植物血凝素样氧化低密度脂蛋白受体-1在动脉粥样硬化兔中的表达及氟伐他汀干预的实验研究
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摘要
【目的】通过建立家兔食饵性动脉粥样硬化模型,探讨氟伐他汀对植物血凝素样氧化低密度脂蛋白受体-1(Lectin-like oxidized low-densitylipoprotein receptor-1,LOX-1)蛋白及基因表达的影响,以及其与动脉粥样硬化斑块稳定性的关系,进而阐明LOX-1在动脉粥样硬化发生发展中的重要作用,并为治疗动脉粥样硬化提供一条新的思路。
【方法】将24只雄性新西兰大白兔按不同处理方式随机分为3组:正常对照组(control group,C组,n=8)、动脉粥样硬化模型组(atherosclerosis group,AS组,n=8)和氟伐他汀干预组(fluvastatin-treated group,FLUT组,n=8)。C组喂普通饮食,AS组喂高脂饮食,FLUT组喂高脂饮食的同时加用氟伐他汀干预,饲养16周后处死。取胸主动脉,分别行HE染色观察胸主动脉形态学变化,免疫组织化学染色检测LOX-1的蛋白表达水平及巨噬细胞在动脉粥样硬化斑块中的浸润水平,半定量逆转录多聚酶链式反应(reverse transcription polymerase chainreaction,RT-PCR)测定兔胸主动脉中LOX-1基因表达的水平。于0周、16周耳缘静脉取空腹血,测定血清总胆固醇(total cholesterol,TC)和低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)。
【结果】
1、胸主动脉形态学观察结果显示:AS组胸主动脉内膜明显增厚,管腔明显变窄,FLUT组较AS组内膜明显变薄,管腔显著扩大(P＜0.05),C组无斑块形成,内膜结构正常。
2、血脂测定结果:0周时C组、AS组、FLUT组血清总胆固醇的浓度分别为0.81±0.22 mmol/L,0.81±0.21mmol/L,0.82±0.20mmol/L;16周时C组、AS组FLUT组血清总胆固醇的浓度分别为0.75±0.22 mmol/L,38.85±8.15mmol/L,16.68±5.92mmol/L;0周时C组、AS组、FLUT组血清低密度脂蛋白胆固醇的浓度分别为0.49±0.14mmol/L,0.51±0.13mmol/L,0.48±0.11mmol/L;16周时C组、AS组、FLUT组血清低密度脂蛋白胆固醇的浓度分别为0.44±0.04mmol/L,14.05±1.18mmol/L,7.64±0.80mmol/L。16周时AS组、FLUT组血清总胆固醇、低密度脂蛋白胆固醇浓度明显高于C组(P＜0.05),FLUT组与AS组血清总胆固醇、低密度脂蛋白胆固醇浓度有统计学差异(P＜0.05)。C组较0周无统计学差异,AS组与FLUT组均较各自0周时显著升高(P＜0.05)。
3、LOX-1免疫组织化学染色分析结果显示:阳性颗粒主要表达在增厚的内膜中内皮细胞和泡沫细胞的胞浆及胞膜,AS组阳性染色信号的平均光密度值为0.2335±0.0149,FLUT组阳性染色信号的平均光密度值为0.1387±0.0129。AS组LOX-1抗原表达明显强于FLUT组(P＜0.05)。
4、巨噬细胞免疫组织化学染色分析结果显示:阳性颗粒主要表达在增厚的内膜中巨噬细胞的胞浆部位,从免疫组化结果看,AS组巨噬细胞浸润明显多于正常饮食组(p＜0.01),FLUT组巨噬细胞浸润较高脂饮食组明显减少(P＜0.01)。
5、逆转录聚合酶链反应检测结果显示:FLUT组(相对系数0.4215±0.1300)LOX-1 mRNA表达水平明显低于AS组(相对系数1.3617±0.1223,P＜0.05)。
【结论】氟伐他汀能够抑制动脉粥样硬化兔胸主动脉LOX-1蛋白及基因的表达,同时明显减少巨噬细胞在动脉粥样硬化斑块中的浸润,这可能是它发挥内皮保护作用,抑制AS及增加AS斑块稳定性的机制之一。
[Objective] To explore the intervention effects of fluvastatin on expression of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) and observe the relationship between expression of LOX-1 and the stability of atherosclerotic plaque, further elucidate the important role of LOX-1 during the development of atherosclerosis and provide a new thinking for the atherosclerotic treatment.
