Abstract 9379: Ferroptosis Inhibitor Exerts Greater Efficacy Than Apoptosis and Necroptosis Inhibitors on Improving Cardiac Function via Restoring Cardiac Mitochondrial Function and Attenuating Cardiomyocyte Death in Rats With Iron-Overloaded Cardiomyopathy

Abstract

Introduction: Iron overload cardiomyopathy (IOC) is a common cause of death in iron overload patients. Previous studies reported that iron overload led to cardiac mitochondrial dysfunction and cardiomyocyte death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart remains to be clarified. Hypothesis: We tested the hypothesis that apoptosis, necroptosis and ferroptosis play equally important roles in IOC; and inhibitors of the three cell death pathways have equal beneficial effect on improving cardiac function in iron-overloaded rats. Methods: Male Wistar rats received intraperitoneal injection of iron dextran, 5 days/week for 4 weeks. Then, the rats were divided into 5 groups (n=4/group) being treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (necrostatin-1), ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, mitophagy, apoptosis, necroptosis and ferroptosis were determined. Results: Iron-overloaded rats showed impaired cardiac and mitochondrial function associated with excessive mitophagy and increased expression of apoptosis- and ferroptosis-related proteins. All cell death inhibitors could decrease cardiac mitophagy, apoptosis and ferroptosis in iron overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial depolarization and bax/bcl-2 ratio (Figure A). Therefore, ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by the restored left ventricular ejection fraction (Figure B), whereas z-VAD-FMK and necrostatin-1 only partially improved this parameter. Conclusions: Ferroptosis might be the dominant type of cardiomyocyte death in IOC, and inhibition of ferroptosis is a potential therapeutic strategy against this condition.