Pathogenesis of Oxidative Stress in Chagasic Myocarditis

Chagasic cardiomyopathy （CCM）是拉丁美洲和墨西哥的一种主要公共卫生威胁，在美国被认为是一种新兴的传染病。来自该疾病不同临床阶段患者的心内膜活检表明，心肌炎症和纤维化在其发病机制中起重要作用。由于在进行性CCM过程中只有少数寄生虫被检测到，因此其他因素被认为参与了激活和/或维持炎症反应。然而，这些因素是未知的。我们已经在实验模型中表明，克氏体感染引起线粒体功能障碍，这与氧化修饰和呼吸链复合物活性的改变、活性氧（ROS）的产生以及心肌的持续氧化损伤有关。我们的其他研究表明，抗氧化治疗可以有效地限制被克氏锥虫感染的小鼠心脏细胞中促炎细胞因子的产生和炎症细胞的募集。在这个项目中，我们将确定1)线粒体ROS和呼吸链缺陷在诱导心肌细胞的促炎反应和随后在查加斯心脏的炎症细胞募集中的关键作用，以及2)线粒体氧化还原诱导的反应在进行性疾病心功能障碍中的生物学意义。我们的中心假设是，克氏绦虫诱导的线粒体膜和呼吸复合物损伤导致持续的ROS生成。这些活性氧在维持氧化应激和激发心肌细胞的促炎细胞因子中起着关键作用，从而为恰加斯心脏中炎症细胞的持续募集提供刺激。该项目的完成将对线粒体ROS在启动和/或维持导致CCM心功能障碍的病理过程（炎症、氧化损伤、纤维化）中的作用提供基本的理解。未来的分子和机制研究将确定设计用于管理线粒体功能或增强抗氧化防御能力的疗法是否能有效降低CCM的严重程度。

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.