The adherence of monocytes to the endothelium is an early event in atherogenesis. We have investigated this process by examining whether native and oxidized low-density and high-density lipoproteins could modulate this process. Only oxidized low-density lipoprotein caused a significant dose-dependent and time-dependent increase in U937 monocyte-like cell line binding to human endothelial cells, by a process which required de nova protein synthesis. Interestingly, E-selectin, intercellular adhesion molecule-1, vascular cell-adhesion molecule or P-selectin induction was not apparent in this system suggesting the presence of an alternative system for the interaction of endothelial cells with monocyte-like cells in response to oxidized low-density lipoprotein. Highdensity lipoprotein completely suppressed oxidized low-density-lipoprotein-induced adhesion of U937 cells to the endothelial monolayer, while oxidized high-density lipoprotein did not. These data suggest that the balance between native and oxidized lipoproteins may play a role in the formation of the atherosclerotic lesion by modulating monocyte endothelial interactions.One of the earliest detectable events in human and experimental atherosclerosis is the adherence of circulating monocytes to the arterial endothelial lining [l]. Monocyte recruitment may involve changes in endothelial adhesiveness for monocytes [2] and the local production of monocyte chemotactic molecules [3]. Several molecules that are inducible on the endothelial surface and can support the adhesion of monocytes have been identified [4 -71. Indeed, these molecules could be involved in the recruitment of monocytes in atherosclerosis, since intercellular adhesion molecule-1 (ICAM-1) and E-selectin are expressed in human atherosclerotic lesions in vivo [8] [3] and increase the levels of monocyte colony-stimulating factor (M-CSF) which may promote macrophage differentiation [ 171. Although heterogeneous oxidized LDL are present in the blood [18], in the artery wall [19] and in atherosclerotic lesions [20], no data are available about the modulation of endothelial behavior by LDL which have been oxidized to various extents.Epidemiological evidence establishes an inverse correlation between the levels of plasma high-density-lipoprotein cholesterol and atherosclerosis [211. However, the biochemical mechanism(s) of action of high-density lipoproteins (HDL) in preventing the development of atherosclerotic lesions are not established. The most widely accepted hypothesis is that HDL facilitate the clearance of cholesterol from the atheromatous plaques and its transport to the liver for excretion [21]. In addition, HDL have been reported to play a protective role in atherogenesis by preventing the generation of oxidatively modified LDL [22, 231. Interestingly, HDL oxidation can occur in vitro 124, 251 and in vivo [26], and oxidized HDL have been shown to possess a broad range of biological activities [27-301. In this study, we investigate the effects of mildly and extensively oxidized LDL on the adh...