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Infection and Immunity, April 2005, p. 2496-2503, Vol. 73, No. 4
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.4.2496-2503.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of Endothelin 1 in the Pathogenesis of Chronic Chagasic Heart Disease

Departments of Pathology,¹ Medicine,² Physiology and Biophysics,³ Cell Biology, Albert Einstein College of Medicine, Bronx, New York,⁵ Department of Molecular Genetics and the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas,⁷ Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina,⁶ Instituto Nacional de Cardiologia, Mexico City, Mexico⁴

Received 19 October 2004/ Returned for modification 1 December 2004/ Accepted 8 December 2004

On the basis of previous observations, endothelin 1 (ET-1) has been suggested as contributing to the pathogenesis of Chagasic cardiomyopathy. Therefore, ET-1^flox/flox;-MHC-Cre(+) mice in which the ET-1 gene was deleted from cardiac myocytes and ET-1^flox/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-1^flox/flox;-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-1^flox/flox;-MHC-Cre(+) mice; i.e., RVID was not changed in infected ET-1^flox/flox;-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-1^flox/flox;-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.

Editor: W. A. Petri, Jr.

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