Trypanosoma cruzi infection (Chagas' disease) of mice causes activation ofthe mitogen-activated protein kinase cascade and expression of endothelin-1 in the myocardium

Chagas' disease, caused by the parasite Trypanosoma cruzi, is an important cause of heart disease. Previous studies from this laboratory revealed that microvascular spasm and myocardial ischemia were observed in infected mice . Infection of endothelial cells with this parasite increased the synthesis of biologically active endothelin-1 (ET-1). Therefore, in the myocardium o f T. cruzi-infected mice, we examined ET-1 expression and the p42/44-mitoge n activated protein kinase (MAPK)-AP-1 pathway that regulates the expressio n of ET-1. There was parasitism and myonecrosis in the myocardium of infect ed C57BL/6 mice. Reverse transcriptase polymerase chain reaction (RT-PCR) a nalysis revealed elevated mRNA expression of transcription factor AP-1 (c-j un and c-fos) and increased AP-1 DNA binding activity as determined by elec trophoretic mobility shift assay (EMSA). Western blot analysis demonstrated an increase in the phosphorylated forms of extracellular signal-regulated kinase (ERK1/2). ET-1 mRNA was upregulated in the myocardium of infected mi ce. Immunohistochemical and immunoelectron microscopy using anti-ET-1 antib ody detected increased expression in cardiac myocytes and endothelium of th ese mice. These data suggest that ET-1 contributes to chagasic cardiomyopat hy and that the mechanism of the increased expression of ET-1 is a result o f the activation of the MAPK pathway by T. cruzi infection.