Identification of molecules associated with disease progression of autoimmune myocarditis to dilated cardiomyopathy

Abstract

Myocarditis is an inflammatory disease characterized by immune infiltrates into the myocardium. In many patients, the disease progresses to a chronic phase dilated cardiomyopathy (DCM) in which there is extensive fibrosis leading to ventricular dilation and impaired cardiac function. Less than 50% of these patients survive more than 5 years. Immunosuppressive treatments such as corticosteroids (CSs) are effective in managing the acute phase of the disease, but do not prevent progression to the DCM. Using the experimental autoimmune myocarditis (EAM) animal model, we previously demonstrated that the inflammatory cytokine macrophage migration inhibitory factor (MIF) plays a role in resistance to CS treatment. MIF knockout mice were treated with the corticosteroid Dexamethasone (Dex) and proved to be resistant to both EAM and DCM. We also observed that treatment with MIF inhibitors and Dex decreased the expression of chemokines and adhesion molecules and implicated these molecules in the progression of disease. Within these, osteopontin (OPN), a powerful chemoattractant, was downregulated. We hypothesized that OPN plays a role in the disease process and investigated its role in EAM and DCM using OPN knockout mice. Our results show that OPN knockout mice developed EAM, but that progression to DCM was impaired. Furthermore, we observed a decrease in CD45+CD133+ fibroblast progenitor cells infiltrating the myocardium in the absence of OPN, which could contribute to attenuated disease in KO mice. This study may provide insights into the mechanisms driving progression of EAM to DCM and point to potential therapeutic targets.