Ligand Specificity of LOX-1, a Novel Endothelial Receptor for Oxidized Low Density Lipoprotein

From the Departments of Geriatric Medicine (H.M., N.K., H.O., E.N., T.K.) and Pharmacology (T.S., T.A., H.H., T.M.), Graduate School of Medicine, Kyoto University, Japan.

Correspondence to Noriaki Kume, MD, PhD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-01, Japan. E-mail nkume{at}Kuhp.Kyoto-u.ac.jp

Abstract—Endothelial dysfunction, or activation, elicited by oxidized low density lipoprotein (Ox-LDL) and its lipid constituents has been shown to play a key role in the pathogenesis of atherosclerosis. We recently have identified a novel receptor for Ox-LDL-designated lectin-like Ox-LDL receptor (LOX-1) in vascular endothelial cells. To examine ligand specificity of LOX-1, we established CHO cell lines stably expressing both human and bovine LOX-1 (LOX-1-CHO). LOX-1-CHO bound and degraded¹²⁵I-labeled Ox-LDL but did not significantly degrade ¹²⁵I-labeled acetylated LDL (Ac-LDL). Fucoidin and maleylated BSA (M-BSA), which inhibit¹²⁵I-Ox-LDL binding to class A scavenger receptors, did not inhibit ¹²⁵I-Ox-LDL binding or degradation in LOX-1-CHO. Polyinosinic acid and carrageenan, in contrast, significantly reduced ¹²⁵I-Ox-LDL binding to LOX-1-CHO by 62% and 60%, respectively. Delipidated and untreated ¹²⁵I-Ox-LDL were bound and degraded equally in LOX-1-CHO; furthermore, excess amounts of unlabeled, delipidated Ox-LDL inhibited binding and degradation of untreated ¹²⁵I-Ox-LDL. Taken together, LOX-1 is a receptor for Ox-LDL but not for Ac-LDL. LOX-1 recognizes protein moiety of Ox-LDL, and its ligand specificity is distinct from other receptors for Ox-LDL, including class A and B scavenger receptors.

Key Words: endothelial cell • LOX-1 • oxidized LDL • atherosclerosis

This article has been cited by other articles:

				H. H. Shih, S. Zhang, W. Cao, A. Hahn, J. Wang, J. E. Paulsen, and D. C. Harnish CRP is a novel ligand for the oxidized LDL receptor LOX-1 Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1643 - H1650. [Abstract] [Full Text] [PDF]

				M Ethier-Chiasson, J-C Forest, Y Giguere, A Masse, C Marseille-Tremblay, E Levy, and J Lafond Modulation of placental protein expression of OLR1: implication in pregnancy-related disorders or pathologies Reproduction, October 1, 2008; 136(4): 491 - 502. [Abstract] [Full Text] [PDF]

				H. Satoh, E. Kiyota, Y. Terasaki, T. Sawamura, K. Takagi, H. Mizuta, and M. Takeya Expression and Localization of Lectin-like Oxidized Low-density Lipoprotein Receptor-1 (LOX-1) in Murine and Human Placentas J. Histochem. Cytochem., August 1, 2008; 56(8): 773 - 784. [Abstract] [Full Text] [PDF]

				T. Thum and J. Borlak LOX-1 Receptor Blockade Abrogates oxLDL-induced Oxidative DNA Damage and Prevents Activation of the Transcriptional Repressor Oct-1 in Human Coronary Arterial Endothelium J. Biol. Chem., July 11, 2008; 283(28): 19456 - 19464. [Abstract] [Full Text] [PDF]

				M. R. Marwali, C.-P. Hu, B. Mohandas, A. Dandapat, P. Deonikar, J. Chen, I. Cawich, T. Sawamura, M. Kavdia, and J. L. Mehta 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., September 1, 2007; 322(3): 1324 - 1332. [Abstract] [Full Text] [PDF]

				J. L. Mehta, N. Sanada, C. P. Hu, J. Chen, A. Dandapat, F. Sugawara, H. Satoh, K. Inoue, Y. Kawase, K.-i. Jishage, et al. Deletion of LOX-1 Reduces Atherogenesis in LDLR Knockout Mice Fed High Cholesterol Diet Circ. Res., June 8, 2007; 100(11): 1634 - 1642. [Abstract] [Full Text] [PDF]

				M. Kamei, K. Yoneda, N. Kume, M. Suzuki, H. Itabe, K.-i. Matsuda, T. Shimaoka, M. Minami, S. Yonehara, T. Kita, et al. Scavenger Receptors for Oxidized Lipoprotein in Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1801 - 1807. [Abstract] [Full Text] [PDF]

				A. M. Aslanian and I. F. Charo Targeted Disruption of the Scavenger Receptor and Chemokine CXCL16 Accelerates Atherosclerosis Circulation, August 8, 2006; 114(6): 583 - 590. [Abstract] [Full Text] [PDF]

