Lipoproteins and Prostaglandin Synthesis

Cannon, Paul

Abstract

This research project is designed to explore the molecular basis of the interaction between plasma high density lipoproteins (HDL) and cells of the vessel wall (endothelial, smooth muscle) which leads to increased biosynthesis of prostacyclin (PGI2). Using endothelial and vascular smooth muscle cells grown in tissue culture, the mechanism of HDL binding and uptake by the cells will be investigated and related to prostaglandin synthesis. The respective roles of specific HDL apoproteins (apo A-I, apo A-II, apo-E, apo A-IV), and of the lipid moieties in stimulating cellular PGI2 synthesis will be explored using a variety of approaches (HDL-recombinants, native HDL with lipid content altered by lipid exchange proteins, labeled arachidonate in HDL phospholipids and cholesteryl esters, cells prelabeled with 3H-arachidonate). These will test our hypothesis that as a consequence of HDL interaction with the cells arachidonate esterified in HDL phospholipids and cholesteryl esters is hydrolyzed and made available as substrate for prostacyclin synthesis. The potential relevance of the HDL-cell-PGI2 interaction to the antithrombotic and antiatherogenic effects of HDL will also be explored in studies using cultured vascular smooth muscle cells and intima-media preparations from normal and hypercholesterolemic rabbits. We will also test the hypothesis that HDL-induced stimulation of PGI2 synthesis by vascular smooth muscle cells increases cholesteryl hydrolase activity in cholesteryl ester loaded smooth muscle cells and enhances the hydrolysis of cytoplasmic cholesteryl esters and efflux of cholesterol from the cells. The overall objective is tostudy the effects of plasma lipoproteins on cellular prostaglandin synthesis and potential relationships of these processes to atherosclerosis and thrombosis.