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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Disease Models, Animal
  • GPI-Linked Proteins
  • Heart / drug effects*
  • Heart / physiopathology
  • Hemochromatosis Protein
  • Hepcidins / genetics
  • Humans
  • Iron / metabolism
  • Iron Overload / drug therapy*
  • Iron Overload / genetics
  • Iron Overload / metabolism
  • Iron Overload / pathology
  • Membrane Proteins / genetics*
  • Mice
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Oxidative Stress / drug effects
  • Protein Kinases / genetics
  • Resveratrol
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sodium-Calcium Exchanger / genetics
  • Stilbenes / administration & dosage

Substances

  • GPI-Linked Proteins
  • HJV protein, mouse
  • Hemochromatosis Protein
  • Hepcidins
  • Membrane Proteins
  • NCX1 protein, mouse
  • Sodium-Calcium Exchanger
  • Stilbenes
  • Iron
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Resveratrol