Cardiac gene expression profiling provides evidence for cytokinopathy as a molecular mechanism in Chagas' disease cardiomyopathy.
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.
Cunha-Neto
Edecio
E
Laboratory of Immunology, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil.
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
D000293:Adolescent; D000328:Adult; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002598:Chagas Cardiomyopathy / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006321:Heart / Q000196:embryology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018932:Chemokine CCL2; D016207:Cytokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma; D009320:Atrial Natriuretic Factor