Mechanisms of Vascular Dysfunction in Homocysteinemia

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DESCRIPTION (provided by applicant): Hyperhomocysteinemia, or elevation of plasma total homocysteine, is an emerging risk factor for cardiovascular disease and stroke. Numerous retrospective and prospective studies have suggested that hyperhomocysteinemia is an independent risk factor, and that the magnitude of risk is similar to that for conventional risk factors such as hypercholesterolemia or hypertension. The potential cardiovascular benefits of homocysteine-lowering therapy are currently being evaluated in several prospective clinical trials. Despite its clear association with clinical cardiovascular disease, however, the mechanisms responsible for the vascular pathology of hyperhomocysteinemia are still incompletely understood. Our group was among the first to demonstrate that moderate hyperhomocysteinemia produces impaired vascular function in vivo. To better examine the mechanisms of vascular dysfunction in hyperhomocysteinemia, we have developed genetic and dietary approaches to produce hyperhomocysteinemia in mice. Our data, and data from others, have provided strong evidence that endothelial dysfunction during hyperhomocysteinemia is related to impaired bioavailability of endothelium-derived nitric oxide (NO). Proposed mechanisms include oxidative inactivation of NO and decreased production of NO due to inhibition of endothelial nitric oxide synthase by asymmetric dimethylarginine (ADMA). The goals of this project are to define the role of ADMA in decreasing NO bioavailability and to determine the sources of reactive oxygen species (ROS) that mediate vascular dysfunction in hyperhomocysteinemia. A key feature of our experimental design is the use of genetically-altered mice to examine the contributions of ADMA, the inducible isoform of nitric oxide synthase, and vascular NAD(P)H oxidases in impairing endothelial function during hyperhomocysteinemia. This project has the potential to suggest novel therapeutic approaches to the prevention and treatment of vascular disease associated with hyperhomocysteinemia.