摘要
氧化低密度脂蛋白（ox-ldl）通过lox-1作用于内皮细胞、巨噬细胞、血小板、成纤维细胞和平滑肌细胞等多种细胞，在动脉粥样硬化中起着中心作用。lox-1是一种50kDa的跨膜糖蛋白，可作为氧化低密度脂蛋白、修饰脂蛋白、活化血小板和提前糖基化终产物的受体。在内皮细胞中，Ox-LDL通过lox-1，引起白细胞粘附分子增加，激活凋亡途径，增加活性氧种类，导致内皮功能障碍。在血管平滑肌细胞和成纤维细胞中，它们刺激增殖、迁移和胶原合成。在巨噬细胞上表达的LX-1抑制巨噬细胞迁移并刺激泡沫细胞形成。它们还刺激金属蛋白酶的产生，并导致斑块不稳定和血栓形成。调节lox-1的药物是抗动脉粥样硬化的理想靶点。许多自然产生的化合物被证明可以调节lox-1的表达和动脉粥样硬化。目前，新的药物设计技术被用于识别能与lox-1结合并通过ox-ldl抑制其激活的分子。此外，使用RNA干扰和抗lox-1单克隆抗体的技术目前正在临床研究中。
关键词: 氧低密度脂蛋白和氧低密度脂蛋白1，氧低密度脂蛋白1动脉粥样硬化，内皮细胞氧低密度脂蛋白1，氧化应激氧低密度脂蛋白1，氧化低密度脂蛋白，动脉粥样硬化，氧化低密度脂蛋白。
[1]
Parthasarathy, S.; Raghavamenon, A.; Garelnabi, M.O.; Santanam, N. Oxidized low-density lipoprotein. Methods Mol. Biol., 2010, 610, 403-417.
[2]
Yoshimoto, R.; Fujita, Y.; Kakino, A.; Iwamoto, S.; Takaya, T.; Sawamura, T. The discovery of LOX-1, its ligands and clinical significance. Cardiovasc. Drugs Ther., 2011, 25(5), 379-391.
[4]
Williams, K.J.; Tabas, I. The response-to-retention hypothesis of atherogenesis reinforced. Curr. Opin. Lipidol., 1998, 9(5), 471-474.
[5]
Sawamura, T.; Kume, N.; Aoyama, T.; Moriwaki, H.; Hoshikawa, H.; Aiba, Y.; Tanaka, T.; Miwa, S.; Katsura, Y.; Kita, T.; Masaki, T. An endothelial receptor for oxidized low-density lipoprotein. Nature, 1997, 386(6620), 73-77.
[6]
Aoyama, T.; Sawamura, T.; Furutani, Y.; Matsuoka, R.; Yoshida, M.C.; Fujiwara, H.; Masaki, T. Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. Biochem. J., 1999, 339(Pt 1), 177-184.
[7]
Angel, P.; Imagawa, M.; Chiu, R.; Stein, B.; Imbra, R.J.; Rahmsdorf, H.J.; Jonat, C.; Herrlich, P.; Karin, M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell, 1987, 49(6), 729-739.
[9]
Nagase, M.; Abe, J.; Takahashi, K.; Ando, J.; Hirose, S.; Fujita, T. Genomic organization and regulation of expression of the lectin-like oxidized low-density lipoprotein receptor (LOX-1) gene. J. Biol. Chem., 1998, 273(50), 33702-33707.
[10]
Hermonat, P.L.; Zhu, H.; Cao, M.; Mehta, J.L. LOX-1 transcription. Cardiovasc. Drugs Ther., 2011, 25(5), 393-400.
[11]
Sentinelli, F.; Filippi, E.; Fallarino, M.; Romeo, S.; Fanelli, M.; Buzzetti, R.; Berni, A.; Baroni, M. G. The 3′-UTR C>T polymorphism of the oxidized LDL-receptor 1 (OLR1) gene does not associate with coronary artery disease in Italian CAD patients or with the severity of coronary disease. Nutr. Metab. Cardiovasc. Dis., 2006, 16(5), 345-352.
