Early Dapagliflozin and Melatonin Treatment Ameliorated <scp>LV</scp> Fibrosis via Suppressing TGF‐β1/Smads and Activating Nrf2‐ <scp>ARE</scp> Signaling in <scp>MI</scp> Rodent

ABSTRACT This study tested whether combined dapagliflozin (DAPA) and melatonin (Mel) therapy was superior to merely one for ameliorating the left ventricular (LV) fibrosis/remodeling and improving LV ejection fraction (LVEF) in rats after acute myocardial infarction (AMI). In vitro study demonstrated that DAPA treatment significantly suppressed the TGF‐β/Smads signaling, whereas Mel treatment significantly upregulated Nrf2/ARE signaling in ischemia–reperfusion (IR) H9C2 cells (all P&lt; 0.001). Additionally, simultaneously silencing TGF‐β and overexpression of Nrf2 in H9C2 cells significantly suppressed fibrotic and upregulated antioxidant signaling (all P&lt; 0.001). Adult male Sprague–Dawley rats were categorized into groups 1 (sham‐operated‐control)/2 (AMI)/3 (AMI + DAPA)/4 (AMI + Mel)/5 (AMI + DAPA‐Mel), and the hearts were harvested by day 28. By day 28 after AMI induction, the LVEF was highest in group 1, lowest in group 2, and significantly higher in group 5 than in groups 3 and 4, but it did not differ between groups 3 and 4, whereas the LV systolic/diastolic dimensions exhibited an opposite pattern of LVEF among the groups (all P&lt; 0.0001). The protein expressions of TGF‐β/Smads signaling exhibited an opposite pattern, whereas the protein expressions of Nrf2/ARE signaling displayed an identical pattern of LVEF among the groups (all P&lt; 0.0001). The protein expressions of oxidative‐stress/DNA‐mitochondria damaged/inflammatory biomarkers and histopathological/anatomical findings demonstrated that the infarct and fibrotic areas/LV‐chamber dimensions/cardiomyocyte size exhibited an opposite manner of LVEF among the groups (all P&lt; 0.0001). In conclusion, combined DAPA‐Mel therapy was superior to merely one for improving LVEF and inhibiting fibrosis/LV remodeling in AMI rodents.