[Methods] Twenty-four male NewZealand white rabbits were randomly and equally divided into three groups: control group(C group, n=8), fed with normal diet;atherosclerosis group(AS group, n=8), fed with high lipids diet and fluvastatin-treated group(FLUT group, n=8), fed with high lipids diet and treated with fluvastatin. They were fed for 16 weeks, the thoracic aortae were harvested, the concentrations of serum total cholesterol (TC) and low-density lipoprotein cholesterol(LDL-C) were measured. We used hematoxylin and eosin (HE) staining to observe the morphology of thoracic aortae and immunohistochemical staining to measure the expression of LOX-1 protein, the soakage of the macrophage in plaques was also examined by immunohistochemitry.The LOX-1 mRNA was analyzed by RT-PCR.
[Results]
1. The morphology of the thoracic aorta:the intima of thoracic aorta in fluvastatin-treated group was thinner than that in AS group(P<0.05), and the lumina of thoracic aorta in fluvastatin-treated group was larger than that in AS group(P<0.05),the intima structure of thoracic aorta in C group was normal, there was no plaque in it.
2. The concentration of serum TC and LDL-C in AS group and FLUT group at 16 weeks was significant higher than that at 0 weeks (P<0.05), there was significant difference between AS group and FLUT group(P<0.05).
3. The immunohistochemical staining results of LOX-1 : the buffy particle mainly expressed on plasm and membrane of endothelial cells and foam cells in incrassate intima , the average optical density value of LOX-1 positive staining signal in AS group and FLUT group was 0.2335±0.0149, 0.1387±0.0129, respectively, with significant difference between them(P<0.05).
4. The immunohistochemical staining results of macrophage:the soakage of the macrophage in atherosclerotic plaque of AS group and FLUT group was significant higher than those of control group (p<0.05); the soakage of the macrophage in atherosclerotic plaque of FLUT group was significant lower than AS group(p<0.05).
5. The relative value of LOX-1 mRNA in AS group and FLUT group was 0.6870±0.1278, 0.4300±0.1415, respectively, with significant difference between them(P<0.05).
[Conclusion] Fluvastatin could inhibit the expression of LOX-1 and the soakage of macrophage in atherosclerotic plaques in aorta of atherosclerotic rabbit by significantly lowering serum TC and LDL-C, which may be one of mechanisms of its effect on endothelial protection and stabilizing the atherosclerotic plaques .
【方法】将24只雄性新西兰大白兔按不同处理方式随机分为3组:正常对照组(control group,C组,n=8)、动脉粥样硬化模型组(atherosclerosis group,AS组,n=8)和氟伐他汀干预组(fluvastatin-treated group,FLUT组,n=8)。C组喂普通饮食,AS组喂高脂饮食,FLUT组喂高脂饮食的同时加用氟伐他汀干预,饲养16周后处死。取胸主动脉,分别行HE染色观察胸主动脉形态学变化,免疫组织化学染色检测LOX-1的蛋白表达水平及巨噬细胞在动脉粥样硬化斑块中的浸润水平,半定量逆转录多聚酶链式反应(reverse transcription polymerase chainreaction,RT-PCR)测定兔胸主动脉中LOX-1基因表达的水平。于0周、16周耳缘静脉取空腹血,测定血清总胆固醇(total cholesterol,TC)和低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)。
【结果】
1、胸主动脉形态学观察结果显示:AS组胸主动脉内膜明显增厚,管腔明显变窄,FLUT组较AS组内膜明显变薄,管腔显著扩大(P＜0.05),C组无斑块形成,内膜结构正常。
2、血脂测定结果:0周时C组、AS组、FLUT组血清总胆固醇的浓度分别为0.81±0.22 mmol/L,0.81±0.21mmol/L,0.82±0.20mmol/L;16周时C组、AS组FLUT组血清总胆固醇的浓度分别为0.75±0.22 mmol/L,38.85±8.15mmol/L,16.68±5.92mmol/L;0周时C组、AS组、FLUT组血清低密度脂蛋白胆固醇的浓度分别为0.49±0.14mmol/L,0.51±0.13mmol/L,0.48±0.11mmol/L;16周时C组、AS组、FLUT组血清低密度脂蛋白胆固醇的浓度分别为0.44±0.04mmol/L,14.05±1.18mmol/L,7.64±0.80mmol/L。16周时AS组、FLUT组血清总胆固醇、低密度脂蛋白胆固醇浓度明显高于C组(P＜0.05),FLUT组与AS组血清总胆固醇、低密度脂蛋白胆固醇浓度有统计学差异(P＜0.05)。C组较0周无统计学差异,AS组与FLUT组均较各自0周时显著升高(P＜0.05)。
3、LOX-1免疫组织化学染色分析结果显示:阳性颗粒主要表达在增厚的内膜中内皮细胞和泡沫细胞的胞浆及胞膜,AS组阳性染色信号的平均光密度值为0.2335±0.0149,FLUT组阳性染色信号的平均光密度值为0.1387±0.0129。AS组LOX-1抗原表达明显强于FLUT组(P＜0.05)。
4、巨噬细胞免疫组织化学染色分析结果显示:阳性颗粒主要表达在增厚的内膜中巨噬细胞的胞浆部位,从免疫组化结果看,AS组巨噬细胞浸润明显多于正常饮食组(p＜0.01),FLUT组巨噬细胞浸润较高脂饮食组明显减少(P＜0.01)。
5、逆转录聚合酶链反应检测结果显示:FLUT组(相对系数0.4215±0.1300)LOX-1 mRNA表达水平明显低于AS组(相对系数1.3617±0.1223,P＜0.05)。
【结论】氟伐他汀能够抑制动脉粥样硬化兔胸主动脉LOX-1蛋白及基因的表达,同时明显减少巨噬细胞在动脉粥样硬化斑块中的浸润,这可能是它发挥内皮保护作用,抑制AS及增加AS斑块稳定性的机制之一。
[Objective] To explore the intervention effects of fluvastatin on expression of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) and observe the relationship between expression of LOX-1 and the stability of atherosclerotic plaque, further elucidate the important role of LOX-1 during the development of atherosclerosis and provide a new thinking for the atherosclerotic treatment.
