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1998 Fiscal Year Final Research Report Summary

Molecular mechanisms of atherogenesis

Research Project

Project/Area Number 08407026
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

KITA Tooru  Kyoto University, Faculty of Medicine, Professor, 医学研究科, 教授 (60161460)

Co-Investigator(Kenkyū-buntansha) YOKODE Masayuki  Kyoto University, Faculty of Medicine, Lecturer, 医学研究科, 講師 (20252447)
DOI Toshio  Kyoto University, Faculty of Medicine, Lecturer, 医学研究科, 講師 (60183498)
MURAKAMI Motonobu  Kyoto University, Faculty of Medicine, Associate Professor, 医学研究科, 助教授 (10157761)
ISHII Kenji  Kyoto University, Faculty of Medicine, Lecturer, 医学研究科, 講師 (00212811)
WAKATUKI Yosio  Kyoto University, Faculty of Medicine, Lecturer, 医学研究科, 講師 (40220826)
Project Period (FY) 1996 – 1998
KeywordsAtherosclerosis / oxidezed LDL / lysophosphatidylcholine / MAP kinases / PI 3 kinase / LOX-1 / TNF-2 / シアストレス
Research Abstract

Endothelial dysfunction, or activation, elicited by oxidized low density lipoprotein (Ox-LDL) or its lipid constituent has been implicated in the pathogenesis of atherosclerosis. Lysophosphatidylcholine (lyso-PC), a phospholipid component of Ox-LDL, has been shown to induce expression of endothelial-leukocyte adhesion molecules, such as VCAM-1 and ICAM-1, and smooth muscle growth factors, including PDGF A and B chains and HB-EGF, which appear to play crucial roles in recruitment of circulating monocytes and T-lymphocytes into atherosclerotic lesions and migration and proliferation of medical smooth muscle cells into atherosclerotic intima.
One of the aims of our studies is to define transcriptional and signal transduction mechanisms involved in lyso-PC-induced gene expression. We have found that elevated levels of intracellular cyclic AMP inhibited lyso-PC-induced expression of PDGF and ICAM-1: Furthermore, lyso-PC-induced expression of PDGF was dependent upon protein tyrosine phosphory … More lation. We, Therefore, explored the protein that can rapidly phosphorylated in the tyrosine residue. We have revealed that a protein with a molecular mass of 130kDa, which was designated p130, was rapidly and transiently tyrosine-phosphorylated by lyso-PC. By use of immunoblotting and immunoprecipitation, we have identified p130 as PECAM-1 which was expressed on the intercellular junction of cultured endothelial cells. Our study also have demonstrated that MAP kinases, such as ERK and JNK, were activated by lyso-PC, which appeared to depend upon protein tyrosine phosphorylation. Taken together, tyrosine phosphorylation of PECAM-1 may be the upstream of MAP kinase activation by lyso-PC.
On the other hand, vascular endothelial cells can take up Ox-LDL via receptor-dmediated endocytosis. Our recent studied have identified, for the first time, a receptor for Ox-LDL expressed in the cell-surface of vascular endothelial cells. By immunoblotting and Northern blotting, we have found that expression of LOX-1 can be upregulated by an inflammatory cytokine TNF-α and laminar flow fluid shear stress. Nuclear run-off assays have revealed that TNF-α and flow fluid shear stress can stimulate transcription of LOX-1 gene. Unregulated expression of LOX-1 by TNF-α was associated a cell line which stably expresses LOX-1 on the cell-surface. By use of this cell line, we have found that LOX-1 can bind, internalize, and degrade Ox-LDL but not significantly acetylated LDL. Binding and degradation of Ox-LDL by LOX-1 was suppressed by reagents, such as polyinosinic acid and carageenan. In contrast, fucoidin and maleylated serum albumin, which had been shown to inhibit Ox-LDL binding and degradation by class A macrophage scavenger receptors, did not significantly inhibit Ox-LDL binding or degradation by LOX-1. Delipidation of Ox-LDL did not affect the ability to bind LOX-1; therefore, protein portion of Ox-LDL particles appeared to be the ligand of LOX-1. These results, thus, indicated that ligand specificity of LOX-1 is different from that of class A or B scavenger receptors. Less

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Hiroshi Ochi,Noriaki Kume,et al: "Tyrosine phosphorylation on of platelet endothelial cell adhesion molecule-1 induced by lysophosphatidylcholine in cultured endothelial cells"Biochem.Biophys,Res.Commun. vol.243. 862-868 (1998)

