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(Circulation Research. 1997;80:810-818.)
© 1997 American Heart Association, Inc.

Articles

Induction of P-Selectin by Oxidized Lipoproteins

Separate Effects on Synthesis and Surface Expression

Devendra K. Vora, Zhuang-Ting Fang, Stephanie M. Liva, Timothy R. Tyner, Farhad Parhami, Andrew D. Watson, Thomas A. Drake, Mary C. Territo, , Judith A. Berliner

From the Departments of Pathology (Z.-T.F., T.R.T., F.P., A.D.W., T.A.D., J.A.B.) and Medicine (D.K.V., S.M.L., M.C.T.), University of California, Los Angeles.

Correspondence to Devendra Vora, MD, Sam Nassi Fellow in Cardiology, Department of Medicine/Cardiology, 10833 Le Conte Ave, 47-123 CHS, University of California, Los Angeles, CA 90024.

Abstract Leukocyte binding to the endothelium is one of the earliest events in the occurrence of atherosclerosis. Leukocyte adhesion molecules involved in this process have not been definitely identified. We have found that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) for 24 hours caused a 2- to 3-fold increase of P-selectin protein, with little change in P-selectin surface expression. A 15-minute histamine treatment of cells exposed to MM-LDL caused a 50% to 100% increase in P-selectin surface expression compared with cells not treated with the lipoprotein. This increase resulted in a 2-fold increase in binding of leukocytes to the endothelium. Immunostaining of permeabilized HAECs after MM-LDL treatment also revealed a highly reproducible increase in intracellular P-selectin associated with rod-shaped structures, typical of Weibel-Palade bodies. Oxidized phospholipids were shown to be mainly responsible for the action of MM-LDL. This increased P-selectin expression was associated with MM-LDL–induced cAMP elevation. Like histamine, highly oxidized low-density lipoprotein, especially the oxidized fatty acids, caused immediate redistribution of P-selectin to the cell surface followed by reinternalization. Immunohistochemical staining showed that endothelial cells on human fatty streak lesions expressed increased levels of P-selectin compared with nonlesion areas. These studies suggest that P-selectin may play an important role in early recruitment of mononuclear cells to the subendothelium in human atherosclerosis and that oxidized lipoproteins may contribute to the increased expression of this molecule by increasing intracellular stores and causing redistribution to the cell surface.

Key Words: atherosclerosis • oxidized low-density lipoprotein • minimally modified low-density lipoprotein • P-selectin • endothelial cell