Resveratrol Prevents Iron-overload Cardiomyopathy by up Regulating Serca2a and by Exerting Anti-oxidant Effects

Introduction: Iron-overload cardiomyopathy is a world wide epidemic with high morbidity and mortality which has both acquired and genetic causes. Cardiac iron-deposition results in progressive myocardial damage and dysfunction due to increased oxidative stress. Hypothesis: We hypothesized that resveratrol supplementation prevents oxidative stress and iron-overload cardiomyopathy. Methods and Results: We developed an acquired iron-overload model by treating 10 week old male C57BL6 mice sub-acutely/chronicaly with iron-dextran (5 mg/25g) i.p. for 4 or 12 wks, and a genetic model by treating 4 wk old hemojuvelin (HJV) knockout male mice with high iron diet for 6 months. The natural antioxidant, resveratrol, was given at 190 mg/kg/day. Iron-overload hearts showed significant iron deposition. Hemodynamic (+dP/dt/-dP/dt max =1.0 vs 1.7) and echocardiographic (E/A: 1.46±0.043 vs 1.27±0.06, p 2+ transients were slowed in iron-overloaded cardiomyocytes and normalized with resveratrol treatment. In contrast, chronic iron-overload was associated with increased myocardial fibrosis in HJVKO and chronic iron-overload models. Resveratrol treatment prevented the development of diastolic dysfunction (E/A: 1.27±0.06 vs 1.67±0.13 and E’/A’:1.2±0.05 vs 0.80±0.02, p Conclusions: Cardiac iron-overload resulted in abnormal Ca 2+ cycling with reduced SERCA2a levels and increased myocardial fibrosis, leading to impaired myocardial relaxation and increased stiffness. Resveratrol therapy increased SERCA2a protein, decreased myocardial fibrosis leading to protection from iron-overload induced cardiac dysfunction.