Newly developed reconstituted high-density lipoprotein containing sphingosine-1-phosphate induces endothelial tube formation

Reconstituted high-density lipoprotein (rHDL) has been shown to produce a rapid regression of atherosclerosis in animal models and humans. Sphingosine-l-phosphate (S l P), which is a bioactive lipid in HDL, plays a role in mitogenesis, endothelial cell motility, and cell survival, as well as organization and differentiation into a vessel. In this study, we examined the direct role of a newly developed rHDL, [POPC(1-palmitoyl-2-oleoyl phosphatidylcholine)/S l P/apolipoproteinA-I(A-l)]rHDL containing S I P in tube formation in endothelial cells (ECs) as well as cholesterol efflux in macrophage. The effect of (POPC/S l P/A-I)rHDL on cholesterol efflux in macrophage was similar to that of conventional rHDL, (POPC/A-I)rHDL. In addition, (POPC/S I P/A-I)rHDL induced EC proliferation through the activation of phospho-Akt and phospho-extracellular-signal-regulated kinases (p-ERK) 1/2 and EC tube formation, and this effect was blocked by inhibitors of Akt, ERK and endothelial nitric-oxide synthase (eNOS). In addition, (P0PC/S1P/A-I)rHDL-induced p-ERK1/2 activation and EC tube formation can be mainly attributed to SlP-stimutated signaling through SIP2 and SIP3 as determined by an anti-sense strategy. In conclusion, (POPC/S]P/A-I)rHDL induces cholesterol efflux independently of SIP but has additional SIP-mediated effects on EC tube formation mediated by Akt/ERK/NO through SIP2 and SIP3. In the future, these new discs may be useful for the treatment of atherosclerotic and ischernic cardiovascular disease, such as acute coronary syndrome and atherosclerosis obliterans. (C) 2006 Elsevier Ireland Ltd. All rights reserved.