[12]
Mango, R.; Biocca, S.; del Vecchio, F.; Clementi, F.; Sangiuolo, F.; Amati, F.; Filareto, A.; Grelli, S.; Spitalieri, P.; Filesi, I.; Favalli, C.; Lauro, R.; Mehta, J.L.; Romeo, F.; Novelli, G. In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction. Circ. Res., 2005, 97(2), 152-158.
[13]
Biocca, S.; Filesi, I.; Mango, R.; Maggiore, L.; Baldini, F.; Vecchione, L.; Viola, A.; Citro, G.; Federici, G.; Romeo, F.; Novelli, G. The splice variant LOXIN inhibits LOX-1 receptor function through hetero-oligomerization. J. Mol. Cell. Cardiol., 2008, 44(3), 561-570.
[14]
Kurnaz, O.; Aydogan, H.Y.; Isbir, C.S.; Tekeli, A.; Isbir, T. Is LOX-1 K167N polymorphism protective for coronary artery disease? In Vivo, 2009, 23(6), 969-973.
[15]
Pirillo, A.; Norata, G. D.; Catapano, A. L. LOX-1, Ox-
LDL, and atherosclerosis. Mediators Inflamm, 2013, 2013, 25(5), 419-29.
[16]
Xu, S.; Ogura, S.; Chen, J.; Little, P.J.; Moss, J.; Liu, P. LOX-1 in atherosclerosis: biological functions and pharmacological modifiers. Cell. Mol. Life Sci., 2013, 70(16), 2859-2872.
[17]
Matarazzo, S.; Quitadamo, M.C.; Mango, R.; Ciccone, S.; Novelli, G.; Biocca, S. Cholesterol-lowering drugs inhibit lectin-like oxidized low-density lipoprotein-1 receptor function by membrane raft disruption. Mol. Pharmacol., 2012, 82(2), 246-254.
[18]
Li, D.; Mehta, J.L. 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), 2889-2895.
[19]
Chen, J.; Mehta, J.L.; Haider, N.; Zhang, X.; Narula, J.; Li, D. Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells. Circ. Res., 2004, 94(3), 370-376.
[20]
Salvayre, R.; Auge, N.; Benoist, H.; Negre-Salvayre, A. Oxidized low-density lipoprotein-induced apoptosis. Biochim. Biophys. Acta, 2002, 1585(2-3), 213-221.
[21]
Pernow, J.; Shemyakin, A.; Böhm, F. New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus. Life Sci., 2012, 91(13-14), 507-516.
[22]
Li, D.; Singh, R.M.; Liu, L.; Chen, H.; Singh, B.M.; Kazzaz, N.; Mehta, J.L. Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells. Cardiovasc. Res., 2003, 57(1), 238-243.
[23]
Morawietz, H.; Rueckschloss, U.; Niemann, B.; Duerrschmidt, N.; Galle, J.; Hakim, K.; Zerkowski, H.R.; Sawamura, T.; Holtz, J. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation, 1999, 100(9), 899-902.
[24]
Blair, A.; Shaul, P.W.; Yuhanna, I.S.; Conrad, P.A.; Smart, E.J. Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J. Biol. Chem., 1999, 274(45), 32512-32519.
[25]
Ryoo, S.; Bhunia, A.; Chang, F.; Shoukas, A.; Berkowitz, D.E.; Romer, L.H. OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream RhoA signaling. Atheroscler., 2011, 214(2), 279-287.
[26]
Rueckschloss, U.; Galle, J.; Holtz, J.; Zerkowski, H.R.; Morawietz, H. Induction of NAD(P)H oxidase by oxidized low-density lipoprotein in human endothelial cells: antioxidative potential of hydroxymethylglutaryl coenzyme A reductase inhibitor therapy. Circulation, 2001, 104(15), 1767-1772.
[27]
Li, D.; Liu, L.; Chen, H.; Sawamura, T.; Mehta, J.L. LOX-1, an oxidized LDL endothelial receptor, induces CD40/CD40L signaling in human coronary artery endothelial cells. Arterioscler. Thromb. Vasc. Biol., 2003, 23(5), 816-821.
