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Here, the authors show that sentrin\u2010specific protease 1 (SENP1) is downregulated in post\u2010MI mice and in patients with severe heart failure. By generating cardiomyocyte\u2010specific SENP1 knockout and overexpression mice to assess cardiac function and ventricular remodeling responses under physiological and pathological conditions. Increased cardiac fibrosis in the cardiomyocyte\u2010specific SENP1 deletion mice, associated with increased fibronectin (Fn) expression and secretion in cardiomyocytes, promotes fibroblast activation in response to myocardial injury. Mechanistically, SENP1 deletion in mouse cardiomyocytes increases heat shock protein 90 alpha family class B member 1 (HSP90ab1) SUMOylation with (STAT3) activation and Fn secretion after ventricular remodeling initiated. Overexpression of SENP1 or mutation of the HSP90ab1 Lys72 ameliorates adverse ventricular remodeling and dysfunction after MI. Taken together, this study identifies SENP1 as a positive regulator of cardiac repair and a potential drug target for the treatment of MI. Inhibition of HSP90ab1 SUMOylation stabilizes STAT3 to inhibit the adverse ventricular remodeling response.<\/jats:p>","DOI":"10.1002\/advs.202400741","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T01:45:22Z","timestamp":1720748722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["SENP1\u2010Mediated HSP90ab1 DeSUMOylation in Cardiomyocytes Prevents Myocardial Fibrosis by Paracrine Signaling"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3541-5543","authenticated-orcid":false,"given":"Zhihao","family":"Liu","sequence":"first","affiliation":[{"name":"First Teaching Hospital of Tianjin University of Traditional Chinese Medicine National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion  Tianjin 300193 China"},{"name":"State Key Laboratory of Component\u2010Based Chinese Medicine  Tianjin 301617 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