2001 年度実績報告書

レクチン様酸化LDL受容体の機能と病態生理への関わり

研究課題

研究課題/領域番号	13770053
研究種目	奨励研究(A)
研究機関	国立循環器病センター
研究代表者	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)
キーワード	酸化LDL / 動脈硬化 / LOX-1 / 炎症
研究概要	報告者は先に内皮細胞で主にはたらくと考えられる酸化LDLの受容体LOX-1の同定に成功した。この分子の生体内での役割、動脈硬化およびその他の疾患における位置づけを明らかにする事を目的として本研究を行った。酸化LDLがLOX-1を介して細胞に作用すると、細胞内で活性酸素種が産生され、その後の情報伝達としてNF-kBが活性化されること、同時に生じた活性酸素種によりNOが消去され内皮細胞からのNOの放出が減少することを明らかにし、LOX-1が内皮細胞機能を変化させる重要な役割を果たしていることを示唆した。また、LOX-1の発現を糖尿病ラットで解析し、LOX-1の発現が血管内皮細胞で亢進する事、特に、動脈硬化が起こりやすい血管分岐部での発現が顕著である事を明らかにするとともに、糖尿病の際に生体内に起きる糖化反応により生じるAGE化蛋白がLOX-1のリガンドとなることも明らかになり、動脈硬化の強いリスクファクターである糖尿病との強い関連が示唆された。またLOX-1のリガンド結合メカニズムについて解析を行い、LOX-1のC末端にある10残基がリガンド結合に必須であり、特にその中の塩基性アミノ酸が重要であることを明らかにした。また、他の部位の塩基性アミノ酸もリガンド結合に重要な役割をおっており、電気的な相互作用がリガンド結合に重要と考えられた。一方、新しいLOX-1のリガンドとしてバクテリアやフィブロネクチンを同定し、LOX-1の生理機能がこのようなリガンドとの相互作用により発揮される可能性を示した。さらに、LOX-1遺伝子ノックアウトマウスやLOX-1遺伝子トランスジェニックマウスの作成に成功し、LOX-1の生理的、病態生理的役割を生体レベルで解析している。

研究成果

(18件)

すべてその他

すべて文献書誌 (18件)

[文献書誌] Honjo, M: "Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility"Invest Ophthalmol Vis Sci. 42. 137-144 (2001)
[文献書誌] Halvorsen, B: "8-iso-Prostaglandin F2 increases expression of LOX-1 in JAR cells"Hypertension. 37(4). 1184-1190 (2001)
[文献書誌] White, S.J: "Identification of peptides that target the endothelial cell-specific LOX-1 receptor"Hypertension. 37(2). 449-455 (2001)
[文献書誌] Cominacini, L: "The binding of oxidized low-density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide"J Biol Chem. 276(17). 13750-13755 (2001)
[文献書誌] Nagase, M: "Redox-sensitive regulation of LOX-1 geneexpression in vascular endothelium"Biochem Biophys Res Commun. 281(3). 720-725 (2001)
[文献書誌] Chen, M: "Conserved carboxyl-terminal residues within the lectin-like domain of LOX-1 are essential for oxidized LDL binding"Biochem J. 355(Pt2). 289-296 (2001)
[文献書誌] Kakutani, M: "Accumulation of LOX-1 ligand in plasma and atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits : Identification by a novel enzyme immunoassay"Biochem Biophys Res Commun. 282(1). 180-185 (2001)
[文献書誌] Chen, M: "Activation-dependent surface expression of LOX-1 in human platelets"Biochem Biophys Res Commun. 282(1). 153-158 (2001)
[文献書誌] Shimaoka, T: "LOX-1 supports adhesion of Gram-positive and Gram-negative bacteria"J Immunol. 166. 5108-5114 (2001)
[文献書誌] Chen, M: "Requirements of basic amino acid residues within the lectin-like domain of LOX-1 for the binding of oxidized low-density lipoprotein"FEBS Lett. 499. 215-219 (2001)
[文献書誌] Honjo, M: "Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes"Arch Ophthalmol. 119. 1171-1178 (2001)
[文献書誌] Iwakura, A: "Pericardial Fluid from Patients with Ischemic Heart Disease Induces Myocardial Cell Apoptotis via an Oxidant Stress-sensitive p38 Mitogen-activated Protein Kinase Pathway"J Mol Cell Cardiol. 33. 419-430 (2001)
[文献書誌] Morawietz, H: "Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells"Biochem Biophys Res Commun. 284. 961-965 (2001)
[文献書誌] Shimaoka, T: "Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) supports cell adhesion to fibronectin"FEBS Lett. 504. 65-68 (2001)
[文献書誌] Chen, M: "Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium : possible role of lox-1 ligand and age"Biochem Biophys Res Commun. 287. 962-968 (2001)
[文献書誌] Iwai-Kanai, B: "Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Apoptosis in Cultured Neonatal Rat Cardiac Myocytes"Circulation. 104. 2948-2954 (2001)
[文献書誌] Jono T: "Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE)"FEBS Lett. 511. 170-174 (2001)
[文献書誌] Morawietz, H: "Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1"Clin. Sci.. (in press). (2002)

