Macrovascular disease due to accelerated atherosclerosis is the major cause of mortality in patients with both types 1 and 2 diabetes. Despite this, the factors that place the individual with diabetes at risk for atherosclerotic vascular disease are incompletely understood. This program-is built around two central themes: (1) that a decrease in the biological activity of endothelium-derived nitric oxide (NO) is a common defect in patients with diabetes that accelerates atherosclerosis and (2) that in diabetes, this decrease in NO is due to an increase in oxidative stress related to hyperglycemia and dyslipidemia. The four closely-linked projects in this program each address these themes. Project 1 will examine the hypothesis that hyperglycemia and dyslipidemia accelerate atherosclerosis by increasing the susceptibility of LDL to oxidation. In addition, the effects of hyperglycemia on cellular responses to oxidized LDL will be explore& Project 2 will evaluate the effects of hyperglycemia and other alterations in the diabetic milieu on the L-arginine/NO pathway (arginine transport and NO synthesis) in both cultured endothelial cells and intact aorta. In concert with project 3, it will assess in hyperlipidemic, diabetic rabbits whether the acceleration of atherosclerosis and its prevention by pharmacological agents are antedated by changes in this pathway. Project 3 will characterize the diabetic rabbit model in which the ingestion of a high-sucrose, high-fat diet accelerates atherosclerosis. Use will be made of this model to examine the relationship of atherogenesis to the expression of adhesion molecules and to determine the effect on the atherogenic process of interventions aimed at NO and oxidized lipoproteins. Project 4 will examine the relation of hyperglycemia, dyslipidemia and oxidative stress to endothelial cell dysfunction in humans using both a non-invasive brachial-artery ultrasound method and brachial artery infusions of vasoactive substances with measurements of forearm blood flow. Results with the two methods will compared. In addition, the effects of treatments that diminish oxidative stress and lower plasma lipids and/or glucose will be determined. The studies in this program should provide important new insights into the pathogenesis of macrovascular disease in diabetes. They will also provide the groundwork both for detecting early and reversible manifestations of this complication in humans (Project 4) and for devising therapeutic approaches for preventing it.