Pathogenesis of Oxidative Stress in Chagasic Myocarditis

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DESCRIPTION (provided by applicant): Chagasic cardiomyopathy (CCM), a major public health threat in Latin America and Mexico, is recognized as an emerging infectious disease in the U.S. Endomyocardial biopsies from patients in different clinical stages of the disease have suggested that myocardial inflammation and fibrosis play an important role in its pathogenesis. Because only a few, if any, parasites are detected during progressive CCM, other factors are believed involved in activation and/or sustaining the inflammatory response. These factors are, however, not known. We have shown in experimental models that infection by T. cruzi elicits mitochondrial dysfunction associated with oxidative modifications and altered activities of the respiratory chain complexes, generation of reactive oxygen species (ROS), and sustained oxidative damage in the myocardium. Our other studies show that antioxidant treatment is effective in limiting production of proinflammatory cytokines in cardiomyocytes, and recruitment of inflammatory cells in murine hearts infected by T. cruzi. In this project, we will determine 1) the pivotal role of mitochondrial ROS and respiratory chain deficiencies in eliciting the proinflammatory response in cardiomyocytes and subsequent recruitment of inflammatory cells in chagasic hearts, and 2) the biological significance of the mitochondrial redox-induced responses in cardiac dysfunction with progressive disease. Our central hypothesis is that T. cruzi-induced injuries of the mitochondrial membranes and respiratory complexes result in sustained ROS generation. These ROS are critical in sustaining oxidative stress and eliciting pro-inflammatory cytokines in cardiomyocytes, and thus provide stimuli for the consistent recruitment of inflammatory cells in chagasic hearts. Completion of the proposed project will provide a basic understanding of the role of mitochondrial ROS in initiating and/or sustaining pathological processes (inflammation, oxidative damage, fibrosis,) that contribute to cardiac dysfunction in CCM. Future molecular and mechanistic studies would determine whether therapies designed to manage the mitochondrial function or to enhance antioxidant defense capacity would effectively reduce severity of CCM.