Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation.

Thomas L Lynch,Sakthivel Sadayappan,Murugesan Velayutham,Suresh Govindan,Arturo J Cardounel,Michelle Michels,Mayandi Sivaguru,David Barefield,Jolanda Van Der Velden,Cristobal Dos Remedios

doi:10.1155/2015/424751

Abstract

Cardiomyopathies can result from mutations in genes encoding sarcomere proteins including MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). However, whether oxidative stress is augmented due to contractile dysfunction and cardiomyocyte damage in MYBPC3-mutated cardiomyopathies has not been elucidated. To determine whether oxidative stress markers were elevated in MYBPC3-mutated cardiomyopathies, a previously characterized 3-month-old mouse model of dilated cardiomyopathy (DCM) expressing a homozygous MYBPC3 mutation (cMyBP-C(t/t)) was used, compared to wild-type (WT) mice. Echocardiography confirmed decreased percentage of fractional shortening in DCM versus WT hearts. Histopathological analysis indicated a significant increase in myocardial disarray and fibrosis while the second harmonic generation imaging revealed disorganized sarcomeric structure and myocyte damage in DCM hearts when compared to WT hearts. Intriguingly, DCM mouse heart homogenates had decreased glutathione (GSH/GSSG) ratio and increased protein carbonyl and lipid malondialdehyde content compared to WT heart homogenates, consistent with elevated oxidative stress. Importantly, a similar result was observed in human cardiomyopathy heart homogenate samples. These results were further supported by reduced signals for mitochondrial semiquinone radicals and Fe-S clusters in DCM mouse hearts measured using electron paramagnetic resonance spectroscopy. In conclusion, we demonstrate elevated oxidative stress in MYPBC3-mutated DCM mice, which may exacerbate the development of heart failure.

Highlights

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide and affects 5.1 million people in the United States [1]
To confirm the presence of dilated cardiomyopathy (DCM) in the cardiac myosin binding protein-C (cMyBP-C)(t/t) mice used here, we implemented parasternal long-axis M-mode echocardiography and assessed cardiac function in these animals compared to WT animals (Figure 1(a))
We found a significant reduction in ejection fraction (EF) (Figure 1(d)) and fractional shortening (FS) (Figure 1(e)) in DCM hearts compared to WT hearts signifying impaired cardiac function in DCM hearts

Summary

Introduction

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide and affects 5.1 million people in the United States [1]. Cardiomyopathies are a leading cause of HF and are still associated with substantial morbidity and mortality despite optimal treatment [2]. Novel therapeutic targets and treatments are required. Over the past 20 years, many inherited mutations within genes encoding proteins of the cardiac sarcomere have been identified as causing dilated (DCM) and hypertrophic (HCM) cardiomyopathy [2]. The genetic basis of HCM has been well established with more than 1400 mutations in genes encoding sarcomeric proteins having been identified [3, 4]. Mutations in MYBPC3, which encodes the contractile regulatory protein cardiac myosin binding protein-C (cMyBP-C), are the most

Methods

Results

Conclusion