Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts

Abstract

During myocardial infarction, delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium‐glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3‐dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I‐201 (a STAT3 inhibitor), or phlorizin + S3I‐201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post‐infarction was associated with increased RONS levels, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL‐10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Compared with phlorizin, the extent of dapagliflozin towards M2 polarization was significantly higher. The effects of SGLT2 inhibitors on M2 polarization were nullified by adding S3I‐201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL‐10 levels can be reversed by 3‐morpholinosydnonimine, a peroxynitrite generator. These observations provide a novel mechanism of SGLT2 inhibitors‐mediated M2 polarization through a RONS‐dependent STAT3‐mediated pathway and selective SGLT2 inhibitors are more effective in attenuating cardiac fibrosis during postinfarction remodeling.