Cardioprotective effects of metformin and empagliflozin in STZ-induced diabetic rats: Role of BACH1-mediated ferroptosis and YAP1/PD-L1 signaling
Abstract
Aims: Diabetic cardiomyopathy (DCM) is a serious complication driven by diabetes-associated oxidative stress and ferroptosis. This study compared the cardioprotective efficacy of metformin and empagliflozin in streptozotocin (STZ)-induced diabetic rats, focusing on ferroptosis-related mechanisms.
Materials and methods: Forty adult male Sprague-Dawley rats were divided into a control group (n = 10) and a diabetic group induced by STZ (55 mg/kg; n = 30). Following successful induction, the surviving diabetic rats were subdivided into untreated, metformin-treated (200 mg/kg/day), and empagliflozin-treated (10 mg/kg/day) subgroups (n = 8 each). After 12 weeks, biochemical, molecular, and histological analyses were conducted.
Key findings: Diabetic rats showed a 6.4-fold increase in fasting blood glucose (FBG) and a 3.9-fold rise in lactate dehydrogenase (LDH). These systemic changes were accompanied by marked myocardial oxidative stress imbalance and a 1.5-fold increase in cardiac iron. BTB and CNC homology 1 (BACH1) mRNA expression was upregulated 2.2-fold, coupled with suppression of heme oxygenase 1 (HO-1) and glutathione peroxidase 4 (GPX4) to 0.5 and 0.7-fold, respectively. Histological analysis revealed a 4-fold increase in the percentage area of collagen fibers, alongside a 6.2-fold and 4.5-fold increase in Yes-associated protein 1 (YAP1) and programmed death ligand 1 (PD-L1), respectively, and a 0.3-fold reduction in nuclear factor erythroid 2-related factor 2 (NRF2)…
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