2000 Fiscal Year Annual Research Report

粥状動脈硬化に関する分子細胞生物学的研究

Research Project

Project/Area Number	11694266
Research Institution	KYOTO UNIVERSITY
Principal Investigator	北徹京都大学, 医学研究科, 教授 (60161460)
Co-Investigator(Kenkyū-buntansha)	久米典昭京都大学, 医学研究科, 講師 (20252455) 若月芳雄京都大学, 医学研究科, 講師 (40220826) 横出正之京都大学, 医学研究科, 講師 (20252447) 堀内久徳京都大学, 医学研究科, 助手 (90291426) 荒井秀典京都大学, 医学研究科, 助手 (60232021)
Keywords	JAM / LOX-1 / Egr-1 / MCP-1 / 動脈硬化 / 内皮細胞 / Lysophosphatidylcholine / 酸化LDL
Research Abstract	本研究費を得て、海外とも有効に共同研究を進め、本年度は以下の成果を得た。動脈硬化初期病変形成の分子メカニズム解明に向け研究を進め、本年度は以下の結果を得た。(1)すでに、動脈硬化巣形成には低比重リポ蛋白質(LDL)の酸化が重要であることが我々を含む世界の研究室で明らかにされてきたが、我々の見出した酸化LDL受容体LOX-1に可溶型が存在することを明らかにした。また、lOX-1は糖化機構を明らかにし、糖化が機能発現に重要であることを示した。(2)酸化LDLで増加するリン脂質Lysophosphatidylcholine(LPC)が転写因子Egr-1を発現誘導し、Egr-1を介して動脈硬化に関わる遺伝子発現を制御することを見出した。(3)新規酸化LDL受容体SR-PSOXを見出し、動脈硬化への関与を示すとともに、桿菌の接着にも重要であることを明らかにした。(4)動脈硬化の形成には、マクロファージの遊走が重要であるが、遊走因子MCP-1がマクロファージを活性化する際、細胞接着と遊走には、異なる細胞内情報伝達経路で情報が伝わることを明らかにした。(5)動脈硬化の最終段階は、血小板活性化に引き続く血栓形成にあるが、我々が見出した内皮細胞に発現している細胞接着因子JAMが血小板にも発現しており、血小板活性化に伴い強くリン酸化されることを見出した。さらに、セミインタクト血小板のシステムを確立し、血小板凝集には低分子量GTP結合蛋白質Rhoが、また、α顆粒放出にはRab4が重要な働きをしていることを見出した。これらのデータは、2000年に行われた国際動脈硬化学会、欧州生命科学学会、国際細胞生物学、米国循環器学会等にて発表することができ、国際的にも評価を得た。

Research Products

(14 results)

All Other

All Publications (14 results)

[Publications] Kataoka,H.,Yokode,M., et al.: "Novel Snail-related zinc finger transcription factor Smuc regulates the activities of basic helix-loop-helix transcription factors"Nucleic Acids Research. 28. 626-633 (2000)
[Publications] Kataoka,H.,Kume,N.,Miyamoto,S et al.: "Biosynthesis and posttranslational processing of lectin-like oxidized LDLreceptor-1 (LOX-1). N-linked glycosylation affects the cell-surface expression and the ligand binding"Journal of Biological Chemistry. 275. 6573-6579 (2000)
[Publications] Murase,T.,Kume,N.,Kataoka,H., et al.: "Identification of soluble forms of lectin-like oxidized low density lipoprotein receptor-1 "Arteriosclerosis Thrombosis and Vascular Biology. 20. 715-720 (2000)
[Publications] Takeoka,H.,Iehara,N., et al.: "A multifunctional transcription factor(Alp145) regulates the smooth muscle phenotype in mesangial cells"Biochemical and Biophysical Research Communications. 18;252(2). 290-295 (2000)
[Publications] Murayama T,Yokode M, et al.: "Overexpression of low density lipoprotein receptor eliminates apolipoprotein B100-containing lipoproteins from circulation and markedly prevents early atherogenesisi in apolipoprotein E-deficient mice"Atherosclerosis. 153. 295-302 (2000)
[Publications] Shirai,Y.,Wakatstuki,Y., et al.: "Induction and Maintenance of Immune Effector Cells in the Gastric Tissue of Mice Orally Immunized to Helicobacter pylori Requires Salivary Glands"Gastroenterol. 118. 749-759 (2000)
[Publications] Minami,M.,Kume,N., et al.: "Transforming Growth Factor-β 1 Increases the Expression of Lectin-like Oxidized Low-Density Lipoprotein Receptor-1"Biochemical and Biophysical Research Communications. 272. 357-361 (2000)
[Publications] Shirakawa,R.,Yoshioka,A., et al.: "Small GTPase Rab4 Regulates Ca2+-induced α-Granule Secretion in Platelets."Journal of Biological Chemistry. 275. 33844-33849 (2000)
[Publications] Ozaki,H.,Ishii,K.,Arai, et al.: "Junctional Adhesion Molecule (JAM) Is Phosphorylated by Protein Kinase C upon Platelet Activation"Biochemical and Biophysical Research Communications. 276. 873-878 (2000)
[Publications] Shimaoka,T.,Kume,N.,Minami, et al.: "Molecular cloning of a novelscavenger receptor for oxidized low density lipoprotein, SR-PSPX, on macrophages"Journal of Biological Chemistry. 275. 40663-40666 (2000)
[Publications] Nishioka,H.,Horiuchi,H.,Tabuchi, et al.: "Small GTPase Rho regulates thrombin-induced platelet aggregation"Biochemical and Biophysical Research Communications. 280. 970-975 (2001)
[Publications] Kataoka,H.,Kume,N.,Miyamoto,S. et al.: "Oxidized low density lipoprtoein (Ox-LDL) modulates Bax/Bcl-2 throughl ectin-like Ox-LDL receptor-1 in vascular smooth muscle cells"Arteriosclerosis Thrombosis and Vascular Biology. (In press). (2001)
[Publications] Shimaoka,T.,Kume,N.,Minami,M., et al.: "LOX-1 supports adhesion of Gram-positive and Gram-negative bacteria"The Journal of Immunology. (In press). (2001)
[Publications] Ashida,N.,Arai,H. et al: "Distinct signaling pathways for MCP-1-dependent integrin activation and chemotaxis"Journal of biological chemistry. (In press). (2001)

