High-Density Lipoprotein Stimulates Endothelial Cell Migration and Survival Through Sphingosine 1-Phosphate and Its Receptors

Abstract

Objective-Plasma high-density lipoprotein (HDL) level is inversely correlated with the risk of atherosclerosis. However, the cellular mechanism by which HDL exerts antiatherogenic actions is not well understood. In this study, we focus on the lipid components of HDL as mediators of the lipoprotein-induced antiatherogenic actions. Methods and Results-HDL and sphingosine 1-phosphate (S1P) stimulated the migration and survival of human umbilical vein endothelial cells. These responses to HDL and S1P were almost completely inhibited by pertussis toxin and other specific inhibitors for intracellular signaling pathways, although the inhibition profiles of migration and survival were different. The HDL-stimulated migration and survival of the cells were markedly inhibited by antisense oligonucleotides against the S1P receptors EDG-1/S1P 1 and EDG-3/S1P 3 . Cell migration was sensitive to both receptors, but cell survival was exclusively sensitive to S1P 1 . The S1P-rich fraction and chromatographically purified S1P from HDL stimulated cell migration, but the rest of the fraction did not, as was the case of the cell survival. Key Words: high-density lipoprotein Ⅲ sphingosine 1-phosphate Ⅲ migration Ⅲ EDG Ⅲ endothelial cell P lasma lipoproteins are responsible for the transport of cholesterol to cells and the control of cholesterol synthesis. 1-3 Low-density lipoprotein (LDL) provides cholesterol to cells through LDL receptors, whereas high-density lipoprotein (HDL) has been shown to remove excess cholesterol from the cells. The so-called reverse transport of cholesterol is thought to be an important mechanism for the antiatherogenic actions of HDL. 1,2 Recent studies have shown that HDL induces cytoprotective actions, 3,4 proliferation, 5 and migration in endothelial cells, 2,6 activities presumably independent of cholesterol metabolism, 2,3 although the mechanism by which HDL induces these antiatherogenic actions has not been well characterized. It has been reported recently that HDL activates endothelial nitric oxide (NO) production through the scavenger receptor-BI (SR-BI). 7 NO production has been shown to be involved in the cytoprotective action of endothelial cells. 8 In endothelial cells, sphingosine 1-phosphate (S1P) has been shown to regulate a wide range of cellular activities associated with angiogenesis, wound healing, apoptosis, and atherosclerosis. 3,4,8 -18 S1P promotes cell migration, 10 -13,16 -18 DNA synthesis, 10 cell survival, 4,9 cell barrier integrity, 15 NO production, 8,14,16,17 and the expression of several cell adhesion molecules. 3 We recently reported that S1P accumulates in the lipoprotein fraction, especially the HDL fraction, and that HDL-associated S1P mediates the cytoprotective actions of HDL in human umbilical vein endothelial cells (HUVECs). 4,19 Nofer et al 20 reported that sphingosylphosphorylcholine (SPC) and lysosulfatide (LSF) were major components of HDL responsible for these cytoprotective actions. Thus, lipoproteinassociated lipids may also be involved in some HDL-induced...

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