application) This application seeks five years of support to investigate the vascular effects of homocyst(e)ine in humans. A relationship between plasma homocysteine and atherosclerotic disease is well-recognized, but it is not yet clear whether homocyst(e)ine is a true risk factor for atherosclerosis or a marker for thromboembolic and atherosclerotic diseases. Because of in vitro evidence suggesting that homocyst(e)ine can damage vascular endothelial cells, the principal investigator and his coinvestigators have begun to examine the effects of experimental induction of hyperhomocyst(e)inemia on endothelial function in vivo in humans. This project tests the hypothesis that moderate hyperhomocyst(e)inemia causes endothelial dysfunction in humans and that this effect on the endothelium is mediated by increases in oxidant stress.
Three specific aims will be tested.
Aim I will examine the effects of chronic hyperhomocyst(e)inemia on endothelial function in both genetic and environmentally modulated models of hyperhomocyst(e)inemia, and will further study the effect of correction of plasma homocyst(e)ine levels on endothelial functional assays.
Specific Aim II will investigate whether rapid induction of abnormal plasma homocyst(e)ine levels in normal subjects by methionine loading and folate restriction leads to detectable endothelial dysfunction.
Specific Aim III will assess whether rapidly induced hyperhomocyst(e)inemia alters a variety of biochemical indices of oxidant stress and whether antioxidant therapies can reverse some or all of the endothelial function abnormalities detected in this model. Methodologies to be used include ultrasound-Doppler flow-dependent vasodilation, intra-arterial administration of pharmacologic agents with plethysmography to evaluate resistance vessel endothelial function, and non-invasive assessment of vascular structure, as well as measurement of a variety of factors important to vascular tone, platelet aggregation and coagulation. These human studies will examine further whether coexisting risk factors for atherosclerosis alter endothelial susceptibility to hyperhomocyst(e)inemia, and potential differences in the effects of homocyst(e)ine on endothelial function due to gender or race also will be explored. These studies will take advantage of a distinctive collaboration by investigators at the University of Iowa with expertise in human vascular physiology, hemostasis and thrombosis in homocyst(e)ine, and human molecular genetics. In summary, the project will provide a unique opportunity to test in vivo in humans the concept that homocyst(e)ine contributes directly to atherosclerosis by deleterious effects on endothelial function and to explore several potential mechanisms for these effects.
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