The role of endothelin in the pathogenesis of Chagas' disease

Infection with Trypanosoma cruzi causes a generalised vasculitis of several vascular beds. This vasculopathy is manifested by vasospasm, reduced blood flow, focal ischaemia, platelet thrombi, increased platelet aggregation an d elevated plasma levels of thromboxane A(2) and endothelin-1, In the myoca rdium of infected mice, myonecrosis and a vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium are obs erved. Immunohistochemistry studies employing anti-endothelin-1 antibody re vealed increased expression of endothelin-1, most intense in the endocardia l and vascular endothelium. Elevated levels of mRNA for prepro endothelin-1 , endothelin converting enzyme and endothelin-1 were observed in the infect ed myocardium. When T. cruzi-infected mice were treated with phosphoramidon , an inhibitor of endothelin converting enzyme, there was a decrease in hea rt size and severity of pathology. Mitogen-activated protein kinases and th e transcription factor activator-protein-1 regulate the expression of endot helin-1. Therefore, we examined the activation of mitogen-activated protein kinases in the myocardium by T. cruzi. Western blot demonstrated an extrac ellular signal regulated kinase. In addition, the activator-protein-1 DNA b inding activity, as determined by electrophoretic mobility shift assay, was increased. Increased expression of cyclins A and cyclin D1 was observed in the myocardium, and immunohistochemistry studies revealed that interstitia l cells and vascular and endocardial endothelial cells stained intensely wi th antibodies to these cyclins. These data demonstrate that T. cruzi infect ion of the myocardium activates extracellular signal regulated kinase, acti vator-protein-1, endothelin-1, and cyclins. The activation of these pathway s is likely to contribute to the pathogenesis of chagasic heart disease. Th ese experimental observations suggest that the vasculature plays a role in the pathogenesis of chagasic cardiomyopathy. Additionally, the identificati on of these pathways provides possible targets for therapeutic intervention s to ameliorate or prevent the development of cardiomyopathy during T, cruz i infection. (C) 2001 Australian Society for Parasitalogy Inc. Published by Elsevier Science Ltd. All rights reserved.