Profiling gene transcription reveals a deficiency of mitochondrial oxidative phosphorylation in Trypanosoma cruzi-infected murine hearts:: implications in chagasic myocarditis development

In this study, we report the host genetic responses that characterize Trypanosoma cruzi-induced myocarditis in a murine model of infection and disease development. The mRNA species from the myocardium of infected mice were assessed using cDNA microarray technology at immediate early, acute, and chronic stages of infection. The immediate early reaction of the host to T cruzi infection was marked by up-regulation of transcripts indicative of promflammatory and interferon-induced immune responses. Following acute infection, overexpression of transcripts for extracellular matrix (ECM) proteins, possibly initiated in response to myocardial injuries by invading and replicating parasites, was suggestive of active reparative and remodeling reactions. Surprisingly, progression to the cardiac disease phase was associated with coordinated down-regulation of a majority (>70%) of the differentially expressed genes. Among the most repressed genes were the troponins, essential for contractile function of the myofibrils, and the genes encoding components of oxidative phosphorylation (OXPHOS) pathways. Reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and biochemical assays confirmed the microarray results and provided evidence for the deficiency of OXPHOS complex IV in the chagasic murine heart. We discuss the apparent role of OXPHOS dysfunction in the cardiac hypertrophic and remodeling processes with the development of chagasic cardiomyopathy (CCM). (C) 2003 Elsevier Science B.V. All rights reserved.