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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.

SUBMITTER: Cunha-Neto E

PROVIDER: S-EPMC1603558 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy.

Cunha-Neto Edecio E Dzau Victor J VJ Allen Paul D PD Stamatiou Dimitri D Benvenutti Luiz L Higuchi M Lourdes ML Koyama Natalia S NS Silva Joao S JS Kalil Jorge J Liew Choong-Chin CC

The American journal of pathology 20050801 2

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 microarra ...[more]

PMID: 16049318

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Project description:Chagas disease is caused by Trypanosoma cruzi which is endemic in Latin America. T. cruzi infection results in a latent infection with approximately a third of latently infected patients developing chronic Chagas cardiomyopathy (CCM). CCM is a common cause of cardiomyopathy in endemic regions and has a poor prognosis compared to other cardiomyopathies. The factors responsible for the transition from the asymptomatic indeterminate latent stage of infection to CCM are poorly understood. Our previous studies demonstrated that lipid metabolism and diet are important determinants of disease progression. In the present study, we analyzed various serum metabolomic biomarkers such as acylcarnitines, amino acids, biogenic amines, glycerophospholipids, and sphingolipids in murine models of CCM, where the mice specifically develop either left or right ventricular cardiomyopathy based on the diets fed during the indeterminate stage in a murine model of Chagas disease. Our data provide new insights into the metabolic changes that may predispose patients to CCM and biomarkers that may help predict the risk of developing cardiomyopathy from T. cruzi infection. Author Summary. Chronic Chagas cardiomyopathy (CCM) is a parasitic disease prevalent in Latin America. Currently, no effective drugs or vaccines are available to prevent or cure CCM. The factors involved in the disease severity and progression are poorly understood to design new therapeutic interventions. In order to rapidly identify Chagas patients with a higher risk to develop CCM, a new set of biomarkers specific to Chagas disease is needed. We performed serum metabolomic analyses in chronic T. cruzi-infected mice fed on different diets and identified cardiac ventricular-specific metabolite biomarkers that could define CCM severity. In this paper, we present the results of serum metabolomic analyses and discuss its correlations to the diet-induced metabolic regulations in the pathogenesis of CCM in a murine model of Chagas disease.

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Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy.

Publications

Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy.

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