Dapagliflozin Suppressed Cuproptosis and Myocardial Fibrosis in Myocardial Infarction Through HIF-1α/TGF-β Pathway

Myocardial infarction (MI) and postmyocardial remodeling are the most common causes of heart failure worldwide and seriously affect the quality of life and prognosis of patients. Dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, is a novel class of hypoglycemic drug that has been proven to have cardiovascular protective effects. However, the underlying mechanisms by which dapagliflozin affects MI have yet to be elucidated.

An MI mouse model was created by ligating the left anterior descending branch of the coronary artery. Hematoxylin‒eosin (HE) and Masson's trichrome (Masson) staining were used to assess myocardial damage. The levels of fibrosis-related and cuproptosis-related markers were assessed via Western blot analysis. A hypoxia-induced cardiomyocyte fibrosis model was constructed in vitro. The DCFH-DA probe was used to measure the levels of reactive oxygen species (ROS), and flow cytometry was used to identify cell apoptosis.

Dapagliflozin improved heart function, ameliorated fibrosis in the myocardium, and alleviated myocardial injury. Moreover, dapagliflozin reduced the copper ion concentration and ROS accumulation and inhibited the expression of cuproptosis-related markers. Dapagliflozin suppressed the expression of HIF-1α/TGF-β signal and the overexpression of HIF-1α effectively reversed the dapagliflozin-mediated myocardial protective effects.

Dapagliflozin reduced myocardial fibrosis by suppressing HIF-1α/TGF-β-mediated cuproptosis.