1998 Fiscal Year Annual Research Report

内皮依存性の血管収縮と血管細胞増殖調節機構に関する研究

Research Project

Project/Area Number	07101002
Research Institution	National Cardiovascular Center Research Institute
Principal Investigator	眞崎知生国立循環器病センター研究所, 所長 (60009991)
Co-Investigator(Kenkyū-buntansha)	沢村達也国立循環器病センター研究所, バイオサイエンス部, 室長 (30243033)
Keywords	血管内皮 / エンドセリン / 一酸化窒素 / 血管収縮 / 細胞増殖 / 酸化LDL / エンドセリン受容体 / ジストログリカン
Research Abstract	本研究計画では、血管系における一酸化窒素(NO)とエンドセリン(ET)の相互作用に注目し、内皮における合成系、平滑筋の収縮弛緩系での、ETの作用を明らかにすることを目的とした。研究成果:1.内皮の酸化LDL受容体をクローニングした。この受容体は老化あるいはアポトーシスを起こした細胞を貧食する。酸化LDLによってこの受容体の発現が誘発され、ET-1の産生が増強される。動脈硬化の初発病態に重要と考えられている。2.酸化LDLの増加により、親和性の高い陽イオン性アミノ酸トランスポーターが抑制されNOの産生が低下する。このNOの減少は外液のアミノ酸量を増加することによって回復する。神経に特異的な同トランスポーターをクローニングした。3.ETで誘発される収縮の機構に関しては、生理的な低濃度では非選択的陽イオンチャネルが活性化され、外界のカルシウムイオンが流入、これによってET誘発収縮が起こると考えられる。非選択イオンチャネルには少なくとも3種類あり、ET収縮には、SK&F96365に感受性のあるチャネルが重要である。NOによって同じチャネルの抑制が起こることが示された。trpチャネルについてはクローニングしたが、これが収縮に関与する可能性は少ない。4.それぞれのET受容体の細胞内ドメインの特別の部分がそれぞれのG蛋白質の結合に関与する。特に受容体のC末端側のシステインのパルミチン化はGαi,Gαqの結合に重要である。ETによる細胞増殖作用はPKCを介する系、PI3Kまた、チロシンキナーゼを介する系が活性化され、いずれもMAPKの活性化を介する。ET_BはGαiを介してP53発現を伴うアポトーシスを起こす。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] H.Hasegawa et al.: "Purification of a novel endothelin-converling enzyme specific for big endothelin-3" FEBS Letters. 428. 304-308 (1998)
[Publications] K.Oka et al.: "Lectin-like oxidized low-density lipoprotein receptor I mediates phagocytosis of aged/apoptotic cells in endothelial cells" Proc.Natl.Acad Sci.USA. 95. 9535-9540 (1998)
[Publications] Y.Iwamuro et al.: "Activation of two types of Ca^<2+> -permeable nonselective cation channel by endothelin-1 in A7r5 cells" Br.J.Pharmacol.124. 1541-1549 (1998)
[Publications] N.Kume et al.: "Inducible expression of Lectin-like oxidized LDL receptor-I in vascular endothelial cells" Circ.Res.83. 322-327 (1998)
[Publications] T.Murase et al.: "Fluid shear stress transcriptionally induces Lectin-like oxidezed LDL receptor-1 in vascular endothelial cells" Circ.Res.83. 328-333 (1998)
[Publications] X.F.Zhang et al.: "Role of nonselective cation channels as Ca^<2+> entry pathway in endothelin-1-induced contraction and their suppression by nitric oxide" Eur.J.Pharmacol.352. 237-245 (1998)
[Publications] K.Ono et al.: "Desensitization of ET_A endothelin receptor-inediated negative chronotropic response in right atria-species difference and intracellular mechanisms" Br.J.Pharmacol.125. 787-797 (1998)
[Publications] T.Kido et al.: "The processing pathway of endothelin-1 production." J.Cardiovas.Pharmacol.31,Suppl.1. S13-S15 (1998)
[Publications] Y.Okamoto et al.: "Cysteine residues in the carboxyl terminal domain of the endothelin-B receptor are required for coupling with G-proteins" J.Cardiovas.Pharmacol.31,Suppl.1. S230-S232 (1998)
[Publications] M.Okazawa et al.: "Endothelin-induced apoptosis of A375 human melanoma cells" J.Biol.Chem.273. 12584-12592 (1998)
[Publications] H.Tanaka et al.: "Novel mutations of the endothelin B receptor gene in patients with hirschsprung's disease and their characterization" J.Biol.Chem.273. 11378-11383 (1998)
[Publications] B.Nicholson et al.: "Increased Cat3-mediated cationic amino acid transport functionally compensates in cat1 knockout cell lines" J.Biol.Chem.273. 14663-14666 (1998)
[Publications] H.Hoshikawa et al.: "Iligh affinity binding of oxidized LDL to mouse lectin-like oxidized LDL receptor(LOX-1)" Biochem.Biophys.Res.Commun.245. 841-846 (1998)
[Publications] H.Ninomiya et al.: "Paracrine endothelin signaling in the control of basal cell proliferation in guinea pig tracheal epithelium" J.Pharmacol.Exp.Ther.286. 469-480 (1998)
[Publications] K.Kikuta et al.: "High-affinity arginine transport of bovine aortic endothelial cells is impaired by lysophosphatidylcholine" Circ.Res.83. 1088-1096 (1998)
[Publications] Y.Iwamuro et al.: "Activation of three types of voltage-independent Ca^<2+> -entry channel in A7r5 cells by endothelin-1 as revealed by a novel Ca^<2+> -entry channel blocker LOE 908" Br.J.Pharmacol.(in press).
[Publications] T.Aoyama et al.: "Structure and chromosomal assignment of human lectin-like oxidized LDL receptor-1(LOX-1)" Biochem.J.,in press.
[Publications] T.Inuri et al.: "Selective activation of excitation-contraction coupling pathways by ET_A and ET_B in tracheal smooth muscle" Br.J.Pharmacol.,. (in press).