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      「研究成果報告書概要(和文)」より
  • [Publications] Eiichiro Nishi,Noriaki Kume,et al: "Lysophosphatidylcholine enhances cytokine-induced interferon gamma expression in human T lymphocytes"Circulation Research. vol.83. 508-515 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Noriaki Kume,Takatoshi Murase et al: "Inducible expression of lectin-like oxidized LDL receptor-1 in vascular endothelial cells"Circulation Research. vol.83. 322-327 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takatoshi Murase,Noriaki Kume,et al: "Fluid shear stress transcriptionally induces lectin-like oxidized LDL receptor-1 in vascular endothelial cells"Circulation Research. vol.83. 328-333 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hideaki Moriwaki,Noriaki Kume,et al: "Ligand specificity of LOX-1,a novel endothelial receptor for oxidized low density lipoprotein"Arterioscler.Thromb.Vasc.Biol. vol.18. 1541-1547 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Eiichiro Nishi, Noriaki Kume, Hiroshi Ochi, Hideaki Moriwaki, Shigeki Higashiyama, Naoyuki Taniguchi, Toru Kita: "Lysophysphtidylcholine induces heparin-binding epidermal growth factor-like growth factor and interferon-γ in human T-lymphocytes."Ann.N.Y.Acad.Sci. 811. 519-524 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Atsushi Sasaki, Noriaki Kume, Eiichiro Nishi, Kenjiro Tanoue, Masayuki Miyasaka, Toru Kita: "P-selection and vascular cell adhesion molecule-1 are focally expressed in aortas of hypercholesterolemic rabbits before intimal accumulation of macrophages and Tlymphocytes."Arterioscler. Thromb. Vasc. Biol. 17. 310-316 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tatsuya Sawamura, Noriaki Kume, Takuma Aoyama, Hideaki Moriwaki, Hajime Hoshikawa, Yuichi Aiba, Takeshi Tanaka, Soichi Miwa, Yoshimoto Katsura, Toru Kita, Tomoh Masaki: "An endothelial receptor for oxidized low-density lipoprotein"Nature. 386. 73-77 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Eiichiro Nishi, Noriaki Kume, Hiroshi Ochi, Hideaki Moriwaki, Yoshio Wakutsuki, Shigeki Higashiyma, Shigeki Higashiyama, Naoyuki Taniguchi, Toru Kita: "Lysophosphatidycholine increases expression of heparin-binding epidermal growth factor-like growth factor in human Tlymphocytes."Cire.Res.. 80. 638-644 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hiroshi Ochi, Noriaki Kume, Eiichiro Nishi,m Hideaki Moriwaki, Michitaka Masuda, Keigi Fujiwara, Toru Kita: "Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 induced by lysophosphatidylcholine in cultured endothelial cells."Biochem.Biophys.Res.Commun.. 243. 862-868 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Eiichiro Nishi, Noriaki Kume, Yasushi Ueno, Hiroshi Ochi, Hideaki Moriwaki, Toru Kita: "Lysophosphatidylcholine enhances cytokine-induced interferon gamma expression in human Tlymphocytes."Cire.Res.. 83. 508-515 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Noriaki Kume, Takatoshi Murase, Hideaki Moriwaki, Takuma Aoyama, Tatsuya Sawamura, Tomoh Masaki, Toru Kita: "inducible expression of lectin-like oxidized LDL receptor-1 in vascular endothelial cells."Cire.Res. 83. 322-327 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takatoshi Murase, Noriaki Kume, Risa Korenaga, Joji Ando, Tatsuya Sawamura, Tomoh Masaki, Toru Kita: "Fluid shear stress transcriptionally induces lectin-like oxidized LDLreceptor-1 in vascular endothelial cells."Cire.Res. 83. 328-333 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hideaki Moriwaki, Noriaki Kume, Tatsuya Sawamura, Takuma Aoyama, Hajime Hoshikawa, Hiroshi Ochi, Eiichiro Nishi, Tomoh Masaki, Toru Kita: "Ligand specificity of lOX-1, a novel endothelial receptor for oxidized low density lipoprotein."Arterioscler.Thromb.Vasc.Biol. 18. 1541-1547 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hideaki Moriwaki, Noriaki Kume, Hiroharu Kataoka, Takatoshi Murase, Eiichiro Nishi, Tatsuya Sawamura, Tomoh Masaki, Toru Kita: "Expression of lectin-like oxizied low density lipoprotein receptor-1 in human and murine macrophages-upregulated expression by TNF-a"FEBS Lett.. 440. 29-32 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shizuka Sakata-Kaneko, Yoshio Wakatsuki, Takashi Usui, Yoichi Matsunaga, Toshiyuki Itoh, Eiichiro Nishi, Noriaki Kume, Toru Kita: "Lysophosphatidylcholine upregulates CD40L expression in newly activated human CD4+ Tcells."FEBS Lett. 433. 161-165 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Harunobu Ozaki, Kenji Ishii, Hidenori Akira, Noriaki Kume, Toru Kita: "Lysophosphatidylcholine activates mitogen-activated protein kinases by a tyrosine kinase-dependent pathway in bovine aortic endothelial cells."Atherosclerosis. 143. 261-266 (1999)

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      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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