Hypertension and myocardial infarction (MI), the most common causes of heart failure in blacks, result in hemodynamic overload of the left ventricle (LV) thereby initiating the process of myocardial remodeling. Oxidative stress is increased in remodeling myocardium, and the progression to failure is prevented by antioxidants. We found that reactive oxygen species (ROS) and mechanical strain induce the cellular hallmarks of myocardial remodeling in vitro-hypertrophy, fetal gene expression and apoptosis in cardiac myocytes, and activation of metalloproteinases in cardiac fibroblasts. Glucose-6-phosphate dehydrogenase (G6PD) is responsible for generation of NADPH and maintenance of the reduced glutathione pool, and thereby helps to reduce the level of ROS in the cell. Our central hypothesis is that ROS mediate myocardial remodeling in response to hemodynamic overload, and that genetic depletion of G6PD impairs the antioxidant capacity of the myocardium thereby leading to more rapid and deleterious LV remodeling. We will use G6PD-deficient mice to test the role of myocardial G6PD in determining the myocardial phenotypes caused by hemodynamic overload. In mice with chronic hypertension or MI, myocardial remodeling will be assessed at the organ level by measuring LV dilation and contractile function under highly controlled conditions using the isovolumic, Langendorff preparation. The temporal course of LV remodeling will be monitored by echocardiography. At the tissue level, the myocardial effects of G6PD deficiency will be assessed by measuring myocyte dimensions, fetal gene expression, apoptosis, and the activation of metalloproteinases. We will use cardiac myocytes and fibroblasts cultured from neonatal mouse hearts as in vitro system to examine further the role of G6PD in determining the antioxidant capacity of the cell, the phenotypic responses to mechanic strain and defined ROS, and the efficacy of potential therapeutic approaches. There experiments will elucidate the role of G6PD in pathologic myocardial remodeling, and suggest possible therapeutic strategies.
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