Fisetin attenuates isoproterenol-induced cardiac ischemic injury in vivo by suppressing RAGE/NF-κB mediated oxidative stress, apoptosis and inflammation.

ABSTRACT

BACKGROUND: The therapeutic options for the reducing the damage caused by myocardial ischemia are limited and not devoid of adverse effects. The role of the flavanoid, fisetin, predominantly found in strawberry and apple, is yet to be explored in the heart. STUDY DESIGN: Male Wistar rats (n = 48) were administered fisetin (10, 20 & 40 mg/kg/day, orally) or vehicle for 28 days while ISO, 85 mg/kg, subcutaneously, was also administered at 24 h interval on the 27th and 28th day. On the 29th day, rats were anaesthetized and right carotid artery was cannulated to record hemodynamic parameters. Subsequently, blood sample was collected and heart was removed to evaluate various parameters. RESULTS: Fisetin at doses of 10 and 20 mg/kg reversed ISO induced detrimental alterations in blood pressure and left ventricular pressures and reduced the myocardial injury markers CK-MB and LDH in the serum. These findings were supported by amelioration of ISO induced histological and ultrastructural damage by fisetin. The disequilibrium in the levels of pro and anti oxidants in the myocardial tissue caused by ISO was also normalized Furthermore, apoptosis was evident from enhanced DNA fragmentation and raised pro-apoptotic proteins (bax, caspase-3, cytochrome-c) as well as suppressed anti-apoptotic protein (Bcl-2) in case of ISO treatment which again was reversed by fisetin. A molecular mechanism for this protection was elucidated as downregulation of RAGE and NF-κB However fisetin at 40 mg/kg revealed a deteriorating effect which was similar to ISO group of rats. CONCLUSION: Hence, through our study, the role of fisetin in cardioprotection has been uncovered via a molecular pathway.