Thiadiazolidinone-8, A Gsk3 Beta Inhibitor, Ameliorates Aldosterone-Induced Cardiac Inflammation And Fibrosis By Regulating Autophagy

Aldosterone (Aldo)-salt-induced cardiovascular inflammation plays an important role in the pathogenesis of cardiac fibrosis. GSK-3 beta contributes to inflammatory cardiac diseases, and thiadiazolidinone-8 (TDZD-8) is able to repress the expression of inflammatory cytokines by acting as a specific GSK-30 inhibitor. However, the role of TDZD-8 in Aldo-salt-induced cardiac inflammation and fibrosis has not been clearly documented. In the present study, rats were treated with Aldo-salt in the absence or presence of TDZD-8 for 4 weeks, and then hemodynamic and cardiac parameters were assayed at various time points. We found that the expression levels of pro-inflammatory cytokines (IL-1 beta and TNF-alpha) and fibrosis (TGF-beta and collagen I) were increased in cardiac tissues by Aldo-salt infusion, whereas TDZD-8 treatment reversed these alterations. TDZD-8 also suppressed Aldo-salt-induced endothelial-to-mesenchymal transition (EndoMT), as indicated by increased expression of VE-cadherin and decreased expression of alpha-SMA. Furthermore, TDZD-8 upregulated the protein levels of LC3-II in cardiac tissues, and p62 degradation, indicating that autophagy was activated by TDZD-8 in cardiac tissues. More importantly, autophagy inhibition by specific inhibitors attenuated the function of TDZD-8 in inhibiting EndoMT and perivascular fibrosis. Taken together, these results demonstrate that TDZD-8 plays a protective role in Aldo-salt-induced cardiac fibrosis by activating autophagy.