Elsevier

Cardiovascular Pathology

Volume 9, Issue 5, September–October 2000, Pages 257-265
Cardiovascular Pathology

Articles
Myocardial Expression of Endothelin-1 in Murine Trypanosoma cruzi Infection

https://doi.org/10.1016/S1054-8807(00)00045-4Get rights and content

Abstract

Chagas' disease, caused by Trypanosoma cruzi, is an important cause of myocarditis and chronic cardiomyopathy and is accompanied by microvascular spasm and myocardial ischemia. We reported previously that infection of cultured endothelial cells with T. cruzi increased the synthesis of biologically active endothlein-1 (ET-1). In the present study, we examined the role of ET-1 in the cardiovascular system of CD1 mice infected with the Brazil strain of T. cruzi and C57BL/6 mice infected with the Tulahuen strain during acute infection. In the myocardium of infected mice myonecrosis and multiple pseudocysts were observed. There was also an intense vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium. Immunohistochemistry studies employing anti-ET-1 antibody revealed increased expression of ET-1 that was most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for preproET-1, endothelin converting enzyme and ET-1 were observed in the same myocardial samples. Plasma ET-1 levels were significantly elevated in infected CD1 mice 10–15 days post infection. These observations suggest that increased levels of ET-1 are a consequence of the initial invasion of the cardiovascular system and provide a mechanism for infection-associated myocardial dysfunction.

Section snippets

Infection of Mice

Eight- to ten-week-old male CD1 mice (Jackson Laboratories, Bar Harbor, ME) were infected with 104 trypomastigotes of the Brazil strain of T. cruzi. Eight-week old C57BL/6 mice (Jackson Laboratories, Bar Harbor, ME) were infected with 104 trypomastigotes of the Tulahuen strain. Hearts were obtained at various time-points post-infection, for histology, immunohistochemistry, and total RNA isolation.

Histology

Hearts were fixed in 10% buffered formalin and stained with hematoxylin and eosin. The slides were

Infection of Mice

Infected CD1 mice had achieved a parasitemia of 106 to 107 trypomastigotes/ml blood by day 30–35 post infection, at which time the mortality rate was 30–50% (21). Infected C57BL/6 mice had 100% mortality by day 20–25 post infection, when the parasitemia was 106–107/ml.

Histology

During acute infection in both mouse models there were intense myonecrosis and multiple areas of pseudocyst formation Figure 1, Figure 2. Necrosis and vasculitis were more severe in the Tulahuen-infected C57BL/6 mice compared with

Discussion

The role of ET-1 in murine T. cruzi infection was investigated in CD1 mice infected with the Brazil strain and the C57BL/6 mouse infected with the Tulahuen strain. In the CD1 model there is a significant mortality by 30–35 days post infection, with a moderately high parasitemia and acute myocarditis and vasculitis. The mice that survive acute infection eventually develop a chronic cardiomyopathy. However, in the C57BL/6 model there is a high parasitemia and 100% mortality by day 25 of

Acknowledgements

These studies were supported in part by grants R01AI-12770 (HBT), R01AI-41752 (MW), R01DK46379 (GJC), and R01CA-75503, and R01CA70896 (RGP) from the National Institutes of Health. This work was also supported by a New Investigator Award (HH) and a Grant in Aid (HBT) from the Heritage Branch of the American Heart Association. We wish to thank Vicki Braunstein for excellent technical assistance.

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