[Methods] Twenty-four male NewZealand white rabbits were randomly and equally divided into three groups: control group(C group, n=8), fed with normal diet;atherosclerosis group(AS group, n=8), fed with high lipids diet and fluvastatin-treated group(FLUT group, n=8), fed with high lipids diet and treated with fluvastatin. They were fed for 16 weeks, the thoracic aortae were harvested, the concentrations of serum total cholesterol (TC) and low-density lipoprotein cholesterol(LDL-C) were measured. We used hematoxylin and eosin (HE) staining to observe the morphology of thoracic aortae and immunohistochemical staining to measure the expression of LOX-1 protein, the soakage of the macrophage in plaques was also examined by immunohistochemitry.The LOX-1 mRNA was analyzed by RT-PCR.
[Results]
1. The morphology of the thoracic aorta:the intima of thoracic aorta in fluvastatin-treated group was thinner than that in AS group(P<0.05), and the lumina of thoracic aorta in fluvastatin-treated group was larger than that in AS group(P<0.05),the intima structure of thoracic aorta in C group was normal, there was no plaque in it.
2. The concentration of serum TC and LDL-C in AS group and FLUT group at 16 weeks was significant higher than that at 0 weeks (P<0.05), there was significant difference between AS group and FLUT group(P<0.05).
3. The immunohistochemical staining results of LOX-1 : the buffy particle mainly expressed on plasm and membrane of endothelial cells and foam cells in incrassate intima , the average optical density value of LOX-1 positive staining signal in AS group and FLUT group was 0.2335±0.0149, 0.1387±0.0129, respectively, with significant difference between them(P<0.05).
4. The immunohistochemical staining results of macrophage:the soakage of the macrophage in atherosclerotic plaque of AS group and FLUT group was significant higher than those of control group (p<0.05); the soakage of the macrophage in atherosclerotic plaque of FLUT group was significant lower than AS group(p<0.05).
5. The relative value of LOX-1 mRNA in AS group and FLUT group was 0.6870±0.1278, 0.4300±0.1415, respectively, with significant difference between them(P<0.05).
[Conclusion] Fluvastatin could inhibit the expression of LOX-1 and the soakage of macrophage in atherosclerotic plaques in aorta of atherosclerotic rabbit by significantly lowering serum TC and LDL-C, which may be one of mechanisms of its effect on endothelial protection and stabilizing the atherosclerotic plaques .
