1999 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 Category	Grant-in-Aid for Scientific Research (B)
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)	眞崎知生国立循環器病センター研究所, 所長 (60009991)
Keywords	レクチン様酸化LDL受容体 / 酸化LDL / 血小板 / 動脈硬化 / 内皮細胞
Research Abstract	LOX-1を抗原として作製したモノクローナル抗体のスクリーニングを、LOX-1による酸化LDLの取り込みを阻害を指標として行った。これまでの研究でLOX-1がアポトーシス細胞を認識し、さらにフォスファチジルセリンがこの際のリガンドとなっていることを明らかにした。このことから活性化に伴いフォスファチジルセリンを表面に露出することが知られている血小板の認識にLOX-1が関係しているのではないかという仮説を立て、得られた中和抗体を用いて検証を行った。LOX-1発現細胞と血小板をインキュベートすると有意な結合が見られ、これはLOX-1に対する抗体により阻害されるとともに、PS結合蛋白であるアネキシンVによっても阻害された。さらに血小板をトロンビンで活性化した上でLOX-1発現細胞と反応させるとより多数の血小板の結合が観察された。これらの結果から、活性化により血小板表面に露出されたPSを介して血小板を結合すると考えられた。抗LOX-1抗体は内皮細胞への血小板の結合も抑制するため、LOX-1は内皮細胞においても主要な働きをしていると考えられる。血小板と内皮細胞とのLOX-1を介した相互作用は内皮細胞からのエンドセリンの放出も促進したことから、単なる表面への結合だけではなく内皮細胞の活性化も引き起こすこともわかった。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Li, D. Y., Zhang, Y. C.: "Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type I receptor activation"Circ Res. 84. 1043-1049 (1999)
[Publications] Aoyama, T.: "Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene"Biochem J. 339. 177-184 (1999)
[Publications] Kataoka, H.: "Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions"Circulation. 99. 3110-3117 (1999)
[Publications] Masaki, T.: "Subcellular mechanisms of endothelin action in vascular system"Eur J Pharmacol. 375. 133-138 (1999)
[Publications] Kaburagi, S.: "The role of endothelin-converting enzyme-1 in the development of alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes"Circulation. 99. 292-298 (1999)
[Publications] Morawietz, H.: "Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein"Circulation. 100. 899-902 (1999)
[Publications] Hosokawa, H.: "Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain"Brain Res. 838. 158-165 (1999)
[Publications] Aoyama, T.: "Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells [In process Citation]"J Mol Cell Cardiol 31. 31. 2101-2114 (1999)
[Publications] Aoyama, T.: "LOX-1 mediates lysophosphatidylcholine-induced oxidized LDL uptake in smooth muscle cells"FEBS letters. 467. 217-220 (2000)
[Publications] Kakutani, M.: "A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1"Proc Natl Acad Sci USA. 97. 360-364 (2000)
[Publications] Chen, M.: "Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits"Arterioscler. Thromb. Vasc. Biol. (in press). (2000)
[Publications] Cominacini, L.: "Oxidized Low-density lipoprotein binding to LOX-1 in endothelial cells induces the activation of NF-kB through an increased production of intracellular reactive oxygen species"J. Biol. Chem. (in press). (2000)

1999 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] Li, D. Y., Zhang, Y. C.: "Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type I receptor activation"Circ Res. 84. 1043-1049 (1999)

[Publications] Aoyama, T.: "Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene"Biochem J. 339. 177-184 (1999)

[Publications] Kataoka, H.: "Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions"Circulation. 99. 3110-3117 (1999)

[Publications] Masaki, T.: "Subcellular mechanisms of endothelin action in vascular system"Eur J Pharmacol. 375. 133-138 (1999)

[Publications] Kaburagi, S.: "The role of endothelin-converting enzyme-1 in the development of alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes"Circulation. 99. 292-298 (1999)

[Publications] Morawietz, H.: "Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein"Circulation. 100. 899-902 (1999)

[Publications] Hosokawa, H.: "Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain"Brain Res. 838. 158-165 (1999)

[Publications] Aoyama, T.: "Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells [In process Citation]"J Mol Cell Cardiol 31. 31. 2101-2114 (1999)

[Publications] Aoyama, T.: "LOX-1 mediates lysophosphatidylcholine-induced oxidized LDL uptake in smooth muscle cells"FEBS letters. 467. 217-220 (2000)

[Publications] Kakutani, M.: "A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1"Proc Natl Acad Sci USA. 97. 360-364 (2000)

[Publications] Chen, M.: "Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits"Arterioscler. Thromb. Vasc. Biol. (in press). (2000)

[Publications] Cominacini, L.: "Oxidized Low-density lipoprotein binding to LOX-1 in endothelial cells induces the activation of NF-kB through an increased production of intracellular reactive oxygen species"J. Biol. Chem. (in press). (2000)

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)