1989 Fiscal Year Annual Research Report

粥状動脈硬化症の成因に関する基礎的研究

Research Project

Project/Area Number	01304063
Research Institution	Kyoto University
Principal Investigator	北徹京都大学, 医学部, 教授 (60161460)
Co-Investigator(Kenkyū-buntansha)	山本徳男東北大学, 遺伝子実験施設, 助教授山田信博東京大学, 医学部, 助手 (40200729) 斎藤康千葉大学, 医学部, 講師 (50101358) 堀内正公熊本大学, 医学部, 講師成宮周京都大学, 医学部, 助教授 (70144350)
Keywords	血管内皮細胞 / 泡沫細胞 / 平滑筋細胞 / 酸化LDL / リポタンパクリパ-ゼ / 動脈硬化
Research Abstract	我々は今回のプロジェクト研究を通じて、血中に増加したLDLが如何なる機構で血管内皮細胞障害、マクロファ-ジの泡沫化および集簇、さらには、SMCの増書殖を惹起するかにつき、種々の分野の専門家と共同研究を行いつつある。先に代表者である北は、遺伝的に高LDL血症、早発粥場動脈硬化症を惹起する家兎WHHLウサギを用いて、LDLの上昇と粥場動脈硬化症の関係について検討してきたが、生体内に存在する酸化LDLが、その発症に密接に関与していることをつきとめた。今回の研究で、酸化LDLがマクロファ-ジに認識し取り込まれ、泡沫細胞形成が行われる際に、酸化LDLに特異的な受容体がマクロファ-ジに存在し、この受容体を介して泡沫化が行なわれることを明らかにした(北、堀内)。さらに、成宮と共同で泡沫化する以前と泡沫化を起こした後でのマクロファ-ジのPGE_2、LTC_4の産出を検討したところ、マクロファ-ジが泡沫化をし始めるまでは、大量のPGE_2、LTC_4が産生されてくるが、一旦泡沫化が完成してくるとPGE_2、LTC_4の産生はもはや抑制されることを見出した。この減少の意味づけを現在行っている。マクロファ-ジでは、PG以外にもリポタンパクリパ-ゼを大量に泡沫化に伴い合成してくるが、この合成機序につきどのレベルで行われているか検討したところ、mRMAのレベル、すなわち転写レベル調節されていることが明らかになってきた(山田)。現在、LDL中のどの因子が調節に関与しているか検討中である。また、一旦マクロファ-ジが泡沫化すると、もはや培養皿から動きが止まることを見い出した。これに関与する因子について検討中である。また平滑筋細胞の増殖に関しても、その因子の精製段階に入っており、その単離を進めている(斎藤)。本研究中に、山本等により、動脈硬化に関与する可能性の高い脂肪酸活性化酸素の精製に成部し、その全構造が決定された。この様に、本年度の研究は順調に進んでおり、次年度以降の成果が待たれる。

Research Products
(19 results)

All Other

All Publications (19 results)