[28]
Li, L.; Renier, G. The oral anti-diabetic agent, gliclazide, inhibits oxidized LDL-mediated LOX-1 expression, metalloproteinase-9 secretion and apoptosis in human aortic endothelial cells. Atheroscler., 2009, 204(1), 40-46.
[29]
Li, D.; Liu, L.; Chen, H.; Sawamura, T.; Ranganathan, S.; Mehta, J.L. LOX-1 mediates oxidized low-density lipoprotein-induced expression of matrix metalloproteinases in human coronary artery endothelial cells. Circulation, 2003, 107(4), 612-617.
[30]
Yang, H.Y.; Bian, Y.F.; Zhang, H.P.; Gao, F.; Xiao, C.S.; Liang, B.; Li, J.; Zhang, N.N.; Yang, Z.M. LOX1 is implicated in oxidized lowdensity lipoproteininduced oxidative stress of macrophages in atherosclerosis. Mol. Med. Rep., 2015, 12(4), 5335-5341.
[31]
Wang, X.; Ding, Z.; Lin, J.; Guo, Z.; Mehta, J.L. LOX-1 in macrophage migration in response to ox-LDL and the involvement of calpains. Biochem. Biophys. Res. Commun., 2015, 467(1), 135-139.
[32]
Eto, H.; Miyata, M.; Kume, N.; Minami, M.; Itabe, H.; Orihara, K.; Hamasaki, S.; Biro, S.; Otsuji, Y.; Kita, T.; Tei, C. Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury. Biochem. Biophys. Res. Commun., 2006, 341(2), 591-598.
[33]
Zhang, Y.; Chen, B.; Ming, L.; Qin, H.; Zheng, L.; Yue, Z.; Cheng, Z.; Wang, Y.; Zhang, D.; Liu, C.; Bin, W.; Hao, Q.; Song, F.; Ji, B. MicroRNA-141 inhibits vascular smooth muscle cell proliferation through targeting PAPP-A. Int. J. Clin. Exp. Pathol., 2015, 8(11), 14401-14408.
[34]
Goyal, T.; Mitra, S.; Khaidakov, M.; Wang, X.; Singla, S.; Ding, Z.; Liu, S.; Mehta, J.L. Current concepts of the role of oxidized LDL receptors in atherosclerosis. Curr. Atheroscler. Rep., 2012.
[35]
Kataoka, H.; Kume, N.; Miyamoto, S.; Minami, M.; Morimoto, M.; Hayashida, K.; Hashimoto, N.; Kita, T. Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 2001, 21(6), 955-960.
[36]
Yang, H.; Mohamed, A.S.; Zhou, S.H. Oxidized low density lipoprotein, stem cells, and atherosclerosis. Lipids Health Dis., 2012, 11, 85.
[37]
Hu, C.; Dandapat, A.; Sun, L.; Chen, J.; Marwali, M.R.; Romeo, F.; Sawamura, T.; Mehta, J.L. LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet. Cardiovasc. Res., 2008, 79(2), 287-293.
[38]
Hu, C.; Dandapat, A.; Sun, L.; Khan, J.A.; Liu, Y.; Hermonat, P.L.; Mehta, J.L. Regulation of TGFbeta1-mediated collagen formation by LOX-1: studies based on forced overexpression of TGFbeta1 in wild-type and lox-1 knock-out mouse cardiac fibroblasts. J. Biol. Chem., 2008, 283(16), 10226-10231.
[39]
Chen, M.; Kakutani, M.; Naruko, T.; Ueda, M.; Narumiya, S.; Masaki, T.; Sawamura, T. Activation-dependent surface expression of LOX-1 in human platelets. Biochem. Biophys. Res. Commun., 2001, 282(1), 153-158.
[40]
Marwali, M.R.; Hu, C.P.; Mohandas, B.; Dandapat, A.; Deonikar, P.; Chen, J.; Cawich, I.; Sawamura, T.; Kavdia, M.; Mehta, J.L. Modulation of ADP-induced platelet activation by aspirin and pravastatin: role of lectin-like oxidized low-density lipoprotein receptor-1, nitric oxide, oxidative stress, and inside-out integrin signaling. J. Pharmacol. Exp. Ther., 2007, 322(3), 1324-1332.
