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.
Highlights
Hereditary hemochromatosis and secondary iron-overload disorders are prevalent on an international scale [1,2,3]
Diastolic dysfunction was accompanied by oxidative stress, fibrosis, and, in the case of wild-type (WT; injected iron dextran), by elevated sodium–calcium exchanger (NCX1) protein levels and reduced myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCa2a) levels [20]
Our results suggest that myocardial oxidative stress, fibrosis, and Ca2+ cycling defects are linked with the diastolic and systolic dysfunction observed at the advanced stage of iron overload
Summary
Hereditary (genetic) hemochromatosis and secondary iron-overload disorders are prevalent on an international scale [1,2,3]. Iron-overload cardiomyopathy results from prolonged exposure to excess iron [4,5]. Known as type 2 primary hemochromatosis, is a genetic iron metabolic disorder associated with a progressive increase in iron stores due to a mutation in hemojuvelin (HJV), a bone morphogenetic co-receptor protein required for hepcidin expression [6,7,8]. Hepcidin is a major regulator of systemic iron homeostasis and prevents excess gastrointestinal iron absorption [1,9]. Type 2 primary hemochromatosis associated with reduced hepcidin expression results in increased gastrointestinal iron absorption leading to systemic iron overload [10]. Aggressive iron overload associated with juvenile hemochromatosis results in an early-onset form of iron-overload cardiomyopathy characterized by heart failure and arrhythmias [11,12,13,14]
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