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Biosci Rep. 2018 Jan 10;38(1). pii: BSR20171302. doi: 10.1042/BSR20171302. Print 2018 Feb 28.

Advanced iron-overload cardiomyopathy in a genetic murine model is rescued by resveratrol therapy.

Das SK1,2,3, Zhabyeyev P1,2,3, Basu R1,2,3, Patel VB1,2,3, Dyck JRB3,4, Kassiri Z2,3,5, Oudit GY6,2,3.

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Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.
Mazankowski Alberta Heart Institute, Edmonton, Canada.
Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Canada.
Department of Physiology, University of Alberta, Edmonton, Canada.
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada


Iron-overload cardiomyopathy is prevalent on a worldwide basis and is a major comorbidity in patients with genetic hemochromatosis and secondary iron overload. Therapies are limited in part due to lack of a valid preclinical model, which recapitulates advanced iron-overload cardiomyopathy. Male hemojuvelin (HJV) knockout (HJVKO) mice, which lack HJV, a bone morphogenetic co-receptor protein required for hepcidin expression and systemic iron homeostasis, were fed a high-iron diet starting at 4 weeks of age for a duration of 1 year. Aged HJVKO mice in response to iron overload showed increased myocardial iron deposition and mortality coupled with oxidative stress and myocardial fibrosis culminating in advanced iron-overload cardiomyopathy. In a parallel group, iron-overloaded HJVKO mice received resveratrol (240 mg/day) at 9 months of age until 1 year of age. Echocardiography and invasive pressure-volume (PV) loop analyses revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. In addition, myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCa2a) levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCa2a levels and suppressed up-regulation of the sodium-calcium exchanger (NCX1). Further, iron-mediated oxidative stress and myocardial fibrosis were suppressed by resveratrol treatment with concomitant activation of the p-Akt and p-AMP-activated protein kinase (AMPK) signaling pathways. A combination of ageing and high-iron diet in male HJVKO mice results in a valid preclinical model that recapitulates iron-overload cardiomyopathy in humans. Resveratrol therapy resulted in normalization of cardiac function demonstrating that resveratrol represents a feasible therapeutic intervention to reduce the burden of iron-overload cardiomyopathy.


cardiomyopathy; fibrosis; heart failure; hemochromatosis; iron overload; oxidative stress

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