[41]
Sakurai, K.; Cominacini, L.; Garbin, U.; Fratta Pasini, A.; Sasaki, N.; Takuwa, Y.; Masaki, T.; Sawamura, T. Induction of endothelin-1 production in endothelial cells via co-operative action between CD40 and lectin-like oxidized LDL receptor (LOX-1). J. Cardiovasc. Pharmacol., 2004, 44(Suppl. 1), S173-S180.
[42]
Yang, S.H.; Li, Y.T.; Du, D.Y. Oxidized low-density lipoprotein-induced CD147 expression and its inhibition by high-density lipoprotein on platelets in vitro. Thromb. Res., 2013, 132(6), 702-711.
[43]
Yavuzer, S.; Yavuzer, H.; Cengiz, M.; Erman, H.; Altıparmak, M.R.; Korkmazer, B.; Balci, H.; Simsek, G.; Yaldıran, A.L.; Karter, Y.; Uzun, H. Endothelial damage in white coat hypertension: role of lectin-like oxidized low-density lipoprotein-1. J. Hum. Hypertens., 2015, 29(2), 92-98.
[44]
Takanabe-Mori, R.; Ono, K.; Wada, H.; Takaya, T.; Ura, S.; Yamakage, H.; Satoh-Asahara, N.; Shimatsu, A.; Takahashi, Y.; Fujita, M.; Fujita, Y.; Sawamura, T.; Hasegawa, K. Lectin-like oxidized low-density lipoprotein receptor-1 plays an important role in vascular inflammation in current smokers. J. Atheroscler. Thromb., 2013, 20(6), 585-590.
[45]
Tan, K.C.B.; Shiu, S.W.M.; Wong, Y.; Leng, L.; Bucala, R. Soluble lectin-like oxidized low density lipoprotein receptor-1 in type 2 diabetes mellitus. J. Lipid Res., 2008, 49(7), 1438-1444.
[46]
Civelek, S.; Kutnu, M.; Uzun, H.; Erdenen, F.; Altunoglu, E.; Andican, G.; Seven, A.; Sahin, A.O.; Burcak, G. Soluble lectin-like oxidized LDL receptor 1 as a possible mediator of endothelial dysfunction in patients with metabolic syndrome. J. Clin. Lab. Anal., 2015, 29(3), 184-190.
[47]
Hayashida, K.; Kume, N.; Murase, T.; Minami, M.; Nakagawa, D.; Inada, T.; Tanaka, M.; Ueda, A.; Kominami, G.; Kambara, H.; Kimura, T.; Kita, T. 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), 812-818.
[48]
Misaka, T.; Suzuki, S.; Sakamoto, N.; Yamaki, T.; Sugimoto, K.; Kunii, H.; Nakazato, K.; Saitoh, S.; Sawamura, T.; Ishibashi, T.; Takeishi, Y. Significance of soluble lectin-like oxidized LDL receptor-1 levels in systemic and coronary circulation in acute coronary syndrome. BioMed Res. Int., 2014, 2014, 649185.
[49]
Balin, M.; Celik, A.; Kobat, M.A.; Baydas, A. Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels predict percutaneous coronary intervention-related periprocedural myocardial infarction in stable patients undergoing elective native single-vessel PCI. J. Thromb. Thrombolysis, 2012, 34(4), 483-490.
[50]
Ou, H.; Lee, W.; Lee, I.; Chiu, T.; Tsai, K.; Lin, C.; Sheu, W.H. Ginkgo biloba extract attenuates ox-LDL-induced oxidative functional damages in endothelial cells. J. Appl. Physiol., 2009, 106, 1674-1685.
[51]
Kang, B.Y.; Khan, J.A.; Ryu, S.; Shekhar, R.; Seung, K.B.; Mehta, J.L. Curcumin reduces angiotensin II-mediated cardiomyocyte growth via LOX-1 inhibition. J. Cardiovasc. Pharmacol., 2010, 55(2), 176-183.