引文
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27. Shin HK, Kim YK, Kim KY et al.Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of superoxide and cytokines via lectin-like oxidized low-density lipoprotein r eceptor-1 activation:prevention by cilostazol. Circulation, 2004, 109(8): 1022-8
28. Li L, Roumeliotis N, Sawamura T et al. Oreactive protein enhance LOX-1 Expression in human aortic endothelial cells:relevance of LOX-1 to Oreactive protein-induced endothelial dysfunction. Circ Res,2004, 95(9): 877-83
29. Li L, Sawamura T,Renier GGlucose enhance human macrophage LOX-1 expression:role for LOX-1 in glucose-induced macrophage foam cell formation. Circ Res, 2004, 94(7)892-901
30. Smirnova IVKajstura T et al. Asymmetric upregulate LOX-1 in activated macrophages:role in foam cell dimethylarginine formation. Am J Physiol Heart Circ Physiol, 2004, 287(2):782-90
31. Holven KB, Scholz H, Halvorsen B et al. Hyperhomocysteinemic subjects have enhanced expression of lectin-like oxidized LDL receptor-1 in mononuclear cells. J Nutr, 2003, 133(11):3588-91
32. Halvorsen B, Staf AC, Henriksen T et al. 8-iso-prostaglandinF(2alpha) increase expression of LOX-1 in JAR cells. Hypertension, 2001,37(4) : 1184-90
33. Chirathaworn C, Pongpanich A, Poovorawan Y et al. Herpes simplex virus 1 induce LOX-1 expression in an endothelial cell line, ECV304. Viral immunol, 2004,17(2):308-14
34. Nagase M , Hirose S , Sawamura T et al . Enhanced expression of lectin-like oxidized low-density lipoprotein receptor(LOX-1)in hypertensive rats. Biochem Biophys Res commun, 1997, 237(3):496-8
35. Kosaka H, Yoneyama H, Zhang L et al.Induction of LOX-1 and iNOS expression by isch mia-reperfusion of rat kidney and the opposing effect of L-arginine. FASEB J , 2003,17(6):636-43
36. Tanimoto A, Murata (?) Nomaguchi M et al.Histamine increase the expression of LOX-1 via H2 receptor in human monocytic THP-1 cells. FEBS Lett, 2001,508(3): 345-9
37. Moriwaki H, Kume N, Sawamura T et al. Ligand specificity of LOX-1, a novel Endothelial receptor for oxidized low-density lipoprotein .Atheroscler Thromb Vase Biol, 1998, 18(10):1541-7
38. Oka K, Sawamura T, Kikuta K et al. Lectin-like oxidized low-density receptor-1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci, 1998, 95(16):9535-40
39. Cominacini L, Pasini AF, Garbin U et al. Oxidized low-density lipoprotein (OX-LDL)binding to OX-LDL receptor-1 in endothelial cells induces the activation of NF-KB through an increased of intracellular reactive oxygen species. Biol Chem, 2000, 275(17):12633-8
40. Cominacini L, Rigoni A, Pasini AF et al.The binding of oxidized low-density lipoprotein(OX-LDL)to OX-LDL receptor-1 reduce the intracellular concentration of nitric oxide in endothelial cells through an increased p roduction of superoxide. Biol Chem, 2001,276(17):13750-5
41.Hayashida K, Kume N, Minami M et al. Lectin-like oxidized LDL receptor-1(LOX-1) supports adhesion of mononuclear leukocytes and a monocyte-like cell line THP-1 cells under static and flow conditions. FEBS Lett, 2002, 511(1-3):133-8
42. Kakutani M, Masaki T Sawamura T et al.A platelet-endothelium mediated by lectin-like oxidized low-density lipoprotein receptor-1.PNAS, 2000,97(1): 360-4
43. Cominacini L, Fratta PA, Garbin U et al. The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells. Am Coll Cardiol, 2003, 41(3):499-507
44. Li D, Singh RM, Liu L, Chen H, Singh BM, Kazz2z N, et al. Oxidized-LDL through LOX-1 increases the expression of angiotens in converting enzyme i n human coronary artery endothelial cells. CardiovascRes,2003, 57(1):238-243
45. Li D, Liu L, Chen H, Sawamura T, Mehta JL. LOX-1, an oxidized LDL Endothelial receptor, inducesC D40/CD40L signaling in human coronary artery endothelial cells.Arterioscler Thromb Vasc Biol,2003, 23(5): 816-821
46. L iD , MehtaJ L.Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol, 2000, 20(4):1116-22
47. Kataoka H, Kume N.Miyamoto S et al. Oxidized LDL modulates Bax-/Bcl-2 through the lectin like OX-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vase Biol, 2001,21(6):955-60
48.Honjo M, Nakamura K, Yamashiro K, et al. Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation. Proc Natl Acad Sci USA , 2003, 100(3):1274-1279
49. Li D, Liu L, Chen H et al. LOX-1 mediates oxidized low-density lipoprotein induced expression of matrix metalloproteinase in human coronary artery endothelial cells. Circulation, 2003, 107(4):612-7
50. Li D, Williams V, Liu L et al. Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction. Am Coll Cardiol, 2003, 41(6):1048-1055
51. Kataoka K, Hasegawa K, Sawamura T et al. LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury. Biochem Biophy Rescommun, 2003,300(3):656-60
52. Ge J, Huang D, Liang C et al. Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 expression contributes to the vein graft atherosclerosis:modulation by losartan. Atherosclerosis, 2004, 177(2): 263-8
