Cardiac Gene Expression Profiling Provides Evidence for Cytokinopathy as a Molecular Mechanism in Chagas' Disease Cardiomyopathy

Abstract

Chronic Chagas' disease cardiomyopathy is a leading cause of congestive heart failure in Latin America, affecting more than 3 million people. Chagas' cardiomyopathy is more aggressive than other cardiomyopathies, but little is known of the molecular mechanisms responsible for its severity. We characterized gene expression profiles of human Chagas' cardiomyopathy and dilated cardiomyopathy to identify selective disease pathways and potential therapeutic targets. Both our customized cDNA microarray (Cardiochip) and real-time reverse transcriptase-polymerase chain reaction analysis showed that immune response, lipid metabolism, and mitochondrial oxidative phosphorylation genes were selectively up-regulated in myocardial tissue of the tested Chagas' cardiomyopathy patients. Interferon (IFN)-gamma-inducible genes represented 15% of genes specifically up-regulated in Chagas' cardiomyopathy myocardial tissue, indicating the importance of IFN-gamma signaling. To assess whether IFN-gamma can directly modulate cardio-myocyte gene expression, we exposed fetal murine cardiomyocytes to IFN-gamma and the IFN-gamma-inducible chemokine monocyte chemoattractant protein-1. Atrial natriuretic factor expression increased 15-fold in response to IFN-gamma whereas combined IFN-gamma and monocyte chemoattractant protein-1 increased atrial natriuretic factor expression 400-fold. Our results suggest IFN-gamma and chemokine signaling may directly up-regulate cardiomyocyte expression of genes involved in pathological hypertrophy, which may lead to heart failure. IFN-gamma and other cytokine pathways may thus be novel therapeutic targets in Chagas' cardiomyopathy.

Current concepts in immunoregulation and pathology of human Chagas disease

“…There is strong evidence for the involvement of these activated T cells in the development of pathology. It has been demonstrated that circulating activated T cells from asymptomatic and symptomatic patients express both inflammatory and anti-inflammatory cytokines, consistent with an active immunoregulation during the chronic phase [36,37]. However, a preferential expression of inflammatory cytokines, especially TNF-alpha and IFN-gamma, was observed in cardiac lesions [35,38].…”

Interferon-γ and other inflammatory mediators in cardiomyocyte signaling during Chagas disease cardiomyopathy

“…Cytokines like IL-7 and IL-15, which promote T cell survival, are also found to have increased expression in CCC heart tissue [6,7] . Significant IFN-γ signaling was observed in the myocardium of CCC patients, including genes that are not ordinarily expressed by inflammatory cells [8] . A similar increase in IFN-γ and TNF-α expression is observed in cardiac tissue from animals infected with T. cruzi [9] .…”

Proteomic inventory of myocardial proteins from patients with chronic Chagas' cardiomyopathy

“…The local cytokine production profile is consistent with a T1-type response, with interferongamma (γ)-induced chemokines (5)(6)(7)(8)(9)(10)(11)(12). Gene expression profiling of CCC myocardial tissues showed that 15% of the known genes selectively up-regulated in CCC are IFN-γ-inducible (12).…”

“…Gene expression profiling of CCC myocardial tissues showed that 15% of the known genes selectively up-regulated in CCC are IFN-γ-inducible (12). Exposure of cardiomyocytes to IFN-γ can up-regulate the expression of atrial natriuretic factor (12), suggesting that IFN-γ may directly modulate gene expression in myocardial cells. These results are consistent with a possible role of IFN-γ-induced chronic inflammation in modulating myocardial gene expression.…”