[Publications] Kita,T.,Ishii,K.,Yokode,M.,kume,N.,Nagano,Y.,Arai,H.& Kawai,C.: "The role of oxidized lwo density lipoprotein in the pathogenesis of atherosclerosis." Eur.Heart J.
[Publications] Kita,T.,Yokode,M.,Ishii,K.,Arai,H.&Nagano,Y.: "The role of atherogenic low density lipoproteins (LDL)in the pathogenesis of atherosclerosis." Ann.N.Y.Acad.Sci.
[Publications] Nakajima,M.,Yamamoto,M.,Ushijubi,F.,Okuma,M.,Fujiwara,M.&Narumiya,S.: "Expression of thromboxane A2 receptor in cultured human erythroleukemia cells and its induction by 12-0-thtradecanoylphorbol-13-acetate." Biochem.Biophys.Res.Commun.158. 958-965 (1989)
[Publications] Ushikubi,F.,Nakajima,M.,Okuma,M.,Fujiwara,M.& Narumiy,S.: "Purification of the thromboxane A_2Prostaglandin H_2receptor from human blood platelets." J.biol.Chem.264. 16496-16501 (1989)
[Publications] Takahashi,K.,Fukuda,S.,S.,Naito,M.,Horiuchi,S.,Takata,K.& Morino,Y.: "Endocytic pathway of high density lipoprotein via trans-golgi system in rat resident peritoneal macrophages." Lab.Lnvest.61. 270-277 (1989)
[Publications] Takata,K.,Horiuchi,S.& Morino,Y.: "scavenger receptor-mediated recognition of maleyl-albumin and its relation to subsequent endocytic degradation." Biochim.Biophys.Acta. 984. 273-280 (1989)
[Publications] Kita,I.,Ishii,K.,Yokode,M.,kume,N.,Nagano,Y.,Arai,H.&Kawi,C.: "the role of oxidized low density lipoprotein in the pathogenesis of atherosclerosis." Eur.Heart J.
[Publications] Kita,T.,Yokode,M.,Ishii,K.,Arai,H.& Nagano,Y.: "The role of atherogenic low density lipoproteins(LDL)in the pathogenesis of atherosclerosis." Ann.N.Y.Acad.Sci.
[Publications] Nakajima,M.,Yamamoto,M.,Ushikubi,F.,Okuma,M.,Fujiwara,M.& Narumiya,S.: "Expression of thromboxane A_2 receptor in cultured human erythroleukemia cells and its induction by 12-0-tetradecanoylphorbol-13-acetate." Buicgem.Biophys.Res.Commun.158. 958-965 (1989)
[Publications] Ushikubi,F.,Nakajima,M.,Okuma,M.,Fujiwara,M.& Narumiya,S.: "Purification of the thromboxane A_2/prostaglandin H_2 receptor from human blood platelets." J.Biol.Chem.264. 16496-16501 (1989)
[Publications] Takahashi,K.,Fukuda,S.,Naito,M.,Horiuchi,S.,Takata,K.& Morino,Y.: "Endocytic pathway of high density lipoprotein via trans-golgi system in at resident peritoneal macrophages." Lab.Invest.61. 270-277 (1989)
[Publications] Kume,N.,Kita,I.,Mikami,A.,Yokode,M.,Ishii,K.,Nagano,Y.& Kawai,C.: "Induction of mRNA for low-density lipoprotein receptors in heterozygous watanabe heritable hyperlipindemic rabbits treated with CS-514 and cholestyramine." Ciruculation. 79. 1084-1090 (1989)
[Publications] Haga,Y.,Takata,K,Araki,N.,Morino,Y.,Sakamoto,K.,Akagi,M.& Horiuchi,S.: "Intracellular accumulation of cholesteryl esters suppresses production of lipopolisaccharide-induced interleukin I by rat peritoneal macrophages." biochem.Biophys.Res.commun.160. 874-880 (1989)
[Publications] Ishikawa,Y.,Nishide,T.,Sasaki,N.,Shirai,K.,Saito,Y.& Yoshida,S.: "Effects of chloroquine on the metabolism of phosphatidylcholine associated with low density lipoprotein in arterial sommth muscle cells." Atherosclerosis. 80. 1-7 (1989)
[Publications] Morisaki,N.,Koyama,N.,Mori,S.,Kanazaki,T.,KOshikawa,T.,Saito,Y.& Yoshida,S.: "Effects of smooth muscle cell derived growth factor(SDGF)in combination with other growth factors on smooth muscle cells." Atherosclerosis. 78. 61-67 (1989)
[Publications] Yamada,N.,Shiimano,H.,Mokuno,H.,Ishibashi,S.,Gotohda,T.,Kawakami,M.,Watanabe,Y.,Akanuma,Y.,Murase,T.,Takaku,F.: "Increased clearance of plasma cholesterol after injection of apolipoprotein E in WHHL rabbits." Proc.Natl.Acad.Sci.USA.86. 665-669 (1989)
[Publications] Ishibashi,S.,Mori,N.,Murase,T.,shimano,H.,Gotohda,T.,Kawakami,M.,Akanuma,Y.,Takaku,F.& Ymada,N.: "Enhanced lipoprotein lipase secretion from human monocyte-derived macrophages caused by hypeririglyceridemic very low density lipoproteins." Arteriosclerosis. 9. 650-655 (1989)
[Publications] Gotoda,T.,Senda,M.,Murase,M.,Ymada,N.,Takaku,F.& Furuichi,Y.: "Detection of familial LPL deficiency by pvu 11RFLP." Nucleic Acids Res.17. 3607 (1989)
[Publications] Suzuki,H.,Kawarabayashi,Y.,Kondo,J.,Abe,T.,Nishikawa,K.,Kimura,S.,Hashimoto,T.& Yamamoto,T: "Structure and regulation of rat long-chain acyl-CoA synthetase." J.Biol.chem.

1989 Fiscal Year Annual Research Report

粥状動脈硬化症の成因に関する基礎的研究

Principal Investigator

北 徹 京都大学, 医学部, 教授 (60161460)

Research Products

[Publications] Kita,T.,Ishii,K.,Yokode,M.,kume,N.,Nagano,Y.,Arai,H.& Kawai,C.: "The role of oxidized lwo density lipoprotein in the pathogenesis of atherosclerosis." Eur.Heart J.

[Publications] Kita,T.,Yokode,M.,Ishii,K.,Arai,H.&Nagano,Y.: "The role of atherogenic low density lipoproteins (LDL)in the pathogenesis of atherosclerosis." Ann.N.Y.Acad.Sci.

