The role of endothelin in the pathogenesis of Chagas' disease

S. B. Petkova, Huan Huang, S. M. Factor, R. G. Pestell, B. Bouzahzah, L. A. Jelicks, Louis M. Weiss, S. A. Douglas, M. Wittner, H. B. Tanowitz

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

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 and elevated plasma levels of thromboxane A2 and endothelin-1. In the myocardium of infected mice, myonecrosis and a vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium are observed. Immunohistochemistry studies employing anti-endothelin-1 antibody revealed increased expression of endothelin-1, most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for prepro endothelin-1, endothelin converting enzyme and endothelin-1 were observed in the infected myocardium. When T. cruzi-infected mice were treated with phosphoramidon, an inhibitor of endothelin converting enzyme, there was a decrease in heart size and severity of pathology. Mitogen-activated protein kinases and the transcription factor activator-protein-1 regulate the expression of endothelin-1. Therefore, we examined the activation of mitogen-activated protein kinases in the myocardium by T. cruzi. Western blot demonstrated an extracellular signal regulated kinase. In addition, the activator-protein-1 DNA binding 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 interstitial cells and vascular and endocardial endothelial cells stained intensely with antibodies to these cyclins. These data demonstrate that T. cruzi infection of the myocardium activates extracellular signal regulated kinase, activator-protein-1, endothelin-1, and cyclins. The activation of these pathways is likely to contribute to the pathogenesis of chagasic heart disease. These experimental observations suggest that the vasculature plays a role in the pathogenesis of chagasic cardiomyopathy. Additionally, the identification of these pathways provides possible targets for therapeutic interventions to ameliorate or prevent the development of cardiomyopathy during T. cruzi infection.

Original languageEnglish (US)
Pages (from-to)499-511
Number of pages13
JournalInternational Journal for Parasitology
Volume31
Issue number5-6
StatePublished - May 1 2001

Fingerprint

Chagas Disease
Endothelins
Endothelin-1
Trypanosoma cruzi
Myocardium
Transcription Factor AP-1
Cyclins
Extracellular Signal-Regulated MAP Kinases
Vasculitis
Mitogen-Activated Protein Kinases
Cardiomyopathies
Infection
Immunohistochemistry
Cyclin A
Thromboxane A2
Antibodies
Cyclin D1
Vascular Endothelium
Electrophoretic Mobility Shift Assay
Platelet Aggregation

Keywords

  • Chagas' cardiomyopathy
  • Cyclins
  • Endothelin-1
  • Mitogen-activated protein kinases
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

Cite this

Petkova, S. B., Huang, H., Factor, S. M., Pestell, R. G., Bouzahzah, B., Jelicks, L. A., ... Tanowitz, H. B. (2001). The role of endothelin in the pathogenesis of Chagas' disease. International Journal for Parasitology, 31(5-6), 499-511.

The role of endothelin in the pathogenesis of Chagas' disease. / Petkova, S. B.; Huang, Huan; Factor, S. M.; Pestell, R. G.; Bouzahzah, B.; Jelicks, L. A.; Weiss, Louis M.; Douglas, S. A.; Wittner, M.; Tanowitz, H. B.

In: International Journal for Parasitology, Vol. 31, No. 5-6, 01.05.2001, p. 499-511.

Research output: Contribution to journalArticle

Petkova, SB, Huang, H, Factor, SM, Pestell, RG, Bouzahzah, B, Jelicks, LA, Weiss, LM, Douglas, SA, Wittner, M & Tanowitz, HB 2001, 'The role of endothelin in the pathogenesis of Chagas' disease', International Journal for Parasitology, vol. 31, no. 5-6, pp. 499-511.
Petkova SB, Huang H, Factor SM, Pestell RG, Bouzahzah B, Jelicks LA et al. The role of endothelin in the pathogenesis of Chagas' disease. International Journal for Parasitology. 2001 May 1;31(5-6):499-511.
Petkova, S. B. ; Huang, Huan ; Factor, S. M. ; Pestell, R. G. ; Bouzahzah, B. ; Jelicks, L. A. ; Weiss, Louis M. ; Douglas, S. A. ; Wittner, M. ; Tanowitz, H. B. / The role of endothelin in the pathogenesis of Chagas' disease. In: International Journal for Parasitology. 2001 ; Vol. 31, No. 5-6. pp. 499-511.
@article{9be5aa72d5c2471f8d17cf111d400e13,
title = "The role of endothelin in the pathogenesis of Chagas' disease",
abstract = "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 and elevated plasma levels of thromboxane A2 and endothelin-1. In the myocardium of infected mice, myonecrosis and a vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium are observed. Immunohistochemistry studies employing anti-endothelin-1 antibody revealed increased expression of endothelin-1, most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for prepro endothelin-1, endothelin converting enzyme and endothelin-1 were observed in the infected myocardium. When T. cruzi-infected mice were treated with phosphoramidon, an inhibitor of endothelin converting enzyme, there was a decrease in heart size and severity of pathology. Mitogen-activated protein kinases and the transcription factor activator-protein-1 regulate the expression of endothelin-1. Therefore, we examined the activation of mitogen-activated protein kinases in the myocardium by T. cruzi. Western blot demonstrated an extracellular signal regulated kinase. In addition, the activator-protein-1 DNA binding 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 interstitial cells and vascular and endocardial endothelial cells stained intensely with antibodies to these cyclins. These data demonstrate that T. cruzi infection of the myocardium activates extracellular signal regulated kinase, activator-protein-1, endothelin-1, and cyclins. The activation of these pathways is likely to contribute to the pathogenesis of chagasic heart disease. These experimental observations suggest that the vasculature plays a role in the pathogenesis of chagasic cardiomyopathy. Additionally, the identification of these pathways provides possible targets for therapeutic interventions to ameliorate or prevent the development of cardiomyopathy during T. cruzi infection.",
keywords = "Chagas' cardiomyopathy, Cyclins, Endothelin-1, Mitogen-activated protein kinases, Trypanosoma cruzi",
author = "Petkova, {S. B.} and Huan Huang and Factor, {S. M.} and Pestell, {R. G.} and B. Bouzahzah and Jelicks, {L. A.} and Weiss, {Louis M.} and Douglas, {S. A.} and M. Wittner and Tanowitz, {H. B.}",
year = "2001",
month = "5",
day = "1",
language = "English (US)",
volume = "31",
pages = "499--511",
journal = "International Journal for Parasitology",
issn = "0020-7519",
publisher = "Elsevier Limited",
number = "5-6",

