hearts and angiotensin II (Ang II)-stimulated neonatal rat cardiomyocytes. Adenovirus-mediated gain- and loss-of-function approaches indicated that USP47 overexpression significantly attenuated Ang II-induced cardiac hypertrophy in vitro and in vivo, whereas endogenous USP47 deficiency promoted the prohypertrophic effect of Ang II. Further investigation demonstrated that USP47 inhibited O-GlcNAcylation in cardiomyocytes by controlling the expression of O-GlcNAcase. Mechanistically, USP47 bound, deubiquitinated, and stabilized protein arginine methyltransferase 5 (PRMT5), thus upregulating O-GlcNAcase expression. We found that the restoration of PRMT5 abolished the prohypertrophic effects of USP47 silence in vitro. Therefore, our results provide the first evidence of the involvement of USP47 in cardiac hypertrophy and identify USP47 as a potential target for hypertrophic therapy.
期刊介绍:
Journal of Cardiovascular Pharmacology is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. The Journal encourages submission in all aspects of cardiovascular pharmacology/medicine including, but not limited to: stroke, kidney disease, lipid disorders, diabetes, systemic and pulmonary hypertension, cancer angiogenesis, neural and hormonal control of the circulation, sepsis, neurodegenerative diseases with a vascular component, cardiac and vascular remodeling, heart failure, angina, anticoagulants/antiplatelet agents, drugs/agents that affect vascular smooth muscle, and arrhythmias.
Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, application of drugs to gain novel insights into physiology or pathological conditions, clinical results with new and established agents, and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases. Please note that JCVP does not publish work based on biological extracts of mixed and uncertain chemical composition or unknown concentration.