53. Puccetti L, Sawamura T, Pasqui AL et al. Atorvastatin reduce platelet-oxidized-LDL receptor expression in hypercholesterolaemic patients. Eur J Clin Invest, 2005,35(1):47-51
54. Wilson SH, Chade AR, Feldstein A et al. Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia. Nephrol Dial Transplant, 2003,18(4):703-9
55. Sugano M, Tsuchida K, Makino N et al. Nifedipine prevents apoptosis of endothelial cells induce by oxidized low-density lipoproteins. Cardiovasc Phamutcol. 2002, 40(1):146-52
56. Zhou MS, Jaimes EA, Raij L. Inhibition of oxidative stress and improvement of endothelial function by amlodipine in angiotensin II-infused rats. Am J, 2004,17(2): 167-171
57. Kobayashi N, Yoshida K, Mita S et al. Betaxolol stimulates eNOS associated with LOX-1 and VEGF in Dahl salt-sensitive rats. Hypertens. 2004, 22(7): 1397-402
58. Chade AR, Best PJ, Rodriguez-Porcel et al. Endothelin-1 receptor blockade Prevents renal injury in experimental hypercholesterolemia. Kidney Int, 2003, 64(3):962-969
59. Mehta JL, Hu B, Chen J et al. Pioglitazone inhibits LOX-1 expression in human coronary artery endothelial cells by reducing intracellular superoxide radical generation. Arterioscler Thromb Vasc Biol, 2003, 23(12):2203-8
60. Chiba Y, Ogita T.Ando K et al. PPARgamm ligands inhibit TNF-Alpha-induced LOX-1 expression in cultured endothelial cells. Biochem Biophys Rescommun, 2001, 286(3):541-6
61. Mehta JL, Chen J , Yu F et al .Aspirin inhibits OX-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res, 2004, 64(2):243-9
62. Thum T, Borlak J. Mechanistic role of cytochrome P450 monooxygenases in oxidized low-density lipoprotein-induced vascular injury:therapy through LOX-1 receptor antagonism? Circ Res,2004,94(1):e1-e13
63. Kobayashi N, Hara K, Tojo A et al. Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK -p90RSK, and Rho-kinase pathway. Hypertension, 2005, 45(4):538-44
64. Park SY, Lee JH, Kim YK et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation. Pharmacol Exp Ther, 2005, 312(3):1241-8
65. Chiba Y, Ando K, Fujida T et al.The protective effects of taurine against renal damage by salt loading in Dahl salt-sensitive rats. Hypertens, 2002, 20 (11):2269-74
2 Mehta JL, Li D.Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. Am Coll Cardiol, 2002, 39(9):1429-1435
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4 Kume N , Kita T. Roles of lectin-like oxidized LDL receptor-1 and its soluble forms in atherogenesis. Curr Opin Lipidol , 2001, 12 (4) : 419-423
5 Kataoka H, Kume N, et al. Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation. 1999 Jun 22;99(24):3110-7.
6 Li D, Mehta JL. Antisense to Lox-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells. Circulation, 2000, 101(25): 2889-95
7 Aoyama T, Fujiwara H, Masaki T et al. Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells . Mot Cell, 1999,31(12):2101-14
8 Li DY, Zhang YC, Philips MI et al. Upregulation of endothelial receptor for oxidized low-density lipoprotein receptor(Lox-1) in cultured human coronary artery endothelial cells by angiotensinI type(?) receptor activation. Circ Res, 1999, 84(9):1043-9
9 Morawietz H , Rueckschloss U ,Niemann B et al .Angiotensin II - induces LOX-1, the Human endothelial receptor for oxidized low-density lipoprotein.Circulation, 1999; 100(9):899-902
10 Rosenson RS. Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities. Atherosclerosis, 2004,173: 1212
11 de Jongh S, Ose L, Szamosi T, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, Double-blind, placebo-controlled trial with simvastatin. Circulation, 2002,106: 2231-2237
12 Wiegman A, Hutten BA, de Groo E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA, 2004, 292:331-337
13 Sawanura T Kume N , Aoyama T et al . An endothelial receptor for oxidized low density lipoprotein. Nature, 1997, 386(6620):73-7
14 Cominacini L, Pasini AF, Garbin U et al. Oxidized low-density lipoprotein(OX-LDL)binding to OX-LDL receptor-1 in endothelial cells induces the activation of NF-KB through an increased of intracellular reactive oxygen species. Biol Chem, 2000, 275(17):12633-8
15 Li DY, Zhang YC, Philips MI et al. Upregulation of endothelial receptor for oxidized low-density lipoprotein receptor(Lox-1) in cultured human coronary artery endothelial cells by angiotensinI typeI receptor activation. Circ Res, 1999, 84(9): 1043-9
16 Dayuan Li, Ling Liu, Hongjiang Chen et al. Lox-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells。Circulation, 2003; 107 (4) :612-617
17 Kakutani M, Masaki T, Sawamura T. A platelet-endotheliam interaction mediated by lectin-like oxidized low density lipoprotein receptor-1. PNAS,2000; 97(1): 360-4
18 Morawietz H , Rueckschloss U , Niemann B et al . Angiotensin II - induces LOX-1, the Human endothelial receptor for oxidized low-density lipoprotein.Circulation,1999;100(9):899-902
19 Shin HK,Kim YK,Kim KY,Lee JH,Hong KW.Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of Superoxide and cytokines via lectin-like oxidized low-denreceptor-1 activation:prevention by cilostazol.Circulation,2004 Mar 2;Vol.109(8),pp.1022-1028.
