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Advanced iron-overload cardiomyopathy in a genetic murine model is rescued by resveratrol therapy
Subhash K Das1,2,3, Pavel Zhabyeyev1,2,3, Ratnadeep Basu1,2,3
1Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.
Insights
A new preclinical model using hemojuvelin knockout mice fed a high-iron diet effectively mimics iron-overload cardiomyopathy. Resveratrol therapy normalized cardiac function, showing its potential for treating this condition.
Area of Science:
- Cardiology
- Hematology
- Pharmacology
Background:
- Iron-overload cardiomyopathy is a significant comorbidity in patients with genetic hemochromatosis and secondary iron overload.
- Current therapies are limited due to the lack of valid preclinical models for advanced iron-overload cardiomyopathy.
Purpose of the Study:
- To develop and validate a preclinical model for iron-overload cardiomyopathy.
- To investigate the therapeutic potential of resveratrol in mitigating iron-overload cardiomyopathy.
Main Methods:
- Male hemojuvelin (HJV) knockout mice were fed a high-iron diet for one year to induce iron overload.
- Resveratrol treatment was administered to iron-overloaded mice from 9 months to 1 year of age.
- Cardiac function was assessed using echocardiography and pressure-volume loop analyses; molecular markers of oxidative stress and fibrosis were evaluated.
Main Results:
- Iron-overloaded HJVKO mice developed advanced iron-overload cardiomyopathy, characterized by increased myocardial iron, oxidative stress, fibrosis, and mortality.
- Resveratrol therapy completely normalized both diastolic and systolic cardiac dysfunction in iron-overloaded mice.
- Resveratrol restored myocardial SERCa2a levels, suppressed NCX1 upregulation, and reduced oxidative stress and fibrosis, partly via activating Akt and AMPK pathways.
Conclusions:
- Aged, iron-overloaded male HJVKO mice represent a valid preclinical model for human iron-overload cardiomyopathy.
- Resveratrol demonstrates significant therapeutic potential, normalizing cardiac function and mitigating key pathological features of iron-overload cardiomyopathy.
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.