				J. L. Mehta, J. Chen, P. L. Hermonat, F. Romeo, and G. Novelli Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): A critical player in the development of atherosclerosis and related disorders Cardiovasc Res, January 1, 2006; 69(1): 36 - 45. [Abstract] [Full Text] [PDF]

				F. Bruni, A. L. Pasqui, M. Pastorelli, G. Bova, M. Cercignani, A. Palazzuoli, T. Sawamura, A. Auteri, and L. Puccetti Different Effect of Statins on Platelet Oxidized-LDLReceptor (CD36 and LOX-1) Expressionin Hypercholesterolemic Subjects Clinical and Applied Thrombosis/Hemostasis, October 1, 2005; 11(4): 417 - 428. [Abstract] [PDF]

				K. Nakajou, S. Horiuchi, M. Sakai, K. Hirata, M. Tanaka, M. Takeya, T. Kai, and M. Otagiri CD36 Is Not Involved in Scavenger Receptor-Mediated Endocytic Uptake of Glycolaldehyde- and Methylglyoxal-Modified Proteins by Liver Endothelial Cells J. Biochem., May 1, 2005; 137(5): 607 - 616. [Abstract] [Full Text] [PDF]

				H. Park, F. G. Adsit, and J. C. Boyington The 1.4 A Crystal Structure of the Human Oxidized Low Density Lipoprotein Receptor Lox-1 J. Biol. Chem., April 8, 2005; 280(14): 13593 - 13599. [Abstract] [Full Text] [PDF]

				S. Y. Park, J. H. Lee, Y. K. Kim, C. D. Kim, B. Y. Rhim, W. S. Lee, and K. W. Hong 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 J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 1241 - 1248. [Abstract] [Full Text] [PDF]

				D. R. Greaves and S. Gordon Thematic review series: The Immune System and Atherogenesis. Recent insights into the biology of macrophage scavenger receptors J. Lipid Res., January 1, 2005; 46(1): 11 - 20. [Abstract] [Full Text] [PDF]

				L. Pavan, A. Hermouet, V. Tsatsaris, P. Therond, T. Sawamura, D. Evain-Brion, and T. Fournier Lipids from Oxidized Low-Density Lipoprotein Modulate Human Trophoblast Invasion: Involvement of Nuclear Liver X Receptors Endocrinology, October 1, 2004; 145(10): 4583 - 4591. [Abstract] [Full Text] [PDF]

				I. V. Smirnova, M. Kajstura, T. Sawamura, and M. S. Goligorsky Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H782 - H790. [Abstract] [Full Text] [PDF]

				I. V. Smirnova, T. Sawamura, and M. S. Goligorsky Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency Am J Physiol Renal Physiol, July 1, 2004; 287(1): F25 - F32. [Abstract] [Full Text] [PDF]

				N. Kume and T. Kita Apoptosis of Vascular Cells by Oxidized LDL: Involvement of Caspases and LOX-1 and Its Implication in Atherosclerotic Plaque Rupture Circ. Res., February 20, 2004; 94(3): 269 - 270. [Full Text] [PDF]

				T. Thum and J. Borlak Mechanistic Role of Cytochrome P450 Monooxygenases in Oxidized Low-Density Lipoprotein-Induced Vascular Injury: Therapy Through LOX-1 Receptor Antagonism? Circ. Res., January 9, 2004; 94 (1): e1 - e13. [Abstract] [Full Text] [PDF]

				J. B. Sedgwick, Y. S. Hwang, H. A. Gerbyshak, H. Kita, and W. W. Busse Oxidized Low-Density Lipoprotein Activates Migration and Degranulation of Human Granulocytes Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 702 - 709. [Abstract] [Full Text] [PDF]

				N. Bruneau, S. Richard, F. Silvy, A. Verine, and D. Lombardo Lectin-like Ox-LDL Receptor Is Expressed in Human INT-407 Intestinal Cells: Involvement in the Transcytosis of Pancreatic Bile Salt-dependent Lipase Mol. Biol. Cell, July 1, 2003; 14(7): 2861 - 2875. [Abstract] [Full Text] [PDF]

				V. V. Kunjathoor, M. Febbraio, E. A. Podrez, K. J. Moore, L. Andersson, S. Koehn, J. S. Rhee, R. Silverstein, H. F. Hoff, and M. W. Freeman Scavenger Receptors Class A-I/II and CD36 Are the Principal Receptors Responsible for the Uptake of Modified Low Density Lipoprotein Leading to Lipid Loading in Macrophages J. Biol. Chem., December 13, 2002; 277(51): 49982 - 49988. [Abstract] [Full Text] [PDF]

				J. L. Mehta and D. Li Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor J. Am. Coll. Cardiol., May 1, 2002; 39(9): 1429 - 1435. [Abstract] [Full Text] [PDF]

				H. Kataoka, N. Kume, S. Miyamoto, M. Minami, M. Morimoto, K. Hayashida, N. Hashimoto, and T. Kita Oxidized LDL Modulates Bax/Bcl-2 Through the Lectinlike Ox-LDL Receptor-1 in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 955 - 960. [Abstract] [Full Text] [PDF]