1998 Fiscal Year Annual Research Report

内皮依存性の血管収縮と血管細胞増殖調節機構に関する研究

Principal Investigator

眞崎 知生 国立循環器病センター研究所, 所長 (60009991)

Research Products

[Publications] H.Hasegawa et al.: "Purification of a novel endothelin-converling enzyme specific for big endothelin-3" FEBS Letters. 428. 304-308 (1998)

[Publications] K.Oka et al.: "Lectin-like oxidized low-density lipoprotein receptor I mediates phagocytosis of aged/apoptotic cells in endothelial cells" Proc.Natl.Acad Sci.USA. 95. 9535-9540 (1998)

[Publications] Y.Iwamuro et al.: "Activation of two types of Ca^<2+> -permeable nonselective cation channel by endothelin-1 in A7r5 cells" Br.J.Pharmacol.124. 1541-1549 (1998)

[Publications] N.Kume et al.: "Inducible expression of Lectin-like oxidized LDL receptor-I in vascular endothelial cells" Circ.Res.83. 322-327 (1998)

[Publications] T.Murase et al.: "Fluid shear stress transcriptionally induces Lectin-like oxidezed LDL receptor-1 in vascular endothelial cells" Circ.Res.83. 328-333 (1998)

[Publications] X.F.Zhang et al.: "Role of nonselective cation channels as Ca^<2+> entry pathway in endothelin-1-induced contraction and their suppression by nitric oxide" Eur.J.Pharmacol.352. 237-245 (1998)

[Publications] K.Ono et al.: "Desensitization of ET_A endothelin receptor-inediated negative chronotropic response in right atria-species difference and intracellular mechanisms" Br.J.Pharmacol.125. 787-797 (1998)

[Publications] T.Kido et al.: "The processing pathway of endothelin-1 production." J.Cardiovas.Pharmacol.31,Suppl.1. S13-S15 (1998)

[Publications] Y.Okamoto et al.: "Cysteine residues in the carboxyl terminal domain of the endothelin-B receptor are required for coupling with G-proteins" J.Cardiovas.Pharmacol.31,Suppl.1. S230-S232 (1998)

[Publications] M.Okazawa et al.: "Endothelin-induced apoptosis of A375 human melanoma cells" J.Biol.Chem.273. 12584-12592 (1998)

[Publications] H.Tanaka et al.: "Novel mutations of the endothelin B receptor gene in patients with hirschsprung's disease and their characterization" J.Biol.Chem.273. 11378-11383 (1998)

[Publications] B.Nicholson et al.: "Increased Cat3-mediated cationic amino acid transport functionally compensates in cat1 knockout cell lines" J.Biol.Chem.273. 14663-14666 (1998)

[Publications] H.Hoshikawa et al.: "Iligh affinity binding of oxidized LDL to mouse lectin-like oxidized LDL receptor(LOX-1)" Biochem.Biophys.Res.Commun.245. 841-846 (1998)

[Publications] H.Ninomiya et al.: "Paracrine endothelin signaling in the control of basal cell proliferation in guinea pig tracheal epithelium" J.Pharmacol.Exp.Ther.286. 469-480 (1998)

[Publications] K.Kikuta et al.: "High-affinity arginine transport of bovine aortic endothelial cells is impaired by lysophosphatidylcholine" Circ.Res.83. 1088-1096 (1998)

[Publications] Y.Iwamuro et al.: "Activation of three types of voltage-independent Ca^<2+> -entry channel in A7r5 cells by endothelin-1 as revealed by a novel Ca^<2+> -entry channel blocker LOE 908" Br.J.Pharmacol.(in press).

[Publications] T.Aoyama et al.: "Structure and chromosomal assignment of human lectin-like oxidized LDL receptor-1(LOX-1)" Biochem.J.,in press.

[Publications] T.Inuri et al.: "Selective activation of excitation-contraction coupling pathways by ET_A and ET_B in tracheal smooth muscle" Br.J.Pharmacol.,. (in press).

眞崎知生国立循環器病センター研究所, 所長 (60009991)