血管内皮細胞の機能変化のメカニズム

• Project/Area Number: 11770053
• Research Category: Grant-in-Aid for Encouragement of Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: General pharmacology
• 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)
• Project Period (FY): 1999 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥2,200,000 (Direct Cost: ¥2,200,000); Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
• Keywords: レクチン様酸化LDL受容体 / 酸化LDL / 高脂血症 / 動脈硬化 / 内皮細胞 / 血小板

Research Abstract

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の発現を高脂血症ウサギで解析し、LOX-1の発現が動脈硬化巣だけでなく、正常な段階にある血管の内皮細胞でも亢進していること、そして抗動脈硬化を持つ薬物によりLOX-1の発現が抑制されることを示した。さらに新しく開発したLOX-1リガンドの測定法を用いて、高脂血症ウサギの血液中のLOX-1レベルが上昇していることを示した。これらのことからLOX-1の受容体レベル、リガンドレベルがともに高脂血症下では早期から上昇し、内皮細胞機能や動脈硬化の進展に影響を与えていると考えられた。
一方、LOX-1が血栓形成や炎症反応にも重要な役割を果たしているという証拠を得ており、LOX-1が酸化LDLの受容体以外のはたらきを通して動脈硬化およびその合併症を含む幅広い疾患において治療の標的分子となりうることが明らかになりつつある。

Research Products

• [Publications] Iwakura,A: "Pericardial fluid from patients with unstable angina induces vascular endothelial cell apoptosis."J Am Coll Cardiol. 35. 1785-1790 (2000)
• [Publications] Minami,M: "Transforming growth factor-beta (1) increases the expression of lectin-like oxidized low-density lipoprotein receptor-1."Biochem Biophys Res Commun. 272. 357-361 (2000)
• [Publications] Kume,N: "Inducible expression of LOX-1, a novel receptor for oxidized LDL, in macrophages and vascular smooth muscle cells."Ann N Y Acad Sci. 902. 323-327 (2000)
• [Publications] Kataoka,H: "Expression of lectin-like oxidized LDL receptor-1 in human atherosclerotic lesions."Ann N Y Acad Sci. 902. 328-335 (2000)
• [Publications] Murase,T: "Identification of soluble forms of lectin-like oxidized LDL receptor-1."Arterioscler Thromb Vasc Biol. 20. 715-720 (2000)
• [Publications] Cominacini,L: "Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappa B through an increased production of intracellular reactive oxygen species."J Biol Chem. 275. 12633-12638 (2000)
• [Publications] Yoneda,T: "Pericardial fluid from patients with ischemic heart disease accelerates the growth of human vascular smooth muscle cells."Jpn Circ J. 64. 495-498 (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. 20. 1107-1115 (2000)
• [Publications] Kataoka,H: "Biosynthesis and post-translational processing of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1).N-linked glycosylation affects cell-surface expression and ligand binding."J Biol Chem. 275. 6573-6579 (2000)
• [Publications] Halvorsen,B: "8-iso-Prostaglandin F2 increases expression of LOX-1 in JAR cells."Hypertension. (in press). (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. (in press). (2001)
• [Publications] Nagase,M: "Redox-sensitive regulation of LOX-1 geneexpression in vascular endothelium."Biochem Biophys Res Commun. (in press). (2001)
• [Publications] Nagase,M: "Redox-sensitive regulation of LOX-1 geneexpression in vascular endothelium."Biochem Biophys Res Commun. (in press). (2001)
• [Publications] Chen,M: "Conserved carboxyl-terminal residues within the lectin-like domain of LOX-1 are essential for oxidized LDL binding."J Biochem. (in press). (2001)
• [Publications] Chen,M: "Activation-dependent surface expression of LOX-1 in human platelets."Biochem Biophys Res Commun. (in press). (2001)
• [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 1 receptor activation"Cir 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. 2102-2114 (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)