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

• Published in: The American journal of pathology Vol. 167; no. 2; pp. 305 - 313
• Main Authors: Cunha-Neto, Edecio, Dzau, Victor J., Allen, Paul D., Stamatiou, Dimitri, Benvenutti, Luiz, Higuchi, M. Lourdes, Koyama, Natalia S., Silva, Joao S., Kalil, Jorge, Liew, Choong-Chin
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.08.2005; ASIP; American Society for Investigative Pathology
• Subjects: Adolescent; Adult; Animals; Atrial Natriuretic Factor - metabolism; Biological and medical sciences; Chagas Cardiomyopathy - genetics; Chagas Cardiomyopathy - metabolism; Chagas Cardiomyopathy - surgery; Chemokine CCL2 - metabolism; Cytokines - metabolism; Female; Gene Expression Profiling; Heart - embryology; Human protozoal diseases; Humans; Infectious diseases; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mice; Middle Aged; Myocytes, Cardiac - drug effects; Oligonucleotide Array Sequence Analysis; Original Research Paper; Parasitic diseases; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Protozoal diseases; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Trypanosomiasis; Heart; Protozoal disease; Cardiomyopathy; Chagas disease; Cardiovascular disease; Parasitosis; Myocardial disease; Mechanism; Gene expression profile; Infection; Anatomic pathology; Heart disease; Circulatory system; Trypanosomiasis
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)62976-8

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)-γ-inducible genes represented 15% of genes specifically up-regulated in Chagas' cardiomyopathy myocardial tissue, indicating the importance of IFN-γ signaling. To assess whether IFN-γ can directly modulate cardio-myocyte gene expression, we exposed fetal murine cardiomyocytes to IFN-γ and the IFN-γ-inducible chemokine monocyte chemoattractant protein-1. Atrial natriuretic factor expression increased 15-fold in response to IFN-γ whereas combined IFN-γ and monocyte chemoattractant protein-1 increased atrial natriuretic factor expression 400-fold. Our results suggest IFN-γ and chemokine signaling may directly up-regulate cardiomyocyte expression of genes involved in pathological hypertrophy, which may lead to heart failure. IFN-γ and other cytokine pathways may thus be novel therapeutic targets in Chagas' cardiomyopathy.