2002 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 / 酸化LDL受容体 / LOX-1 / ノックアウトマウス / トランスジェニックマウス / 血管内皮細胞
Research Abstract	LOX-1遺伝子ノックアウトマウスを解析し、血管内皮細胞へ酸化LDLが作用して起きる現象、すなわち内皮細胞からのNO放出の減少や、接着因子などの発現増加がノックアウトマウスでは顕著に抑制されていることを見出した。また炎症モデルを解析して、LOX-1ノックアウトマウスでは炎症の程度が軽く、その原因として炎症細胞浸潤が弱いことが考えられた。このことから、LOX-1が確かに血管内皮細胞で酸化LDLの作用を媒介していることが明らかになるとともに、炎症の機能分子として働いていることもわかった。また、LOX-1を血管特異的に発現させたトランスジェニックマウスとアポE欠損マウスとの交配により得たマウスの解析を行い、血管へのLOX-1の過剰な発現により酸化LDLの血管への作用が増強し、動脈硬化が増悪することを見出した。また、マクロファージの血管への浸潤も亢進していることが明らかとなった。このことから、LOX-1が動脈硬化促進分子として生体内で機能することが明らかとなった。これらの、LOX-1の生理機能の解析に加え、LOX-1のブロッキング抗体を注射する事によって病態が改善するかどうかを動物モデルを用いて検討を行い、LOX-1を標的とした治療薬の開発の可能性を追求した。エンドトキシンによるブドウ膜炎や、ザイモザンによる関節炎モデルにおいてLOX-1機能の抑制はこれらの炎症を抑制し、臓器障害を軽減した。また、心筋梗塞モデルにおいてもLOX-1機能の抑制は梗塞巣の拡大を抑制した。これらのことより、種々の病態においてLOX-1機能制御が治療に役立つ可能性が示唆された。

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. 103 Suppl 1. 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 MMP 1 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 dephosphorylation 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 USA. 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] 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. 103 Suppl 1. 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 MMP 1 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 dephosphorylation 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 USA. 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)