Severity of autoimmune myocarditis is influenced by Connexin43 expression (171.23)

Abstract Myocarditis, or inflammation of the heart muscle, is associated with severe morbidity and mortality, even in young, otherwise healthy individuals. The disease is initiated by exposure to viruses, parasites, and toxins, but can develop into a chronic autoimmune disease which progresses to severe fibrosis and dilated cardiomyopathy. Work in our lab using experimental autoimmune myocarditis (EAM) as a model, has demonstrated alterations in the sub-cellular localization of the cardiac gap junction protein connexin43 (Cx43) in heart tissue adjacent to myocarditis lesions, a potentially arrythmogenic effect. In the present study, we found the converse to be true; a reduction in Cx43 expression altered the course of EAM, resulting in a more pronounced disease. To generate animals with reduced Cx43, we backcrossed CX43+/- mice on the EAM-resistant C57BL/6 background to the EAM-susceptible BALB/c background. After 8 generations, we initiated EAM by two doses of α myosin heavy chain antigenic peptide at days 0 and 7. Hearts were analyzed 21 days after EAM induction for both the area and intensity of immune infiltrate. We determined that mice heterozygous for Cx43 develop more severe disease than wild type littermates. Closer analysis of infiltrating immune cells by immunofluorescence microscopy revealed differences in myeloperoxidase positive and CD3+ cells, with Cx43 heterozygotes having more of both. These results suggest that Cx43 can alter the course of EAM.