}

TY - JOUR

T1 - The role of endothelin in the pathogenesis of Chagas' disease

AU - Petkova, S. B.

AU - Huang, Huan

AU - Factor, S. M.

AU - Pestell, R. G.

AU - Bouzahzah, B.

AU - Jelicks, L. A.

AU - Weiss, Louis M.

AU - Douglas, S. A.

AU - Wittner, M.

AU - Tanowitz, H. B.

PY - 2001/5/1

Y1 - 2001/5/1

N2 - 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 and elevated plasma levels of thromboxane A2 and endothelin-1. In the myocardium of infected mice, myonecrosis and a vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium are observed. Immunohistochemistry studies employing anti-endothelin-1 antibody revealed increased expression of endothelin-1, most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for prepro endothelin-1, endothelin converting enzyme and endothelin-1 were observed in the infected myocardium. When T. cruzi-infected mice were treated with phosphoramidon, an inhibitor of endothelin converting enzyme, there was a decrease in heart size and severity of pathology. Mitogen-activated protein kinases and the transcription factor activator-protein-1 regulate the expression of endothelin-1. Therefore, we examined the activation of mitogen-activated protein kinases in the myocardium by T. cruzi. Western blot demonstrated an extracellular signal regulated kinase. In addition, the activator-protein-1 DNA binding 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 interstitial cells and vascular and endocardial endothelial cells stained intensely with antibodies to these cyclins. These data demonstrate that T. cruzi infection of the myocardium activates extracellular signal regulated kinase, activator-protein-1, endothelin-1, and cyclins. The activation of these pathways is likely to contribute to the pathogenesis of chagasic heart disease. These experimental observations suggest that the vasculature plays a role in the pathogenesis of chagasic cardiomyopathy. Additionally, the identification of these pathways provides possible targets for therapeutic interventions to ameliorate or prevent the development of cardiomyopathy during T. cruzi infection.

AB - 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 and elevated plasma levels of thromboxane A2 and endothelin-1. In the myocardium of infected mice, myonecrosis and a vasculitis of the aorta, coronary artery, smaller myocardial vessels and the endocardial endothelium are observed. Immunohistochemistry studies employing anti-endothelin-1 antibody revealed increased expression of endothelin-1, most intense in the endocardial and vascular endothelium. Elevated levels of mRNA for prepro endothelin-1, endothelin converting enzyme and endothelin-1 were observed in the infected myocardium. When T. cruzi-infected mice were treated with phosphoramidon, an inhibitor of endothelin converting enzyme, there was a decrease in heart size and severity of pathology. Mitogen-activated protein kinases and the transcription factor activator-protein-1 regulate the expression of endothelin-1. Therefore, we examined the activation of mitogen-activated protein kinases in the myocardium by T. cruzi. Western blot demonstrated an extracellular signal regulated kinase. In addition, the activator-protein-1 DNA binding 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 interstitial cells and vascular and endocardial endothelial cells stained intensely with antibodies to these cyclins. These data demonstrate that T. cruzi infection of the myocardium activates extracellular signal regulated kinase, activator-protein-1, endothelin-1, and cyclins. The activation of these pathways is likely to contribute to the pathogenesis of chagasic heart disease. These experimental observations suggest that the vasculature plays a role in the pathogenesis of chagasic cardiomyopathy. Additionally, the identification of these pathways provides possible targets for therapeutic interventions to ameliorate or prevent the development of cardiomyopathy during T. cruzi infection.

KW - Chagas' cardiomyopathy

KW - Cyclins

KW - Endothelin-1

KW - Mitogen-activated protein kinases

KW - Trypanosoma cruzi

UR - http://www.scopus.com/inward/record.url?scp=0035339909&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035339909&partnerID=8YFLogxK

M3 - Article

C2 - 11334935

AN - SCOPUS:0035339909

VL - 31

SP - 499

EP - 511

JO - International Journal for Parasitology

JF - International Journal for Parasitology

SN - 0020-7519

IS - 5-6

ER -