Actin Carbonylation is Higher in Human Hypertrophic Cardiomyopathy Due to MYH7 Mutations

Abstract

Introduction: Hypertrophic cardiomyopathy(HCM) is frequently caused by mutations in genes encoding sarcomeric proteins. Decreased force development was found in human HCM due to mutations in genes encoding myosin binding protein-C(MYBPC3), myosin heavy chain(MYH7) and in sarcomere mutation-negative HCM(HCMsmn). This is partially caused by the mutation (especially MYH7 mutations), increased cell size and reduced myofibrillar density. However, 10% force reduction could not be explained by the mutation or cellular remodeling. In end-stage human heart failure increased actin-carbonylation, induced by oxidative stress, negatively correlated with myocardial function. Therefore, we investigated whether actin is carbonylated in human HCM.Methods and results: Left ventricular tissue of human HCMsmn, MYBPC3mut and MYH7mut patients was obtained. Non-failing donors were used as control. Actin-carbonylation was analyzed using Oxyblot. Carbonyl groups of myofilament proteins were derivatized by 2,4-dinitrophenyl-hydrazine(DNPH). Protein lysates were processed via SDS-page, western blot and chemiluminescence using appropriate antibodies. Actin-carbonylation was higher in HCM patients compared to donors. It was highest in MYH7mut(Figure).Conclusion: Increased actin-carbonylation could partially underlie reduced force development in human HCM. Increased oxidative stress may contribute to impaired contractile function during disease development in sarcomere mutation-positive and mutation-negative HCM patients.View Large Image | View Hi-Res Image | Download PowerPoint Slide