Cardiac-Specific Overexpression of Melanoma Differentiation–Associated Gene-5 Protects Mice From Lethal Viral Myocarditis

Abstract

Background— Viral myocarditis is among the most common causes of heart failure in children and young adults. The RNA helicase melanoma differentiation–associated gene-5 (MDA5) is critical for host antiviral responses against members of the Picornaviridae family, such as encephalomyocarditis virus (EMCV). MDA5-knockout mice are highly susceptible to EMCV infection and develop significant myocardial injury and left ventricular dysfunction. However, the mechanisms by which MDA5 signaling within cardiac myocytes contributes to the host response against viral infection have not been defined. Methods and Results— We generated cardiac-specific MDA5 transgenic (alpha-myosin heavy chain [αMHC]-MDA5) mice. These mice showed increased baseline cardiac expression of antiviral cytokines and increased cellular infiltration but no alterations in cardiac function and structure. αMHC-MDA5 mice were less susceptible to EMCV infection and had a significantly lower cardiac viral load compared with littermate control mice. The severity of myocarditis, prevalence of cardiac myocyte apoptosis, and cleavage of caspase 3 after EMCV infection were attenuated in αMHC-MDA5 mice. Furthermore, αMHC-MDA5 mice were protected against EMCV-induced myocardial dysfunction. Conclusions— Our data suggest that myocardial MDA5 may be a key molecule in protecting the heart from direct viral injury and myocardial dysfunction.