Deletion of Smad3 Protects Against Diabetic Myocardiopathy in db/db Mice 

Abstract Background: Diabetic cardiomyopathy (DCM) is a common diabetic complication characterized by diastolic relaxation abnormalities, myocardial fibrosis, and chronic heart failure. Although TGF-b/Smad3 signaling has been shown to play a critical role in chronic heart disease, the role and mechanisms of Smad3 in DCM remain unclear. Methods: We generated Smad3 knockout (KO)-db/db, Smad3 wild-type (WT)-db/db, Smad3+/- db/db, and their littermate Smad3 KO/WT-db/m mice. The role of Smad3 in DCM including the left ventricular (LV) ejection fraction (EF), LV fractional shortening (FS), and LV Mass were determined and mechanisms of Smad3 in cardiac inflammation and fibrosis including Smad3-dependent microRNAs were investigated. Results: At the age of 32 weeks, Smad3WT-db/db mice developed moderate to severe DCM as demonstrated by a significant fall in LVEF, LVFS, and a marked increase in LV mass with progressive myocardial fibrosis and inflammation. In contrast, db/db mice lacking Smad3 (Smad3KO-db/db) were protected against the development of DCM with normal cardiac function without myocardial inflammation and fibrosis. Interestingly, db/db mice with deleting one copy of Smad3 (Smad3+/-db/db) did not show any cardioprotective effect. Mechanistically, we found that deletion of Smad3 from db/db mice largely protected cardiac Smad7 from Smurf2-mediated ubiquitin proteasome degradation, thereby inducing IkBa to suppress NF-kB-driven cardiac inflammation. In addition, deletion of Smad3 also altered Smad3-dependent miRNAs by upregulating cardiac miR-29b while suppressing miR-21 to exhibit the cardioprotective effect on Smad3KO-db/db mice. Conclusions: Smad3 is a key mediator in the pathogenesis of DCM. Results from this study imply that targeting Smad3 may be a novel therapy for DCM.