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

• Published in: Bioscience reports 2018-02, Vol.38 (1)
• Main Authors: Das, Subhash K, Zhabyeyev, Pavel, Basu, Ratnadeep, Patel, Vaibhav B, Dyck, Jason R B, Kassiri, Zamaneh, Oudit, Gavin Y
• Format: Article
• Language: English
• Subjects: Age; Aging; AKT protein; AMP-activated protein kinase; Animal models; Animals; Antibodies; Body composition; Ca2+-transporting ATPase; Calcium (reticular); Calcium ions; Cardiac muscle; Cardiomyopathies - drug therapy; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiomyopathy; Comorbidity; Diet; Disease Models, Animal; Echocardiography; Fibrosis; Heart - drug effects; Heart - physiopathology; Heart failure; Hemochromatosis; Hepcidin; Hepcidins - genetics; Homeostasis; Humans; Iron; Iron - metabolism; Iron Overload - drug therapy; Iron Overload - genetics; Iron Overload - metabolism; Iron Overload - pathology; Kinases; Laboratory animals; Lipid peroxidation; Males; Membrane Proteins - genetics; Mice; Myocardium - metabolism; Myocardium - pathology; Na+/Ca2+ exchanger; NCX1 protein; Overloading; Oxidative stress; Oxidative Stress - drug effects; Protein Kinases - genetics; Proteins; Resveratrol; Sarcoplasmic reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sodium-Calcium Exchanger - genetics; Software; Stilbenes - administration & dosage; Survival analysis; Therapy
• ISSN: 0144-8463; 1573-4935
• DOI: 10.1042/BSR20171302

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 Ca 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.