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30 Wiegman A, Hutten BA, de Groo E, et al. Efficency and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA, 2004, 292: 331-337
31 Rosenson RS. Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities. Atherosclerosis, 2004, 173: 1212
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1. Murase T , Kume N , Kataoka H , et al. Identification of soluble forms of lectin-like oxidized LDL receptor-1. Arterioscler Thromb Vasc Biol, 2000, 20(3): 715-7202.
2. Mehta JL, Li D . Identification, regulation and function of a novel le ctin-like oxidized low-density lipoprotein receptor. Am Coll Cardiol, 2002, 39(9):1429-1435
3. Sawanura T Kume N ,Aoyama T etal.An endothelial receptor for oxidized low density lipoprotein. Nature, 1997, 386(6620):73-7
4. Nagase M , Abe J , Takahashi K et al . Genomicorganization and regulation of expression of the lectin-like oxidized low-density lipoprotein receptor(LOX-1)gene. Biol Chem, 1998, 273(50):33702-7
5. Huang Z, Zhang T Yang J et al. Cloning and expression of human lectin-like oxidized low-density lipoprotein receptor-1 in pichia pastoris. Biotechnology letters, 2005, 27(1):9-52
6. Aoyama T Sawamaru T , Furutani Y et al. Structure and chromosomal assignment of the human lectin-like oxidized low-density lipoprotein receptor-1( LOX-1)gene. Bioche J , 1999, 339(1):177-84
7. Ohmori R , Momiyama Y Nagano M et al. An oxidized low-density lipoprotein receptor gene variant is inversely associated with the severity of coronary artery disease. Clin Cardiol,2004, 27(11):641-4
8. Chen Q, Reis SE, Kammerer C et al. Genetic variation in lectin-like oxidized low-density lipoprotein receptor-1(LOX-1) gene and the risk of coronary artery disease. Circulation,2003,107(25):3146-51
9. Kume N ,Kita T .Roles of lectin-like oxidized LDL receptor-1 and its soluble forms in atherogenesis. Curr Opin Lipidol, 2001, 12(4):419-423
10. Park H, Adsit FG, Boyington JC et al. The 1. 4 angstrom crystal structure of the human lectin-like low-density lipoprotein receptor lox-1.Biol Chem, 2005, 280(14): 135 93-9
11. Me Q, Matsunaga S, Niimi S et al . human lectin-like oxidized low-density Lipoprotein receptor-1 functions as a dimmer in living cells.DNA Cell Biol,2004, 23(2): 111-7
12. Kataoka H , Kume N , Miyamoto S, et al. Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation, 1999, 99(24):3110-3117
13. Hayashida k, Kume N, Murase T et al. Serum soluble lectin-like oxidized Low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome:a novel marker for early diagnosis. Circulation, 2005, 112(6): 812-8
14. Li DY, Zhang YC, Philips M Iet al. Upregulation of endothelial receptor for oxidized low-density lipoprotein receptor(Lox-1)in cultured human coronary artery endothelial cells by angiotensinII typeI receptor activation. Circ Res, 1999, 84(9):1043-9
15. Morawietz H , Rueckschloss U ,Niemann B etal . AngiotensinI I-induces Lox-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation, 1999, 100(9):899-902
16. Limor R, Kaplan M, Sawamura T et al. Angiotensin II increase the expression of oxidized low-density lipoprotein receptor-1 in human smooth muscle cells via a lipoxygenase-dependent pathway. Am J Hypertens, 2005, 18(3):299-307
17. Murase T, Kume N, Korenaga R et al. Fluid shear stress transcriptionally induce lectin-like oxidized LDL receptor-1 in vascular endothelial cells. Circ Res,1998,83(3):328-33
18. Kume N, Murase T, Moriwaka H et al. Inducible expression of lectin-like oxidized LDL receptor-1 in vascular endothelial cells. Circ Res, 1998, 83(3): 322-7
19. Chiba Y, Ogita T, Ando K et al.PPARy ligands inhibit TNF-α induced LOX-1 expression in cultured endothelial cells. Biochem Biophys Resconunun,2001,286(3):541-6
20. Minami M, Kume N, Kataok H et al. Transforming growth factor-p1 increase the expression of lectin-like oxidized low-density lipoprotein receptor-1.Biochern Biophys Rescommun, 2000, 272(2):357-61
21. Mukai E, Kurae N, Hayashida K et al. Heparin-binding EGF-like growth factor induce expression of lectin-like oxidized LDL receptor-1 in vascular smooth muscle cells. Atherosclerosis,2004,176(2):289-96
