Dapagliflozin protects against chronic heart failure in mice via inhibiting macrophage-mediated inflammation, independent of SGLT2 [RNA-Seq]
The specific mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) needs to be elucidated. In this study, we use SGLT2 global knockout (SGLT2-KO) mice to assess the mechanism of SGLT2 inhibitor on HF. Dapagliflozin ameliorates both myocardial infarction (MI)-and transverse aortic constriction (TAC) -induced HF. Global SGLT2-deficiency doesn't exert protection against adverse remodeling in both MI- and TAC-induced HF models.  Dapagliflozin blurs MI- and TAC-induced HF phenotypes in SGLT2-KO mice.  Dapagliflozin causes major changes in cardiac fibrosis and inflammation. Based on single-cell RNA sequencing dapagliflozin causes significant differences in the gene expression profile of macrophages and fibroblasts. Moreover, dapagliflozin directly inhibites macrophage inflammation, thereby suppressing cardiac fibroblasts activation. The cardio-protection of dapagliflozin is blurred in mice treated with a C-C chemokine receptor type 2 (CCR2) antagonist. Taken together the protective effects of dapagliflozin against HF are independent of SGLT2, macrophage inhibition is the main target of dapagliflozin against HF. Overall design: RNA-seq was performed in HF-heart tissue to confirm the precise effect of dapagliflozin on myocardial infarction(MI)-induced HFrEF.Group:MI + NS (MI-NS),and MI + dapagliflozin (MI-DAPA).