Abstract
Chronic Chagas disease cardiomyopathy (CCC), an especially aggressive inflammatory dilated cardiomyopathy caused by lifelong infection with the protozoan Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Although chronic myocarditis may play a major pathogenetic role, little is known about the molecular mechanisms responsible for its severity. The aim of this study is to study the genes and microRNAs expression in tissues and their connections in regards to the pathobiological processes. To do so, we integrated for the first time global microRNA and mRNA expression profiling from myocardial tissue of CCC patients employing pathways and network analyses. We observed an enrichment in biological processes and pathways associated with the immune response and metabolism. IFNγ, TNF and NFkB were the top upstream regulators. The intersections between differentially expressed microRNAs and differentially expressed target mRNAs showed an enrichment in biological processes such as Inflammation, inflammation, Th1/IFN-γ-inducible genes, fibrosis, hypertrophy, and mitochondrial/oxidative stress/antioxidant response. MicroRNAs also played a role in the regulation of gene expression involved in the key cardiomyopathy-related processes fibrosis, hypertrophy, myocarditis and arrhythmia. Significantly, a discrete number of differentially expressed microRNAs targeted a high number of differentially expressed mRNAs (>20) in multiple processes. Our results suggest that miRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue. This may have a bearing on pathogenesis, biomarkers and therapy.
Highlights
Chagas disease is a major public health problem in Latin America, resulting from lifelong infection with the protozoan parasite Trypanosoma cruzi
Chronic Chagas disease cardiomyopathy (CCC), an aggressive dilated cardiomyopathy caused by Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America
Our group recently studied the mRNA and miRNA transcriptome in the myocardium of mice acutely infected by T. cruzi [27], and we have previously shown that expression of muscle-enriched miRNAs ("myoMiRs", including miR-1 and miR-133) is downmodulated in CCC myocardium, suggesting miRNA may control expression of pathogenetically relevant genes in CCC [28]
Summary
Chagas disease is a major public health problem in Latin America, resulting from lifelong infection with the protozoan parasite Trypanosoma cruzi. Up to 30 years after acute infection, approximately 30% of the 6 million infected people eventually develop chronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy [1,2]. Most other T. cruzi-infected patients will remain asymptomatic for life (60%) or develop digestive disease, which causes less deaths Chagas disease is the most common cause of nonischemic cardiomyopathy in Latin America, causing approximately 10,000 deaths/year, mainly due to heart failure and severe arrhythmia/sudden death [1]. Migration turned Chagas disease into a global health problem, with an estimated 400,000 infected persons living in nonendemic countries, mainly the United States and Europe. Current anti–T. cruzi drugs have shown to be unable to block progression toward CCC [3]
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