2001 Fiscal Year Annual Research Report

レクチン様酸化LDL受容体を用いた診断、治療、治療薬開発の試み

Research Project

Project/Area Number	11557006
Research Institution	National Cardiovascular Center Research Institute
Principal Investigator	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	酸化LDL / 動脈硬化 / LOX-1 / 炎症
Research Abstract	動脈硬化症の成因に重要と考えられる酸化LDLの受容体LOX-1を我々は先に発見したが、このことを生かして遺伝子工学的にLOX-1の発現を増減させたマウスの解析、LOX-1とそのリガンドとの相互作用を人為的に修飾することによる生理的意義の解明と、治療の可能性の検討、さらにLOX-1を利用したLOX-1リガンド定量の診断的有用性の検討を目的とした。 LOX-1遺伝子過剰発現マウスおよびノックアウトマウスについては現在解析の途上であるが、これまでに得られたin vitroの結果を反映するように、LOX-1が動脈硬化促進的に働く分子であることが明らかになりつつある。また、抗LOX-1中和抗体を用いた解析については多くの成果が得られており、炎症反応、血栓形成反応、虚血再還流障害におけるLOX-1の重要性が明らかになりつつある。また、これらの結果からLOX-1のアンタゴニストが種々の疾患の治療手段として有効であることも示唆された。一方、LOX-1は動脈硬化巣が形成される以前から機能して血管内皮細胞および血管全体の機能を変化させていると考えられるため、比較的健常と考えられる人で、血液中のリガンドを測定し、その診断的価値を検討することが重要である。これまでの研究で血液中のLOX-1リガンド測定系を樹立し、高脂血症動物モデルでLOX-1リガンド濃度が上昇していることを明らかにしている。今年度はさらにヒトの検体を用いて高脂肪食の摂取一回で、血液中のLOX-1リガンドレベルが上昇し、これが抗酸化ビタミンで抑制されることから酸化的な機序によるものである可能性を示した。高脂肪食の摂取により、急速に血管内皮細胞の機能が障害されることが知られているが、本研究で得られた結果は、LOX-1リガンド活性が血管内皮機能をよく反映している事を示唆しており、虚血性心疾患発症予測のよい指標となる

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] 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)
[Publications] Halvorsen, B: "8-iso-Prostaglandin F2 increases expression of LOX-1 in JAR cells"Hypertension. 37(4). 1184-1190 (2001)
[Publications] White, S.J: "Identification of peptides hat target the endothelial cell-specific LOX-1 receptor"Hypertension. 37(2). 449-455 (2001)
[Publications] 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)
[Publications] Nagase, M: "Redox-sensitive regulation of LOX-1 geneexpression in vascular endothelium"Biochem Biophys Res Commun. 281(3). 720-725 (2001)
[Publications] 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)
[Publications] 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)
[Publications] Chen, M: "Activation-dependent surface expression of LOX-1 in human platelets"Biochem Biophys Res Commun. 282(1). 153-158 (2001)
[Publications] Shimaoka, T: "LOX-1 supports adhesion of Gram-positive and Gram-negative bacteria"J Immunol. 166. 5108-5114 (2001)
[Publications] 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)
[Publications] Honjo, M: "Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes"Arch Ophthalmol. 119. 1171-1178 (2001)
[Publications] Iwakura, A: "Pericardial Fluid from Patients with Ichemic 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)
[Publications] Morawietz, H: "Induction of the oxLDL receptor LOX-1 by endothelin-1 in human endothelial cells"Biochem Biophys Res Commun. 284. 961-965 (2001)
[Publications] Shimaoka, T: "Lectin-like oxidized low density lipoprotein receptor-I (LOX-1) supports cell adhesion to fibronectin"FEBS Lett. 504. 65-68 (2001)
[Publications] Chen, M: "Diabetes enhances lectin-like oxidized LDL receptor-I (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and age"Biochem Biophys Res Commun. 287. 962-968 (2001)
[Publications] 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)
[Publications] Jono T: "Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE)"EBBS Lett. 511. 170-174 (2001)
[Publications] Morawietz, H: "Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1"Clin.Sci.. (in press). (2002)

2001 Fiscal Year Annual Research Report

レクチン様酸化LDL受容体を用いた診断、治療、治療薬開発の試み

Principal Investigator

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)

Research Products

[Publications] 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)

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

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

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

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

[Publications] Iwakura, A: "Pericardial Fluid from Patients with Ichemic 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)

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

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

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

[Publications] 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)

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

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

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)