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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.

Author information

1
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.
2
Mazankowski Alberta Heart Institute, Edmonton, Canada.
3
Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.
4
Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Canada.
5
Department of Physiology, University of Alberta, Edmonton, Canada.
6
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada gavin.oudit@ualberta.ca.

Abstract

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.

KEYWORDS:

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

PMID:
29208771
DOI:
10.1042/BSR20171302
[Indexed for MEDLINE]

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