22. Hofnagel O, Luechtenborg B, Stolle K et al. Proinflaramatory cytokines regulate lox-1 expression in vascular smooth muscle cells. Atheroscler Thromb Vasc Biol, 2004, 24(10):1789-95
23. Higuchi S,Tanimoto A, Arima N et al. Effects of histamine and interleukin-4 synthesized in arterial intima on phagocytosis by monocytes/macrophage in relation to Atherosclerosis. FEBSLetter, 2001, 505 (2):217-22
24. Morawietz H, Duerrschmidt N, Niemann B et al. Induction of the OX-LDL receptorLOX-1 by endothelin-1 in human endothelialcells. Biochem Biophys Res commun , 2001, 284(4):961-5
25. Li D, Mehta JL. Antisense to Lox-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells.Circulation, 2000, 101(25):2889-95
26. Aoyama T, Fujiwara H, Masaki T et al. Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells. Mol Cell Cardiol,1999,31(12):2101-14
27. Shin HK, Kim YK, Kim KY et al.Remnant lipoprotein particles induce apoptosis in endothelial cells by NAD(P)H oxidase-mediated production of superoxide and cytokines via lectin-like oxidized low-density lipoprotein r eceptor-1 activation:prevention by cilostazol. Circulation, 2004, 109(8): 1022-8
28. Li L, Roumeliotis N, Sawamura T et al. Oreactive protein enhance LOX-1 Expression in human aortic endothelial cells:relevance of LOX-1 to Oreactive protein-induced endothelial dysfunction. Circ Res,2004, 95(9): 877-83
29. Li L, Sawamura T,Renier GGlucose enhance human macrophage LOX-1 expression:role for LOX-1 in glucose-induced macrophage foam cell formation. Circ Res, 2004, 94(7)892-901
30. Smirnova IVKajstura T et al. Asymmetric upregulate LOX-1 in activated macrophages:role in foam cell dimethylarginine formation. Am J Physiol Heart Circ Physiol, 2004, 287(2):782-90
31. Holven KB, Scholz H, Halvorsen B et al. Hyperhomocysteinemic subjects have enhanced expression of lectin-like oxidized LDL receptor-1 in mononuclear cells. J Nutr, 2003, 133(11):3588-91
32. Halvorsen B, Staf AC, Henriksen T et al. 8-iso-prostaglandinF(2alpha) increase expression of LOX-1 in JAR cells. Hypertension, 2001,37(4) : 1184-90
33. Chirathaworn C, Pongpanich A, Poovorawan Y et al. Herpes simplex virus 1 induce LOX-1 expression in an endothelial cell line, ECV304. Viral immunol, 2004,17(2):308-14
34. Nagase M , Hirose S , Sawamura T et al . Enhanced expression of lectin-like oxidized low-density lipoprotein receptor(LOX-1)in hypertensive rats. Biochem Biophys Res commun, 1997, 237(3):496-8
35. Kosaka H, Yoneyama H, Zhang L et al.Induction of LOX-1 and iNOS expression by isch mia-reperfusion of rat kidney and the opposing effect of L-arginine. FASEB J , 2003,17(6):636-43
36. Tanimoto A, Murata (?) Nomaguchi M et al.Histamine increase the expression of LOX-1 via H2 receptor in human monocytic THP-1 cells. FEBS Lett, 2001,508(3): 345-9
37. Moriwaki H, Kume N, Sawamura T et al. Ligand specificity of LOX-1, a novel Endothelial receptor for oxidized low-density lipoprotein .Atheroscler Thromb Vase Biol, 1998, 18(10):1541-7
38. Oka K, Sawamura T, Kikuta K et al. Lectin-like oxidized low-density receptor-1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci, 1998, 95(16):9535-40
39. Cominacini L, Pasini AF, Garbin U et al. Oxidized low-density lipoprotein (OX-LDL)binding to OX-LDL receptor-1 in endothelial cells induces the activation of NF-KB through an increased of intracellular reactive oxygen species. Biol Chem, 2000, 275(17):12633-8
40. Cominacini L, Rigoni A, Pasini AF et al.The binding of oxidized low-density lipoprotein(OX-LDL)to OX-LDL receptor-1 reduce the intracellular concentration of nitric oxide in endothelial cells through an increased p roduction of superoxide. Biol Chem, 2001,276(17):13750-5
41.Hayashida K, Kume N, Minami M et al. Lectin-like oxidized LDL receptor-1(LOX-1) supports adhesion of mononuclear leukocytes and a monocyte-like cell line THP-1 cells under static and flow conditions. FEBS Lett, 2002, 511(1-3):133-8
42. Kakutani M, Masaki T Sawamura T et al.A platelet-endothelium mediated by lectin-like oxidized low-density lipoprotein receptor-1.PNAS, 2000,97(1): 360-4
