2001 Fiscal Year Annual Research Report

熱帯熱マラリアの病理における血管内皮細胞の酸化LDL受容体LOX-1の役割

Research Project

Project/Area Number	13226140
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)
Co-Investigator(Kenkyū-buntansha)	相川正道東海大学, 総合科学技術研究所, 教授 (90271593)
Keywords	マラリア / 酸化ストレス / LOX-1
Research Abstract	マラリア感染時に酸化ストレスの指標の8-epi PGF2αが増加するとの知見を得たが、8-epi PGF2αがLOX-1の発現を増加させる作用があることが明らかとなった。また、活性酸素やホモシステインによりin vitroでLOX-1の発現が誘導されることが明らかになると同時に、in vivoにおけるangiotensin IIによるLOX-1の発現誘導も活性酸素に依存していることが明らかとなった。さらに、酸化LDLによるNOの減少が活性酸素の産生と並行しておき、これはLOX-1の機能抑制により共に抑えられた。これまでの研究でin vitro酸化した赤血球がLOX-1に結合するとの知見を得ている。マラリア感染により生じる酸化ストレスにより酸化を受けると考えられる赤血球のLOX-1への結合についての検討を行い、熱帯熱マラリア培養時の赤血球(iRBC+RBC)がLOX-1発現細胞に接着することを観察した。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が感染成立にこれらのリガンドとの相互作用を介して直接的に関与している可能性を示した。さらに、LOX-1遺伝子ノックアウトマウスの作成に成功し、C57BL/6の遺伝的背景への置換を行った。これによりマウスにおけるマラリア感染モデルを利用できるようになり、LOX-1のマラリア感染の病理との関連をin vivoで検証することができるようになった。

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 that 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 Jesions 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 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)
[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-1(LOX-1) supports cell adhesion to fibronectin"FEBS Lett. 504. 65-68 (2001)
[Publications] 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)
[Publications] Iwai-Kanai, E: "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)"FEBS 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

熱帯熱マラリアの病理における血管内皮細胞の酸化LDL受容体LOX-1の役割

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 that 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 Jesions 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 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)

[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-1(LOX-1) supports cell adhesion to fibronectin"FEBS Lett. 504. 65-68 (2001)

[Publications] 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)

[Publications] Iwai-Kanai, E: "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)"FEBS 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)