Abstract 18964: 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/dtmax =1.0 vs 1.7) and echocardiographic (E/A: 1.46±0.043 vs 1.27±0.06, p<0.05; E’/A’: 0.77±0.04 vs 1.20±0.05, p<0.01) analysis showed diastolic dysfunction with preserved systolic function with decreased SERCA2a levels (-50%) in the acquired sub-acute model. Adeno-associated virus 9-SERCA2a overexpression in the sub-acute model completely prevented the diastolic dysfunction by increasing SERCA2a protein level while Ca2+ 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<0.01; hemodynamic: +dP/dt/-dP/dt : 1.6 vs 1.1, p<0.01) in these models.Resveratrol treatment decreased lipid peroxidation, increased reduced GSH levels, decreased AcFOXO1, increased SIRT1 level along with complete reversal of myocardial disease markers.
Conclusions: Cardiac iron-overload resulted in abnormal Ca2+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.
Author Disclosures: S.K. Das: None. W. Wang: None. P. Zhabyeyev: None. B.A. McLean: None. D. Fan: None. R. Basu: None. N. Parajuli: None. Z. Kassiri: None. J.R. Dyck: None. R.J. Hajjar: None. N.C. Andrews: None. G.Y. Oudit: None.
- © 2014 by American Heart Association, Inc.