43. Cominacini L, Fratta PA, Garbin U et al. The platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells. Am Coll Cardiol, 2003, 41(3):499-507
44. Li D, Singh RM, Liu L, Chen H, Singh BM, Kazz2z N, et al. Oxidized-LDL through LOX-1 increases the expression of angiotens in converting enzyme i n human coronary artery endothelial cells. CardiovascRes,2003, 57(1):238-243
45. Li D, Liu L, Chen H, Sawamura T, Mehta JL. LOX-1, an oxidized LDL Endothelial receptor, inducesC D40/CD40L signaling in human coronary artery endothelial cells.Arterioscler Thromb Vasc Biol,2003, 23(5): 816-821
46. L iD , MehtaJ L.Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol, 2000, 20(4):1116-22
47. Kataoka H, Kume N.Miyamoto S et al. Oxidized LDL modulates Bax-/Bcl-2 through the lectin like OX-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vase Biol, 2001,21(6):955-60
48.Honjo M, Nakamura K, Yamashiro K, et al. Lectin-like oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inflammation. Proc Natl Acad Sci USA , 2003, 100(3):1274-1279
49. Li D, Liu L, Chen H et al. LOX-1 mediates oxidized low-density lipoprotein induced expression of matrix metalloproteinase in human coronary artery endothelial cells. Circulation, 2003, 107(4):612-7
50. Li D, Williams V, Liu L et al. Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction. Am Coll Cardiol, 2003, 41(6):1048-1055
51. Kataoka K, Hasegawa K, Sawamura T et al. LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury. Biochem Biophy Rescommun, 2003,300(3):656-60
52. Ge J, Huang D, Liang C et al. Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 expression contributes to the vein graft atherosclerosis:modulation by losartan. Atherosclerosis, 2004, 177(2): 263-8
53. Puccetti L, Sawamura T, Pasqui AL et al. Atorvastatin reduce platelet-oxidized-LDL receptor expression in hypercholesterolaemic patients. Eur J Clin Invest, 2005,35(1):47-51
54. Wilson SH, Chade AR, Feldstein A et al. Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia. Nephrol Dial Transplant, 2003,18(4):703-9
55. Sugano M, Tsuchida K, Makino N et al. Nifedipine prevents apoptosis of endothelial cells induce by oxidized low-density lipoproteins. Cardiovasc Phamutcol. 2002, 40(1):146-52
56. Zhou MS, Jaimes EA, Raij L. Inhibition of oxidative stress and improvement of endothelial function by amlodipine in angiotensin II-infused rats. Am J, 2004,17(2): 167-171
57. Kobayashi N, Yoshida K, Mita S et al. Betaxolol stimulates eNOS associated with LOX-1 and VEGF in Dahl salt-sensitive rats. Hypertens. 2004, 22(7): 1397-402
58. Chade AR, Best PJ, Rodriguez-Porcel et al. Endothelin-1 receptor blockade Prevents renal injury in experimental hypercholesterolemia. Kidney Int, 2003, 64(3):962-969
59. Mehta JL, Hu B, Chen J et al. Pioglitazone inhibits LOX-1 expression in human coronary artery endothelial cells by reducing intracellular superoxide radical generation. Arterioscler Thromb Vasc Biol, 2003, 23(12):2203-8
60. Chiba Y, Ogita T.Ando K et al. PPARgamm ligands inhibit TNF-Alpha-induced LOX-1 expression in cultured endothelial cells. Biochem Biophys Rescommun, 2001, 286(3):541-6
61. Mehta JL, Chen J , Yu F et al .Aspirin inhibits OX-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res, 2004, 64(2):243-9
62. Thum T, Borlak J. Mechanistic role of cytochrome P450 monooxygenases in oxidized low-density lipoprotein-induced vascular injury:therapy through LOX-1 receptor antagonism? Circ Res,2004,94(1):e1-e13
63. Kobayashi N, Hara K, Tojo A et al. Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK -p90RSK, and Rho-kinase pathway. Hypertension, 2005, 45(4):538-44
64. Park SY, Lee JH, Kim YK et al. Cilostazol prevents remnant lipoprotein particle-induced monocyte adhesion to endothelial cells by suppression of adhesion molecules and monocyte chemoattractant protein-1 expression via lectin-like receptor for oxidized low-density lipoprotein receptor activation. Pharmacol Exp Ther, 2005, 312(3):1241-8
65. Chiba Y, Ando K, Fujida T et al.The protective effects of taurine against renal damage by salt loading in Dahl salt-sensitive rats. Hypertens, 2002, 20 (11):2269-74