Antiatherogenic effects of high density lipoprotein and sphingosine 1-phosphate

• Project/Area Number: 18590973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Gunma University
• Principal Investigator: KIMURA Takao Gunma University, Facultyof Medicine, Clinical Laboratory Center, Assistant Professor (90396656)
• Co-Investigator(Kenkyū-buntansha): MURAKAMI Masami Gunma University, Graduate School of Medicine, Department of Clinical Laboratory Medidicine, Professor (30241871)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Atherosclerosis / High Density Lipoprotein / Sphingosine 1-phosphate / Endothelial Cell / Nitric Oxide / Adhesion Molecule / 高密度リボ蛋白質HDL / 生理活性物質 / 高密度リポ蛋白質(HDL) / スフィンゴシン1-リン酸(S1P) / Scanvenger Receptor Class B type I(SR-BI) / G蛋白質

Research Abstract

We clarified the molecular mechanisms by which high density lipoprotein (HDL) inhibits the expression of adhesion molecules, including vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, induced by sphingosine 1-phosphate (S1P) and tumor necrosis factor (TNF) alpha in endothelial cells. HDL inhibited S1P-induced nuclear factor kappaB activation and adhesion molecule expression in human umbilical vein endothelial cells. The inhibitory HDL actions were associated with nitricoxide synthase (NOS) activation and were reversed by inhibitors for phosphatidylinositol 3-kinase and NOS. The HDL-induced inhibitory actions were also attenuated by the down-regulation of scavenger receptor class B type I (SR-BI) and its associated protein PDZK1. When TNFalpha was used as a stimulant, the HDL-induced NOS activation and the inhibitory action on adhesion molecule expression were, in part, attenuated by the down-regulation of the expression of S1P receptors, especially S1P(1), in addition to SR-BI. Reconstituted HDL composed mainly of apolipoprotein A-I and phosphatidylcholine mimicked the SR-BI-sensitive part of HDL-induced actions. Down-regulation of S1P(3) receptors severely suppressed the stimulatory actions of S1P. Although G(I/o) proteins may play roles in either stimulatory or inhibitory S1P actions, as judged from pertussis toxin sensitivity, the coupling of S1P(3) receptors to G(12/13) proteins may be critical to distinguish the stimulatory pathways from the inhibitory ones. In summary, even though S1P alone stimulates adhesion molecule expression, HDL overcomes S1P(3) receptormediated stimulatory actions through SR-BI/PDZK1-mediated signaling pathways involving phosphatidylinositol 3-kinase and NOS. In addition, the S1P component of HDL plays a role in the inhibition of TNFalpha-induced actions through S1P receptors, especially S1P(1).

Research Products

• [Journal Article] Previously postulated "ligand-independent" signaling of GPR4 is mediated through proton-sensing mechanisms. (2007)
  • Author(s): Tobo M, Tomura H, Mogi C, Wang JQ, Liu JP, Komachi M, Damirin A, Kimura T, Murata N, Kurose H, Sato K, Okajima F.
  • Journal Title: Cell Signal. 19 Pages: 1745-1753
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Previously postulated "ligand-independent" signaling of GPR4 is mediated through proton-sensing mechanisms (2007)
  • Author(s): Tobo M, Tomura H, Mogi C, Wang JQ, Liu JP, Komachi M, Damirin A, Kimura T, Murata N, Kurose H, Sato K, Okajima F.
  • Journal Title: Cell Signal 19(8) Pages: 1745-53
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Previously postulated "ligand-independent" signaling of GPR4 is mediated through proton-sensing mechanisms (2007)
  • Author(s): Tobo M, Tomura H, Mogi C,Wang JQ, Liu JP, Komachi M, Damirin A, Kimura T, Murata N, Kurose H, Sato K, Okajima F.
  • Journal Title: Cell Signal 19 Pages: 1745-1753
  • Peer Reviewed
• [Journal Article] Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells (2007)
  • Author(s): Damirin A, Tomiran H, Komachi N, Liu JP, Nogi C, Tobo N, Wang JQ, Kimira T, kuwabara A, Yamazaki Y, Ohta B, Im DS, Sato K, Okajima F.
  • Journal Title: Am J Physiol Heart Circ Physiol 292
  • Peer Reviewed
• [Journal Article] Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high-density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells. (2006)
  • Author(s): Kimura T, Tomura H, Mogi C, Kuwabara A, Damirin A, Ishizuka T, Sekiguchi A, Ishiwara M, Im DS, Sato K, Murakami M, Okajima F.
  • Journal Title: J Biol Chem. 281 Pages: 37457-37467
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells (2006)
  • Author(s): Kimura T, Tomura H, Mogi C, Kuwabara A, Ishiwara M, Shibasawa K, Sato K, Ohwada S, Im DS, Kurose H, Ishizuka T, Murakami M, Okajima F.
  • Journal Title: Cell Signal. 18 Pages: 841-850
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high-density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells (2006)
  • Author(s): Kimura T, Tomura H, Mogi C, Kuwabara A, Damirin A, Ishizuka T, Sekiguchi A, Ishiwara M, Im DS, Sato K, Murakami M, Okajima F.
  • Journal Title: J Biol Chem 281(49) Pages: 37457-37467
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells (2006)
  • Author(s): Kimura T, Tomura H, Mogi C, Kuwabara A, Ishiwara M, Shibasawa K, Sato K, Ohwada S, Im DS, Kurose H, Ishizuka T, Murakami M, Okajima F.
  • Journal Title: Cell Signal 18(6) Pages: 841-850
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of scavenger receptor class B type 1 and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells. (2006)
  • Author(s): Kimura T, Tomura H, Mogi C, Kuwabara A, Damirin A, Ishizuka T, Sekiguchi A, Ishiwara M, Im DS, Sato K, Murakami M, Okajima F
  • Journal Title: J Biol Chem. 281・49 Pages: 37457-37467
• [Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells. (2006)
  • Author(s): Kimura T, Tomura H, Mogi C, Kuwabara A, Ishiwara M, Shibasawa K, Sato K, Ohwada S, Im DS, Kurose H, Ishizuka T, Murakami M, Okajima F
  • Journal Title: Cell Signal. 18・6 Pages: 841-850
• [Presentation] 血管内皮細胞における高密度リポ蛋白質の接着分子発現抑制作用〜HDL受容体SR-BIとS1P受容体の役割 (2007)
  • Author(s): 木村孝穂、村上正巳、岡島史和
  • Organizer: 第39回 日本動脈硬化学会総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2007-07-13
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] High density lipoprotein inhibits adhesion molecule expression via scavenger receptor class B type I and sphingosine 1-phosphate specific receptors, S1P1 and S1P3 in endothelial cells (2007)
  • Author(s): Kimura Takao, Murakami Masami, Okajima Fumikazu
  • Organizer: The 39th General Meeting and Annual Scientific Meeting of Japan Atherosclerosis Society
  • Year and Date: 2007-07-13
  • Description: 「研究成果報告書概要(欧文)」より