2001 年度 実績報告書

レクチン様酸化LDL受容体の機能と病態生理への関わり

研究代表者

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)

研究成果

[文献書誌] Honjo, M: "Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility"Invest Ophthalmol Vis Sci. 42. 137-144 (2001)

[文献書誌] Halvorsen, B: "8-iso-Prostaglandin F2 increases expression of LOX-1 in JAR cells"Hypertension. 37(4). 1184-1190 (2001)

[文献書誌] White, S.J: "Identification of peptides that target the endothelial cell-specific LOX-1 receptor"Hypertension. 37(2). 449-455 (2001)

[文献書誌] Cominacini, L: "The binding of oxidized low-density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide"J Biol Chem. 276(17). 13750-13755 (2001)

[文献書誌] Nagase, M: "Redox-sensitive regulation of LOX-1 geneexpression in vascular endothelium"Biochem Biophys Res Commun. 281(3). 720-725 (2001)

[文献書誌] Chen, M: "Conserved carboxyl-terminal residues within the lectin-like domain of LOX-1 are essential for oxidized LDL binding"Biochem J. 355(Pt2). 289-296 (2001)

[文献書誌] Kakutani, M: "Accumulation of LOX-1 ligand in plasma and atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits : Identification by a novel enzyme immunoassay"Biochem Biophys Res Commun. 282(1). 180-185 (2001)

[文献書誌] Chen, M: "Activation-dependent surface expression of LOX-1 in human platelets"Biochem Biophys Res Commun. 282(1). 153-158 (2001)

[文献書誌] Shimaoka, T: "LOX-1 supports adhesion of Gram-positive and Gram-negative bacteria"J Immunol. 166. 5108-5114 (2001)

[文献書誌] Chen, M: "Requirements of basic amino acid residues within the lectin-like domain of LOX-1 for the binding of oxidized low-density lipoprotein"FEBS Lett. 499. 215-219 (2001)

[文献書誌] Honjo, M: "Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes"Arch Ophthalmol. 119. 1171-1178 (2001)

[文献書誌] Iwakura, A: "Pericardial Fluid from Patients with Ischemic Heart Disease Induces Myocardial Cell Apoptotis via an Oxidant Stress-sensitive p38 Mitogen-activated Protein Kinase Pathway"J Mol Cell Cardiol. 33. 419-430 (2001)

[文献書誌] Morawietz, H: "Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells"Biochem Biophys Res Commun. 284. 961-965 (2001)

[文献書誌] Shimaoka, T: "Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) supports cell adhesion to fibronectin"FEBS Lett. 504. 65-68 (2001)

[文献書誌] Chen, M: "Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium : possible role of lox-1 ligand and age"Biochem Biophys Res Commun. 287. 962-968 (2001)

[文献書誌] Iwai-Kanai, B: "Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Apoptosis in Cultured Neonatal Rat Cardiac Myocytes"Circulation. 104. 2948-2954 (2001)

[文献書誌] Jono T: "Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE)"FEBS Lett. 511. 170-174 (2001)

[文献書誌] Morawietz, H: "Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1"Clin. Sci.. (in press). (2002)

2001 年度実績報告書

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)