Role of cardiac myocyte-derived endothelin-1 in chagasic cardiomyopathy: molecular genetic evidence.
Trypanosoma cruzi is the aetiological agent of Chagas' disease, an important cause of chronic cardiomyopathy. We previously demonstrated a role for endothelin-1 (ET-1) in the pathogenesis of chagasic heart disease. In order to explore further the significance of ET-1 in chagasic heart disease, we infected ET-1 (flox/flox); alpha-MHC-Cre(+) (ET-1KO) mice, in which the ET-1 gene has been deleted from cardiac myocytes, with 10(4) T. cruzi (Brazil strain) trypomastigotes. As controls, we used ET-1 (flox/flox);Cre(-) (FLOX) and C57BL/6x129sv (WT) mice. All mice survived and were evaluated 150-160 days post-infection. Cardiac magnetic resonance imaging revealed a significant increase in right ventricular internal diameter in all infected animals except ET-1KO mice (control WT, 1.6+/-0.10 mm; infected WT, 2.8+/-0.15 mm; control FLOX, 2.04+/-0.02 mm; infected FLOX, 2.76+/-0.28 mm). There was no significant difference in right ventricular internal diameter between infected and uninfected ET-1KO mice (control ET-1KO, 1.83+/-0.11 mm; infected ET-1KO, 2.14+/-0.20 mm). In another series of experiments, transthoracic echocardiography was performed on uninfected as well as infected ET-1KO mice, and uninfected and infected FLOX mice. Both infected groups had an increased left ventricular end-diastolic diameter and reduced fractional shortening. In addition, relative wall thickness was also decreased in infected animals. However, the magnitude of these changes was less in infected ET-1KO mice. These data provide further support for a role for ET-1 in the pathogenesis of chronic chagasic heart disease, and indicate that cardiac myocytes are an important source of ET-1 in this disease.
Huang
Huan
H
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park, Bronx, New York, NY 10461, U.S.A. huangh@aecom.yu.edu
Yanagisawa
Masashi
M
Kisanuki
Yaz Y
YY
Jelicks
Linda A
LA
Chandra
Madhulika
M
Factor
Stephen M
SM
Wittner
Murray
M
Weiss
Louis M
LM
Pestell
Richard G
RG
Shtutin
Vitaliy
V
Shirani
Jamshid
J
Tanowitz
Herbert B
HB
D000818:Animals; D002598:Chagas Cardiomyopathy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004452:Echocardiography; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
D019332:Endothelin-1