				M. Kapinsky, M. Torzewski, C. Buchler, C. Q. Duong, G. Rothe, and G. Schmitz Enzymatically Degraded LDL Preferentially Binds to CD14high CD16+ Monocytes and Induces Foam Cell Formation Mediated Only in Part by the Class B Scavenger-Receptor CD36 Arterioscler. Thromb. Vasc. Biol., June 1, 2001; 21(6): 1004 - 1010. [Abstract] [Full Text] [PDF]

				T. Shimaoka, N. Kume, M. Minami, K. Hayashida, T. Sawamura, T. Kita, and S. Yonehara LOX-1 Supports Adhesion of Gram-Positive and Gram-Negative Bacteria J. Immunol., April 15, 2001; 166(8): 5108 - 5114. [Abstract] [Full Text] [PDF]

				I. Spyridopoulos, J. Wischhusen, B. Rabenstein, P. Mayer, D. I. Axel, K.-U. Frohlich, and K. R. Karsch Alcohol Enhances Oxysterol-Induced Apoptosis in Human Endothelial Cells by a Calcium-Dependent Mechanism Arterioscler. Thromb. Vasc. Biol., March 1, 2001; 21(3): 439 - 444. [Abstract] [Full Text] [PDF]

				X Shi, S Niimi, T Ohtani, and S Machida Characterization of residues and sequences of the carbohydrate recognition domain required for cell surface localization and ligand binding of human lectin-like oxidized LDL receptor J. Cell Sci., January 4, 2001; 114(7): 1273 - 1282. [Abstract] [PDF]

				V. Terpstra, E. S. van Amersfoort, A. G. van Velzen, J. Kuiper, and T. J. C. van Berkel Hepatic and Extrahepatic Scavenger Receptors : Function in Relation to Disease Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1860 - 1872. [Full Text] [PDF]

				L. Cominacini, A. F. Pasini, U. Garbin, A. Davoli, M. L. Tosetti, M. Campagnola, A. Rigoni, A. M. Pastorino, V. Lo Cascio, and T. Sawamura Oxidized Low Density Lipoprotein (ox-LDL) Binding to ox-LDL Receptor-1 in Endothelial Cells Induces the Activation of NF-kappa B through an Increased Production of Intracellular Reactive Oxygen Species J. Biol. Chem., April 21, 2000; 275(17): 12633 - 12638. [Abstract] [Full Text] [PDF]

				J. A. Cornicelli, D. Butteiger, D. L. Rateri, K. Welch, and A. Daugherty Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages J. Lipid Res., March 1, 2000; 41(3): 376 - 383. [Abstract] [Full Text]

				T. Murase, N. Kume, H. Kataoka, M. Minami, T. Sawamura, T. Masaki, and T. Kita Identification of Soluble Forms of Lectin-Like Oxidized LDL Receptor-1 Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 715 - 720. [Abstract] [Full Text] [PDF]

				H. Kataoka, N. Kume, S. Miyamoto, M. Minami, T. Murase, T. Sawamura, T. Masaki, N. Hashimoto, and T. Kita Biosynthesis and Post-translational Processing of Lectin-like Oxidized Low Density Lipoprotein Receptor-1 (LOX-1). N-LINKED GLYCOSYLATION AFFECTS CELL-SURFACE EXPRESSION AND LIGAND BINDING J. Biol. Chem., February 25, 2000; 275(9): 6573 - 6579. [Abstract] [Full Text] [PDF]

				S. Parthasarathy, N. Santanam, S. Ramachandran, and O. Meilhac Oxidants and antioxidants in atherogenesis: an appraisal J. Lipid Res., December 1, 1999; 40(12): 2143 - 2157. [Abstract] [Full Text] [PDF]

				A. M Dart and J. P.F Chin-Dusting Lipids and the endothelium Cardiovasc Res, August 1, 1999; 43(2): 308 - 322. [Abstract] [Full Text] [PDF]

				H. Kataoka, N. Kume, S. Miyamoto, M. Minami, H. Moriwaki, T. Murase, T. Sawamura, T. Masaki, N. Hashimoto, and T. Kita Expression of Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 in Human Atherosclerotic Lesions Circulation, June 22, 1999; 99(24): 3110 - 3117. [Abstract] [Full Text] [PDF]

				T. Kita LOX-1, a Possible Clue to the Missing Link Between Hypertension and Atherogenesis Circ. Res., May 14, 1999; 84(9): 1113 - 1115. [Full Text] [PDF]

				T. Shimaoka, N. Kume, M. Minami, K. Hayashida, H. Kataoka, T. Kita, and S. Yonehara Molecular Cloning of a Novel Scavenger Receptor for Oxidized Low Density Lipoprotein, SR-PSOX, on Macrophages J. Biol. Chem., December 22, 2000; 275(52): 40663 - 40666. [Abstract] [Full Text] [PDF]