Abnormal endothelial cell vasodilator function caused by hypercholesterolemia precedes, and may therefore contribute towards atherosclerotic coronary artery disease which is associated with similar endothelial cell dysfunction and vasospasm. The primary aim of the proposed studies is to determine the mechanisms responsible for the early changes in coronary artery endothelial cell vasoactive function during hypercholesterolemia. Studies in the last grant period have shown that pigs fed a high cholesterol diet for nine weeks have selective impairment in the relaxations caused by several endothelium-dependent agonists. Preliminary studies indicate that a lipid soluble antioxidant, proxicol, prevents abnormal endothelial cell function caused by hypercholesterolemia implicating lipoprotein oxidation in vivo in mediating endothelial cell dysfunction. In the proposed studies, hypercholesterolemic pigs will be treated with lipid soluble antioxidants and endothelium depend relaxations and lipid peroxides measured. Previous studies have shown that similar abnormalities in endothelial cell function as those due to hypercholesterolemia are induced in normal pig coronary arteries by exposing them to low density lipoproteins (LDL) in vitro. These studies on isolated arteries have indicated that free radical-mediated lipid peroxidation in vitro may mimic that occurring in vivo. The in vitro studies also suggest that a more cellular approach could lead to greater understanding of the mechanisms of endothelial cell dysfunction in hypercholesterolemia. Preliminary studies in cultured pig aortic endothelium indicate LDL may modulate production of endothelium-derived vasoactive products caused by vasoactive agonists. Proposed studies in cultured endothelial cells will determine the effect of LDL, lipid peroxides, and lipid soluble antioxidants on endothelial cell intracellular free calcium, as well as on the production of endothelium-derived nitric oxide (EDRF-NO) and vasoconstrictor prostanoids. The role of the LDL receptors in modulating the vasoactive actions of LDL and in mediating the endothelial cell production of vasoactive prostanoids will be determined by ligand binding, radiochemical, and immunological techniques, and by the use of recombinant lipoproteins.
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