[52]
Wang, G.F.; Shi, C.G.; Sun, M.Z.; Wang, L.; Wu, S.X.; Wang, H.F.; Xu, Z.Q.; Chen, D.M. Tetramethylpyrazine attenuates atherosclerosis development and protects endothelial cells from ox-LDL. Cardiovasc. Drugs Ther., 2013, 27(3), 199-210.
[53]
Lee, W.J.; Ou, H.C.; Hsu, W.C.; Chou, M.M.; Tseng, J.J.; Hsu, S.L.; Tsai, K.L.; Sheu, W.H. Ellagic acid inhibits oxidized LDL-mediated LOX-1 expression, ROS generation, and inflammation in human endothelial cells. J. Vasc. Surg., 2010, 52(5), 1290-1300.
[54]
Mollace, V.; Ragusa, S.; Sacco, I.; Muscoli, C.; Sculco, F.; Visalli, V.; Palma, E.; Muscoli, S.; Mondello, L.; Dugo, P.; Rotiroti, D.; Romeo, F. The protective effect of bergamot oil extract on lecitine-like oxy-LDL receptor-1 expression in balloon injury-related neointima formation. J. Cardiovasc. Pharmacol. Ther., 2008, 13(2), 120-129.
[55]
Zeya, B.; Arjuman, A.; Chandra, N.C. Lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX-1): a chameleon receptor for oxidized LDL. Biochem., 2016, 55(32), 4437-4444.
[56]
Nishizuka, T.; Fujita, Y.; Sato, Y.; Nakano, A.; Kakino, A.; Ohshima, S.; Kanda, T.; Yoshimoto, R.; Sawamura, T. Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci., 2011, 87(3), 104-113.
[57]
Mehta, J.L.; Chen, J.; Yu, F.; Li, D.Y. Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc. Res., 2004, 64(2), 243-249.
[58]
Li, D.; Chen, H.; Romeo, F.; Sawamura, T.; Saldeen, T.; Mehta, J.L. Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells: role of LOX-1. J. Pharmacol. Exp. Ther., 2002, 302(2), 601-605.
[59]
Falconi, M.; Ciccone, S.; D’Arrigo, P.; Viani, F.; Sorge, R.; Novelli, G.; Patrizi, P.; Desideri, A.; Biocca, S. Design of a novel LOX-1 receptor antagonist mimicking the natural substrate. Biochem. Biophys. Res. Commun., 2013, 438(2), 340-345.
[60]
Thakkar, S.; Wang, X.; Khaidakov, M.; Dai, Y.; Gokulan, K.; Mehta, J.L.; Varughese, K.I. Structure-based design targeted at LOX-1, a receptor for oxidized low-density lipoprotein. Sci. Rep., 2015, 5, 16740.
[61]
Ding, Z.; Wang, X.; Khaidakov, M.; Liu, S.; Mehta, J.L. MicroRNA hsa-let-7g targets lectin-like oxidized low-density lipoprotein receptor-1 expression and inhibits apoptosis in human smooth muscle cells. Exp. Biol. Med. (Maywood), 2012, 237(9), 1093-1100.
[62]
Amati, F.; Diano, L.; Vecchione, L.; Norata, G.D.; Koyama, Y.; Cutuli, L.; Catapano, A.L.; Romeo, F.; Ando, H.; Novelli, G. LOX-1 inhibition in ApoE KO mice using a schizophyllan-based antisense oligonucleotide therapy. Mol. Ther. Nucleic Acids, 2012, 1, e58.
[63]
Sugimoto, K.; Ishibashi, T.; Sawamura, T.; Inoue, N.; Kamioka, M.; Uekita, H.; Ohkawara, H.; Sakamoto, T.; Sakamoto, N.; Okamoto, Y.; Takuwa, Y.; Kakino, A.; Fujita, Y.; Tanaka, T.; Teramoto, T.; Maruyama, Y.; Takeishi, Y. LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. Cardiovasc. Res., 2009, 84(1), 127-136.
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