2002 Fiscal Year Annual Research Report

レクチン様酸化LDL受容体の機能と病態生理への関わり

Research Project

Project/Area Number	13770053
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 / 酸化LDL受容体 / LOX-1 / 血管内皮細胞 / 炎症 / 抗原提示
Research Abstract	酸化LDL受容体LOX-1の遺伝子ノックアウトマウス、トランスジェニックマウスを解析し、血管内皮細胞へ酸化LDLの作用について解析を行うとともに、LOX-1の酸化LDLとは独立した機能についての解析を進めた。ラットのザイモザン誘発関節炎のモデルを用いてLOX-1の炎症における役割を解析した。ザイモザン投与によりLOX-1の組織における発現は顕著に増加した。この系に、抗LOX-1抗体を投与すると炎症細胞の浸潤が抑制されるとともに、組織の浮腫や炎症の結果として起きる関節組織の破壊を抑制することができた。さらに、ラットのエンドトキシン誘発ぶどう膜炎のモデルを用いてLOX-1が炎症においてどのように機能しているか解析した。LOX-1の発現は炎症刺激により顕著に増加するとともに、抗LOX-1抗体の投与により炎症反応、白血球の血管壁への接着が抑制され、LOX-1が炎症細胞の血管壁への接着に影響を与えることにより炎症反応に関与していることが明らかとなった。さらに、in vitroにおける解析によりLOX-1そのものが細胞接着分子であることを明らかにした。一方、ヒトおよびマウス樹状細胞においてLOX-1がClassI MHCを介した抗原提示に関与する重要な分子であることが明らかになった。さらに、抗LOX-1抗体を用いて腫瘍抗原を抗原提示細胞に標的することで効果的に腫瘍免疫を誘導することができ、移植した腫瘍の増殖を抑制することができることが明らかになった。このことは、新しい腫瘍ワクチンの可能性を示すだけでなく、かねてから指摘されている動脈硬化における免疫系の変化についての示唆を与えるものである。

Research Products
(16 results)

All Other

All Publications (16 results)

[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 (2002)
[Publications] Chen, M.: "LOX-1,the receptor for oxidized low-density lipoprotein identified from endothelial cells : implications in endothelial dysfunction and atherosclerosis"Pharmacol Ther. 95(1). 89-100 (2002)
[Publications] Li, D.: "Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells : role of LOX-1"J Pharmacol Exp Ther. 302(2). 601-605 (2002)
[Publications] Honjo, M.: "A Myosin Light Chain Kinase Inhibitor, ML-9,Lowers the Intraocular Pressure in Rabbit Eyes"Exp Eye Res. 75(2). 135-142 (2002)
[Publications] Morawietz, H.: "Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1"Clin Sci. 103Suppl. 9S-12S (2002)
[Publications] Delneste, Y.: "Involvement of LOX-1 in Dendritic Cell-Mediated Antigen Cross-Presentation"Immunity. 17(3). 353-362 (2002)
[Publications] Nakagawa, T.: "Lectin-like oxidized low-density lipoprotein receptor 1 mediates leukocyte infiltration and articular cartilage destruction in rat zymosan-induced arthritis"Arthritis Rheum. 46(9). 2486-2494 (2002)
[Publications] Li, D.: "LOX-1 inhibition in myocardial ischemia-reperfusion injury : modulation of MMP1 and inflammation"Am J physiol. 283. H1795-H1801 (2002)
[Publications] Imanishi, T.: "Oxidized low density lipoprotein potentiation of Fas-induced apoptosis through lectin-like oxidized-low density lipoprotein receptor-1 in human umbilical vascular endothelial cells"Circ J. 66(11). 1060-1064 (2002)
[Publications] Nakagawa, T.: "LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-included cell death---possible role of dephosphorylatin of Akt"Biochem Biophys Res Commun. 299. 91-97 (2002)
[Publications] Honjo, M.: "Statin inhibits leukocyte-endothelial interaction and prevents neuronal death included by ischemia-reperfusion in the rat retina"Arch Ophthalmol. 120(12). 1707-1713 (2002)
[Publications] Honjo, M.: "Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation"Proc Natl Acad Sci U S A. 100(3). 1274-1279 (2003)
[Publications] Kataoka, K.: "LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury"Biochem Biophys Res Commun. 300(3). 656-660 (2003)
[Publications] Li, D.: "LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells"Circulation. 107(4). 612-617 (2003)
[Publications] Cominacini, L.: "The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells"J Am Coll Cardiol. 41(3). 499-507 (2003)
[Publications] Wilson, S.H.: "Lipid-lowering independent effects of simvastatin on the kidney in experimental hypercholesterolemia"Nephrol Dial Transplant. (in press). (2003)

2002 Fiscal Year Annual Research Report

レクチン様酸化LDL受容体の機能と病態生理への関わり

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] 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 (2002)

[Publications] Chen, M.: "LOX-1,the receptor for oxidized low-density lipoprotein identified from endothelial cells : implications in endothelial dysfunction and atherosclerosis"Pharmacol Ther. 95(1). 89-100 (2002)

[Publications] Li, D.: "Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells : role of LOX-1"J Pharmacol Exp Ther. 302(2). 601-605 (2002)

[Publications] Honjo, M.: "A Myosin Light Chain Kinase Inhibitor, ML-9,Lowers the Intraocular Pressure in Rabbit Eyes"Exp Eye Res. 75(2). 135-142 (2002)

[Publications] Morawietz, H.: "Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1"Clin Sci. 103Suppl. 9S-12S (2002)

[Publications] Delneste, Y.: "Involvement of LOX-1 in Dendritic Cell-Mediated Antigen Cross-Presentation"Immunity. 17(3). 353-362 (2002)

[Publications] Nakagawa, T.: "Lectin-like oxidized low-density lipoprotein receptor 1 mediates leukocyte infiltration and articular cartilage destruction in rat zymosan-induced arthritis"Arthritis Rheum. 46(9). 2486-2494 (2002)

[Publications] Li, D.: "LOX-1 inhibition in myocardial ischemia-reperfusion injury : modulation of MMP1 and inflammation"Am J physiol. 283. H1795-H1801 (2002)

[Publications] Imanishi, T.: "Oxidized low density lipoprotein potentiation of Fas-induced apoptosis through lectin-like oxidized-low density lipoprotein receptor-1 in human umbilical vascular endothelial cells"Circ J. 66(11). 1060-1064 (2002)

[Publications] Nakagawa, T.: "LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-included cell death---possible role of dephosphorylatin of Akt"Biochem Biophys Res Commun. 299. 91-97 (2002)

[Publications] Honjo, M.: "Statin inhibits leukocyte-endothelial interaction and prevents neuronal death included by ischemia-reperfusion in the rat retina"Arch Ophthalmol. 120(12). 1707-1713 (2002)

[Publications] Honjo, M.: "Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation"Proc Natl Acad Sci U S A. 100(3). 1274-1279 (2003)

[Publications] Kataoka, K.: "LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury"Biochem Biophys Res Commun. 300(3). 656-660 (2003)

[Publications] Li, D.: "LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells"Circulation. 107(4). 612-617 (2003)

[Publications] Cominacini, L.: "The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells"J Am Coll Cardiol. 41(3). 499-507 (2003)

[Publications] Wilson, S.H.: "Lipid-lowering independent effects of simvastatin on the kidney in experimental hypercholesterolemia"Nephrol Dial Transplant. (in press). (2003)

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)