2000 Fiscal Year Annual Research Report

粥状動脈硬化に関する分子細胞生物学的研究

Principal Investigator

北 徹 京都大学, 医学研究科, 教授 (60161460)

Research Products

[Publications] Kataoka,H.,Yokode,M., et al.: "Novel Snail-related zinc finger transcription factor Smuc regulates the activities of basic helix-loop-helix transcription factors"Nucleic Acids Research. 28. 626-633 (2000)

[Publications] Kataoka,H.,Kume,N.,Miyamoto,S et al.: "Biosynthesis and posttranslational processing of lectin-like oxidized LDLreceptor-1 (LOX-1). N-linked glycosylation affects the cell-surface expression and the ligand binding"Journal of Biological Chemistry. 275. 6573-6579 (2000)

[Publications] Murase,T.,Kume,N.,Kataoka,H., et al.: "Identification of soluble forms of lectin-like oxidized low density lipoprotein receptor-1 "Arteriosclerosis Thrombosis and Vascular Biology. 20. 715-720 (2000)

[Publications] Takeoka,H.,Iehara,N., et al.: "A multifunctional transcription factor(Alp145) regulates the smooth muscle phenotype in mesangial cells"Biochemical and Biophysical Research Communications. 18;252(2). 290-295 (2000)

[Publications] Murayama T,Yokode M, et al.: "Overexpression of low density lipoprotein receptor eliminates apolipoprotein B100-containing lipoproteins from circulation and markedly prevents early atherogenesisi in apolipoprotein E-deficient mice"Atherosclerosis. 153. 295-302 (2000)

[Publications] Shirai,Y.,Wakatstuki,Y., et al.: "Induction and Maintenance of Immune Effector Cells in the Gastric Tissue of Mice Orally Immunized to Helicobacter pylori Requires Salivary Glands"Gastroenterol. 118. 749-759 (2000)

[Publications] Minami,M.,Kume,N., et al.: "Transforming Growth Factor-β 1 Increases the Expression of Lectin-like Oxidized Low-Density Lipoprotein Receptor-1"Biochemical and Biophysical Research Communications. 272. 357-361 (2000)

[Publications] Shirakawa,R.,Yoshioka,A., et al.: "Small GTPase Rab4 Regulates Ca2+-induced α-Granule Secretion in Platelets."Journal of Biological Chemistry. 275. 33844-33849 (2000)

[Publications] Ozaki,H.,Ishii,K.,Arai, et al.: "Junctional Adhesion Molecule (JAM) Is Phosphorylated by Protein Kinase C upon Platelet Activation"Biochemical and Biophysical Research Communications. 276. 873-878 (2000)

[Publications] Shimaoka,T.,Kume,N.,Minami, et al.: "Molecular cloning of a novelscavenger receptor for oxidized low density lipoprotein, SR-PSPX, on macrophages"Journal of Biological Chemistry. 275. 40663-40666 (2000)

[Publications] Nishioka,H.,Horiuchi,H.,Tabuchi, et al.: "Small GTPase Rho regulates thrombin-induced platelet aggregation"Biochemical and Biophysical Research Communications. 280. 970-975 (2001)

[Publications] Kataoka,H.,Kume,N.,Miyamoto,S. et al.: "Oxidized low density lipoprtoein (Ox-LDL) modulates Bax/Bcl-2 throughl ectin-like Ox-LDL receptor-1 in vascular smooth muscle cells"Arteriosclerosis Thrombosis and Vascular Biology. (In press). (2001)

[Publications] Shimaoka,T.,Kume,N.,Minami,M., et al.: "LOX-1 supports adhesion of Gram-positive and Gram-negative bacteria"The Journal of Immunology. (In press). (2001)

[Publications] Ashida,N.,Arai,H. et al: "Distinct signaling pathways for MCP-1-dependent integrin activation and chemotaxis"Journal of biological chemistry. (In press). (2001)

北徹京都大学, 医学研究科, 教授 (60161460)