INDUCTION OF P-SELECTIN BY OXIDIZED LIPOPROTEINS - SEPARATE EFFECTS ON SYNTHESIS AND SURFACE EXPRESSION

Leukocyte binding to the endothelium is one of the earliest events in the occurrence of atherosclerosis. Leukocyte adhesion molecules involv ed in this process have not been definitely identified. We have found that treatment of human aortic endothelial cells (HAECs) with minimall y modified low-density lipoprotein (MM-LDL) for 24 hours caused a 2- t o 3-fold increase of P-selectin protein, with little change in P-selec tin surface expression. A 15-minute histamine treatment of cells expos ed to MM-LDL caused a 50% to 100% increase in P-selectin surface expre ssion compared with cells not treated with the lipoprotein. This incre ase resulted in a 2-fold increase in binding of leukocytes to the endo thelium. Immunostaining of permeabilized HAECs after MM-LDL treatment also revealed a highly reproducible increase in intracellular P-select in associated with rod-shaped structures, typical of Weibel-Palade bod ies. Oxidized phospholipids were shown to be mainly responsible for th e action of MM-LDL. This increased P-selectin expression was associate d with MM-LDL-induced cAMP elevation. Like histamine, highly oxidized low-density lipoprotein, especially the oxidized fatty acids, caused i mmediate redistribution of P-selectin to the cell surface followed by reinternalization. Immunohistochemical staining showed that endothelia l cells on human fatty streak lesions expressed increased levels of P- selectin compared with nonlesion areas. These studies suggest that P-s electin may play an important role in early recruitment of mononuclear cells to the subendothelium in human atherosclerosis and that oxidize d lipoproteins may contribute to the increased expression of this mole cule by increasing intracellular stores and causing redistribution to the cell surface.