[Publications] Nakajima,M.,Yamamoto,M.,Ushijubi,F.,Okuma,M.,Fujiwara,M.&Narumiya,S.: "Expression of thromboxane A2 receptor in cultured human erythroleukemia cells and its induction by 12-0-thtradecanoylphorbol-13-acetate." Biochem.Biophys.Res.Commun.158. 958-965 (1989)

[Publications] Ushikubi,F.,Nakajima,M.,Okuma,M.,Fujiwara,M.& Narumiy,S.: "Purification of the thromboxane A_2Prostaglandin H_2receptor from human blood platelets." J.biol.Chem.264. 16496-16501 (1989)

[Publications] Takahashi,K.,Fukuda,S.,S.,Naito,M.,Horiuchi,S.,Takata,K.& Morino,Y.: "Endocytic pathway of high density lipoprotein via trans-golgi system in rat resident peritoneal macrophages." Lab.Lnvest.61. 270-277 (1989)

[Publications] Takata,K.,Horiuchi,S.& Morino,Y.: "scavenger receptor-mediated recognition of maleyl-albumin and its relation to subsequent endocytic degradation." Biochim.Biophys.Acta. 984. 273-280 (1989)

[Publications] Kita,I.,Ishii,K.,Yokode,M.,kume,N.,Nagano,Y.,Arai,H.&Kawi,C.: "the role of oxidized low density lipoprotein in the pathogenesis of atherosclerosis." Eur.Heart J.

[Publications] Kita,T.,Yokode,M.,Ishii,K.,Arai,H.& Nagano,Y.: "The role of atherogenic low density lipoproteins(LDL)in the pathogenesis of atherosclerosis." Ann.N.Y.Acad.Sci.

[Publications] Nakajima,M.,Yamamoto,M.,Ushikubi,F.,Okuma,M.,Fujiwara,M.& Narumiya,S.: "Expression of thromboxane A_2 receptor in cultured human erythroleukemia cells and its induction by 12-0-tetradecanoylphorbol-13-acetate." Buicgem.Biophys.Res.Commun.158. 958-965 (1989)

[Publications] Ushikubi,F.,Nakajima,M.,Okuma,M.,Fujiwara,M.& Narumiya,S.: "Purification of the thromboxane A_2/prostaglandin H_2 receptor from human blood platelets." J.Biol.Chem.264. 16496-16501 (1989)

[Publications] Takahashi,K.,Fukuda,S.,Naito,M.,Horiuchi,S.,Takata,K.& Morino,Y.: "Endocytic pathway of high density lipoprotein via trans-golgi system in at resident peritoneal macrophages." Lab.Invest.61. 270-277 (1989)

[Publications] Kume,N.,Kita,I.,Mikami,A.,Yokode,M.,Ishii,K.,Nagano,Y.& Kawai,C.: "Induction of mRNA for low-density lipoprotein receptors in heterozygous watanabe heritable hyperlipindemic rabbits treated with CS-514 and cholestyramine." Ciruculation. 79. 1084-1090 (1989)

[Publications] Haga,Y.,Takata,K,Araki,N.,Morino,Y.,Sakamoto,K.,Akagi,M.& Horiuchi,S.: "Intracellular accumulation of cholesteryl esters suppresses production of lipopolisaccharide-induced interleukin I by rat peritoneal macrophages." biochem.Biophys.Res.commun.160. 874-880 (1989)

[Publications] Ishikawa,Y.,Nishide,T.,Sasaki,N.,Shirai,K.,Saito,Y.& Yoshida,S.: "Effects of chloroquine on the metabolism of phosphatidylcholine associated with low density lipoprotein in arterial sommth muscle cells." Atherosclerosis. 80. 1-7 (1989)

[Publications] Morisaki,N.,Koyama,N.,Mori,S.,Kanazaki,T.,KOshikawa,T.,Saito,Y.& Yoshida,S.: "Effects of smooth muscle cell derived growth factor(SDGF)in combination with other growth factors on smooth muscle cells." Atherosclerosis. 78. 61-67 (1989)

[Publications] Yamada,N.,Shiimano,H.,Mokuno,H.,Ishibashi,S.,Gotohda,T.,Kawakami,M.,Watanabe,Y.,Akanuma,Y.,Murase,T.,Takaku,F.: "Increased clearance of plasma cholesterol after injection of apolipoprotein E in WHHL rabbits." Proc.Natl.Acad.Sci.USA.86. 665-669 (1989)

[Publications] Ishibashi,S.,Mori,N.,Murase,T.,shimano,H.,Gotohda,T.,Kawakami,M.,Akanuma,Y.,Takaku,F.& Ymada,N.: "Enhanced lipoprotein lipase secretion from human monocyte-derived macrophages caused by hypeririglyceridemic very low density lipoproteins." Arteriosclerosis. 9. 650-655 (1989)

[Publications] Gotoda,T.,Senda,M.,Murase,M.,Ymada,N.,Takaku,F.& Furuichi,Y.: "Detection of familial LPL deficiency by pvu 11RFLP." Nucleic Acids Res.17. 3607 (1989)

[Publications] Suzuki,H.,Kawarabayashi,Y.,Kondo,J.,Abe,T.,Nishikawa,K.,Kimura,S.,Hashimoto,T.& Yamamoto,T: "Structure and regulation of rat long-chain acyl-CoA synthetase." J.Biol.chem.

北徹京都大学, 医学部, 教授 (60161460)