title: Newly developed reconstituted high-density lipoprotein containing sphingosine-1-phosphate induces endothelial tube formation.
abstract: Reconstituted high-density lipoprotein (rHDL) has been shown to produce a rapid regression of atherosclerosis in animal models and humans. Sphingosine-1-phosphate (S1P), 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)/S1P/apolipoproteinA-I(A-I)]rHDL containing S1P in tube formation in endothelial cells (ECs) as well as cholesterol efflux in macrophage. The effect of (POPC/S1P/A-I)rHDL on cholesterol efflux in macrophage was similar to that of conventional rHDL, (POPC/A-I)rHDL. In addition, (POPC/S1P/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, (POPC/S1P/A-I)rHDL-induced p-ERK1/2 activation and EC tube formation can be mainly attributed to S1P-stimulated signaling through S1P2 and S1P3 as determined by an anti-sense strategy. In conclusion, (POPC/S1P/A-I)rHDL induces cholesterol efflux independently of S1P but has additional S1P-mediated effects on EC tube formation mediated by Akt/ERK/NO through S1P2 and S1P3. In the future, these new discs may be useful for the treatment of atherosclerotic and ischemic cardiovascular disease, such as acute coronary syndrome and atherosclerosis obliterans.
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-Ku, Fukuoka 810-0180, Japan.
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Akira
authors.initials: A
authors.lastname: Kawamura
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Uehara
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000493:pharmacokinetics; D003331:Coronary Vessels / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008075:Lipoproteins, HDL / Q000235:genetics / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D016376:Oligonucleotides, Antisense; D010713:Phosphatidylcholines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D016376:Oligonucleotides, Antisense; D010713:Phosphatidylcholines; C060506:sphingosine 1-phosphate; D002784:Cholesterol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins; D013110:Sphingosine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; D019331:NG-Nitroarginine Methyl Ester