The etiology of chagasic heart disease is multifactorial resulting from compromised microcirculation and the direct invasion of the myocardium by, T. cruzi; both of which may lead to an inflammatory response. In recent years we delineated some of the factors associated with the pathogenesis of T. cruzi-induced heart disease. We have demonstrated that T. cruzi causes expression of iNOS, TNF-alpha and lL-1beta in the myocardium and that infection of cultured cardiac myocytes causes an increase in NO and a decrease in beat rate. Therefore, on the basis of these in vitro and in vivo observations we hypothesize that infection induces the expression of myocardial cytokines and iNOS and contributes to myocardial dysfunction. The hypothesis to be tested in this proposal is that following infection with T cruzi, the host responds by the activation of nuclear factors and cytokines resulting in upregulation of the inflammatory process and induction of iNOS causing a sustained release of toxic concentrations of NO which profoundly alters myocardial function. T. cruzi infection of endothelial cells and cardiac myocytes leads to expression of vascular adhesion molecules and iNOS by activation of IkappaB-alpha (NF-kappaB). We plan to study the mechanism whereby T. cruzi activates this pathway and the specificity of NF-kappaB activation in the transcription of those cytokines that upregulate the inflammatory response and iNOS expression. We hypothesize that the expression of iNOS and the increased synthesis of NO resulting from the activation of NF-kappaB causes cardiac myocyte dysfunction and cell death. Accordingly, using an in vitro model we will examine the influence of T. cruzi infection on cardiac myocytes. Upregulatory vs downregulatory cytokines will be studied and the influence of iNOS expression on cardiac myocyte contractility and cell death will be determined. In addition, we will employ in vitro co- culture techniques to test the hypothesis that T. cruzi infection of macrophages, vascular smooth muscle or endothelial cells results in NO- mediated altered contractility in adjacent cardiac myocytes cells. We will examine the kinetics of myocardial cytokines expression in T. cruzi-infected mice. We believe that expression of myocardial cytokines results in cardiac dysfunction which will be assessed by the administration of specific antibodies and the utilization of cytokine knock out mice. We will examine the kinetics of myocardial iNOS expression in T. cruzi-infected mice and the significance of iNOS in influencing myocardial function in acute and chronic infection will be assessed by utilizing verapamil, inhibitors of NOS, and the iNOS-/- (KO) mouse model. The consequences of myocardial cytokine and iNOS expression on """"""""down-stream"""""""" events will be determined by pathological, biochemical and functional studies (ECG, gated MRI).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI041752-01
Application #
2397325
Study Section
Special Emphasis Panel (ZRG5-TMP (05))
Project Start
1997-07-01
Project End
2001-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Jelicks, Linda A; Chandra, Madluhika; Shtutin, Vitaliy et al. (2002) Phosphoramidon treatment improves the consequences of chagasic heart disease in mice. Clin Sci (Lond) 103 Suppl 48:267S-271S
Chandra, Madhulika; Shirani, Jamshid; Shtutin, Vitaliy et al. (2002) Cardioprotective effects of verapamil on myocardial structure and function in a murine model of chronic Trypanosoma cruzi infection (Brazil Strain): an echocardiographic study. Int J Parasitol 32:207-15
Jelicks, Linda A; Chandra, Madhulika; Shirani, Jamshid et al. (2002) Cardioprotective effects of phosphoramidon on myocardial structure and function in murine Chagas' disease. Int J Parasitol 32:1497-506
Chandra, Madhulika; Tanowitz, Herbert B; Petkova, Stefka B et al. (2002) Significance of inducible nitric oxide synthase in acute myocarditis caused by Trypanosoma cruzi (Tulahuen strain). Int J Parasitol 32:897-905
Martins, G A; Petkova, S B; MacHado, F S et al. (2001) Fas-FasL interaction modulates nitric oxide production in Trypanosoma cruzi-infected mice. Immunology 103:122-9
Petkova, S B; Huang, H; Factor, S M et al. (2001) The role of endothelin in the pathogenesis of Chagas' disease. Int J Parasitol 31:499-511
Petkova, S B; Tanowitz, H B; Magazine, H I et al. (2000) Myocardial expression of endothelin-1 in murine Trypanosoma cruzi infection. Cardiovasc Pathol 9:257-65
Petkova, S B; Ashton, A; Bouzahzah, B et al. (2000) Cell cycle molecules and diseases of the cardiovascular system. Front Biosci 5:D452-60
Jelicks, L A; Shirani, J; Wittner, M et al. (1999) Application of cardiac gated magnetic resonance imaging in murine Chagas' disease. Am J Trop Med Hyg 61:207-14

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