Modulation of PPAR-γ/Nrf2 and AGE/RAGE signaling contributes to the chrysin cardioprotection against myocardial damage following ischemia/reperfusion in diabetic rats

Abstract Objective Advanced glycation end products/receptor for AGEs (AGE/RAGE) signaling has a well-established role in the etiology of diabetic-related cardiovascular disorders. The purpose of the study was to elucidate the role of chrysin, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, against ischemia/reperfusion (IR) injury in diabetic rats and its functional interaction with the AGE/RAGE signaling pathway. Methods A single intraperitoneal injection of streptozotocin (STZ, 70 mg/kg) was administered to rats for induction of diabetes. Rats having blood glucose levels more than 300 mg/dl following a 72 hr STZ injection were classified as diabetic. PPAR-γ antagonist GW9662 (1 mg/kg, i.p.), chrysin (60 mg/kg, p.o.), or both were administered to diabetic rats for 4 weeks. On the 29th day, rats were given ischemia for 45 min and then reperfusion for 1 hr to induce myocardial infarction (MI). Key findings Pretreatment with chrysin significantly improved hemodynamic status, ventricular functions, and cardiac injury markers in diabetic myocardium. Increased PPAR-γ/Nrf2 and decreased RAGE protein expressions were linked to this improvement. Chrysin pretreatment resulted in the upregulation of endogenous antioxidants and reduced TBARS levels. Moreover, chrysin significantly decreased inflammation and apoptosis in diabetic myocardium. Conclusion PPAR-γ/Nrf2 co-activation by chrysin ameliorated IR-induced MI in diabetic rats, possibly via modulating AGE/RAGE signaling.