Abstract
On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1flox/flox;alpha-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1flox/flox;Tie 2 Cre(+) mice in which the ET-1 gene was deleted from endothelial cells were infected with Trypanosoma cruzi. Genetic controls for these cell-specific ET-1 knockout mice were used. Ninety percentage of all mice survived acute infection with the Brazil strain and were evaluated 130 days postinfection. Inflammation and fibrosis were observed in all infected mice; however, fibrosis was reduced in ET-1flox/flox;alpha-MHC-Cre(+) mice. Cardiac magnetic resonance imaging revealed that infection resulted in a significant increase in right ventricular internal diameter (RVID) in all mice except ET-1flox/flox;alpha-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1flox/flox;alpha-MHC-Cre(+) mice. Echocardiography of the left ventricle demonstrated increased left ventricular end-diastolic diameter, reduced fractional shortening, and decreased relative wall thickness in infected mice. However, the magnitude of the changes was significantly less in ET-1flox/flox;alpha-MHC-Cre(+) mice compared to other groups. These data provide further evidence of a role for ET-1, particularly cardiac myocyte-derived ET-1, in the pathogenesis of chronic Chagasic cardiomyopathy.
Highlights
Chagas’ disease caused by infection with the protozoan parasite, Trypanosoma cruzi, is a major cause of acute myocarditis and chronic cardiomyopathy in areas of endemicity in Latin America [51]
Recent evidence suggests that endothelin 1 (ET-1) contributes to the pathogenesis of Chagasic cardiomyopathy [2, 31, 32, 35, 36]
We sought to investigate this by utilizing mice in which the ET-1 gene was knocked out either in cardiac myocytes or endothelial cells
Summary
Chagas’ disease caused by infection with the protozoan parasite, Trypanosoma cruzi, is a major cause of acute myocarditis and chronic cardiomyopathy in areas of endemicity in Latin America [51]. Injury to the endothelial cells during disease states leads to an increase in levels of ET-1. This peptide is synthesized by cardiac myocytes and cardiac fibroblasts [8, 19]. ET-1 is involved in many cell signaling pathways that include calcium mobilization and activation of proinflammatory cytokines, ERK1/2, and cyclin D1 [12, 19, 29, 48] All of these pathways are crucial in the development of cardiovascular dysfunction. Phosphoramidon, an inhibitor of ECE, ameliorated the pathology and reduced the cardiac remodeling in T
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