A large number of epidemiological studies have suggested that hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Despite a relative wealth of epidemiological data, however, the mechanisms by which hyperhomocysteinemia predisposes to vascular events remain poorly understood. Two potential mechanisms that have received recent attention are: 1) increased oxidative stress mediated either directly by oxidation of homocysteine or indirectly by impairment of antioxidant enzyme activity and 2) decreased bioavailability of endothelial nitric oxide mediated either by increased oxidative inactivation of nitric oxide or decreased generation of nitric oxide. Very few studies have been performed to test the hypothesis that these mechanisms are important in the development of vascular dysfunction in vivo. Using dietary approaches in monkeys, the PI was among the first to demonstrate that moderate hyperhomocysteinemia is associated with impaired vascular function. Hyperhomocysteinemia was also associated with elevated plasma levels of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis. More recently, the PI has developed dietary and genetic models to produce hyperhomocysteinemia and vascular dysfunction in mice. There are three specific aims.
Aim 1 will use Murine models to determine whether vascular dysfunction is caused by specific alterations of homocysteine metabolism. Two strains of mice will be studied that have been generated through gene targeting techniques: cystathionine p-synthase (CBS) knockout mice, which have a selective defect in homocysteine trans sulfuration, and methylene tetrahydrofolate reductase (MTHFR) knockout mice, which have a selective defect in homocystine remethylation.
Aim 2, will test the hypothesis that vascular dysfunction in hyperhomocysteinemic mice is caused by increased oxidative stress in vivo.
Aim 3 will attempt to determine the mechanisms of elevation of ADMA in hyperhomocysteinemia.
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