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Although TGF\u2010\u03b2\/Smad3 signalling has been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. We reported here the potential role of Smad3 in the development of DCM by genetically deleting the Smad3 gene from db\/db mice. At the age of 32\u00a0weeks, Smad3WT\u2010db\/db mice developed moderate to severe DCM as demonstrated by a marked increase in the left ventricular (LV) mass, a significant fall in the LV ejection fraction (EF) and LV fractional shortening (FS), and progressive myocardial fibrosis and inflammation. In contrast, db\/db mice lacking Smad3 (Smad3KO\u2010db\/db) were protected against the development of DCM with normal cardiac function and undetectable myocardial inflammation and fibrosis. Interestingly, db\/db mice with deleting one copy of Smad3 (Smad3\u00a0\u00b1\u00a0db\/db) did not show any cardioprotective effects. Mechanistically, we found that deletion of Smad3 from db\/db mice largely protected cardiac Smad7 from Smurf2\u2010mediated ubiquitin proteasome degradation, thereby inducing IB\u03b1 to suppress NF\u2010kB\u2010driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3\u2010dependent miRNAs by up\u2010regulating cardiac miR\u201029b while suppressing miR\u201021 to exhibit the cardioprotective effect on Smad3KO\u2010db\/db mice. In conclusion, results from this study reveal that Smad3 is a key mediator in the pathogenesis of DCM. Targeting Smad3 may be a novel therapy for DCM.<\/jats:p>","DOI":"10.1111\/jcmm.16464","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T06:12:52Z","timestamp":1616047972000},"page":"4860-4869","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Deletion of Smad3 protects against diabetic myocardiopathy in db\/db mice"],"prefix":"10.1111","volume":"25","author":[{"given":"Li","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine Research Center of Integrated Traditional Chinese and Western Medicine The TCM Affiliated Hospital of Southwest Medical University Luzhou China"},{"name":"Department of Medicine and Therapeutics Li Ka Shing Institute of Health Sciences Lui Che Woo Institute of Innovative Medicine The Chinese University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Chun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Research Center of Integrated Traditional Chinese and Western Medicine The TCM Affiliated Hospital of Southwest Medical University Luzhou China"},{"name":"Department of Medicine and Therapeutics Li Ka Shing Institute of Health Sciences Lui Che Woo Institute of Innovative Medicine The Chinese University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong\u2010Jing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Research Center of Integrated Traditional Chinese and Western Medicine The TCM Affiliated Hospital of Southwest Medical University Luzhou China"},{"name":"Department of Medicine and Therapeutics Li Ka Shing Institute of Health Sciences Lui Che Woo Institute of Innovative Medicine The Chinese University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Ru","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medicine and Therapeutics Li Ka Shing Institute of Health Sciences Lui Che Woo Institute of Innovative Medicine The Chinese University of Hong Kong Hong Kong China"},{"name":"Guangdong\u2010Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases Guangdong Provincial People\u2019s Hospital Guangdong Academy of Medical Sciences Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3881-3149","authenticated-orcid":false,"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Research Center of Integrated Traditional Chinese and Western Medicine The TCM Affiliated Hospital of Southwest Medical University Luzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Lian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Research Center of Integrated Traditional Chinese and Western Medicine The TCM Affiliated Hospital of Southwest Medical University Luzhou China"},{"name":"Department of Medicine and Therapeutics Li Ka Shing Institute of Health Sciences Lui Che Woo Institute of Innovative Medicine The Chinese University of Hong Kong Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald C. 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