Role of Ox-LDL and LOX-1 in Atherogenesis

Author(s): Ajoe John Kattoor, Sri Harsha Kanuri, Jawahar L. Mehta*

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 9 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


Oxidized LDL (ox-LDL) plays a central role in atherosclerosis by acting on multiple cells such as endothelial cells, macrophages, platelets, fibroblasts and smooth muscle cells through LOX-1. LOX-1 is a 50 kDa transmembrane glycoprotein that serves as receptor for ox-LDL, modified lipoproteins, activated platelets and advance glycation end-products. Ox- LDL through LOX-1, in endothelial cells, causes increase in leukocyte adhesion molecules, activates pathways of apoptosis, increases reactive oxygen species and cause endothelial dysfunction. In vascular smooth muscle cells and fibroblasts, they stimulate proliferation, migration and collagen synthesis. LOX-1 expressed on macrophages inhibit macrophage migration and stimulate foam cell formation. They also stimulate generation of metalloproteinases and contribute to plaque instability and thrombosis. Drugs that modulate LOX-1 are desirable targets against atherosclerosis. Many naturally occurring compounds have been shown to modulate LOX-1 expression and atherosclerosis. Currently, novel drug design techniques are used to identify molecules that can bind to LOX-1 and inhibit its activation by ox-LDL. In addition, techniques using RNA interference and monoclonal antibody against LOX-1 are currently being investigated for clinical use.

Keywords: Ox-LDL and LOX-1, LOX-1 atherosclerosis, Endothelial cells LOX-1, oxidative stress LOX-1, Oxidized LDL, atherogenesis, oxidized LDL.

Parthasarathy, S.; Raghavamenon, A.; Garelnabi, M.O.; Santanam, N. Oxidized low-density lipoprotein. Methods Mol. Biol., 2010, 610, 403-417.
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.
Ross, R. Atherosclerosis--an inflammatory disease. N. Engl. J. Med., 1999, 340(2), 115-126.
Williams, K.J.; Tabas, I. The response-to-retention hypothesis of atherogenesis reinforced. Curr. Opin. Lipidol., 1998, 9(5), 471-474.
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.
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.
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.
Curran, T.; Franza, B.R., Jr Fos and Jun: the AP-1 connection. Cell, 1988, 55(3), 395-397.
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.
Hermonat, P.L.; Zhu, H.; Cao, M.; Mehta, J.L. LOX-1 transcription. Cardiovasc. Drugs Ther., 2011, 25(5), 393-400.
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.
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.
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.
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.
Pirillo, A.; Norata, G. D.; Catapano, A. L. LOX-1, Ox- LDL, and atherosclerosis. Mediators Inflamm, 2013, 2013, 25(5), 419-29.
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.
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.
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.
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.
Salvayre, R.; Auge, N.; Benoist, H.; Negre-Salvayre, A. Oxidized low-density lipoprotein-induced apoptosis. Biochim. Biophys. Acta, 2002, 1585(2-3), 213-221.
Pernow, J.; Shemyakin, A.; Böhm, F. New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus. Life Sci., 2012, 91(13-14), 507-516.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Yang, H.; Mohamed, A.S.; Zhou, S.H. Oxidized low density lipoprotein, stem cells, and atherosclerosis. Lipids Health Dis., 2012, 11, 85.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pothineni, N.V.K.; Karathanasis, S.K.; Ding, Z.; Arulandu, A.; Varughese, K.I.; Mehta, J.L. LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation. J. Am. Coll. Cardiol., 2017, 69(22), 2759-2768.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [1693 - 1700]
Pages: 8
DOI: 10.2174/0929867325666180508100950

Article Metrics

PDF: 80
HTML: 19