Cardiac hypertrophy is associated with upregulation of alpha myosin heavy chain in Hfe‐deficient mice (907.6)

Abstract

Cardiac hypertrophy is associated with up‐regulation of alpha myosin heavy chain in Hfe‐deficient mice Abitha Sukumaran, JuOae Chang, Ban‐An Khaw and Jonghan Kim Department of Pharmaceutical Sciences, Northeastern University, Massachusetts, United States of America.Cardiac damage induced by iron overload is the common cause of morbidity and mortality in patients with hereditary hemochromatosis (HH). Mutations in HFE are the major cause of hemochromatosis in humans. However, the precise molecular mechanisms involved in the pathogenesis of iron‐induced cardiotoxicity are largely unexplored. Here we investigated the effect of HFE and iron on cardiac damage using Hfe‐deficient (Hfe‐/‐) mice, a model of human HH. At the age of 5‐month, Hfe‐/‐ mice displayed elevated iron levels in the heart (p=0.0352). This was associated with increased mRNA expression of divalent metal transporter 1 (DMT1) that lacks iron‐response element (p=0.0124), which likely promotes non‐transferrin‐bound iron uptake. In addition, heart/body weight ratio was significantly increased (15% greater than controls; p=0.0004; n=6‐9/group). Cardiac hypertrophy in Hfe‐/‐ mice was consistent with increased protein levels of alpha myosin heavy chain (p=0.0381), a marker of cardiomyocytes. All these changes were not observed in 1‐month old mice, suggesting an age‐dependent effect of Hfe deficiency on the pathogenesis of cardiotoxicity. Since reduced anti‐oxidant enzyme activities are associated with hypertrophy, increased cardiac iron in Hfe deficiency could promote oxidative stress and deplete anti‐oxidant enzymes, resulting in the progression of cardiac diseases. Supported in part by NIH ES017781.Grant Funding Source: NIH ES017781