Identification, Regulation and Function of Lox-1, a Novel Receptor for Ox-Ldl

  • Jacob Joseph
  • Dayuan Li
  • Hongjiang Chen
  • Jawahar L. Mehta
Part of the Progress in Experimental Cardiology book series (PREC, volume 8)


Oxidatively modified low-density lipoprotein (ox-LDL) causes endothelial activa-tion, dysfunction and injury, which are considered primary steps in atherogenesis. Recently, a novel lectin-like receptor for ox-LDL (LOX-1) has been identified, primarily in endothe-lial cells. This receptor mediates uptake of ox-LDL into the endothelial cells and activates a variety of signal transduction mechanisms that lead to endothelial cell activation and expres-sion of adhesion molecules. LOX-1 receptor is transcriptionally upregulated by various stimuli accompanying pathogenic states, including TNF-OC, angiotensin II, shear stress and ox-LDL itself. LOX-1 receptor expression has been demonstrated in animal models and humans with hypertension, diabetes mellitus and atherosclerosis. Expression of this receptor may also be pathogenically involved in arterial thrombosis and myocardial ischemia-reperfusion injury. Understanding the regulation and signal transduction pathways of this receptor may lead to new therapies in prevention and treatment of atherosclerosis, and its complications.

Key words

Atherosclerosis Diabetes mellitus Hypertension Oxidized-low-density lipopro-tein Renin-angiotensin-system 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Freeman MW 1997. Scavenger receptors in atherosclerosis, Curr Opin Hematol 4:41–47.PubMedCrossRefGoogle Scholar
  2. 2.
    Steinbrecher UP. 1999. Receptors for oxidized low density lipoprotein. Biochem Biophys Acta 1436:279–298.PubMedCrossRefGoogle Scholar
  3. 3.
    Ross R. 1993.The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809.PubMedCrossRefGoogle Scholar
  4. 4.
    Kume N, Cybulsky MI, Gimbrone MA Jr. 1992. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest 90:1138–1144.PubMedCrossRefGoogle Scholar
  5. 5.
    Kume N, Gimbrone MA Jr. 1994. Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. J Clin Invest 93:907–911.PubMedCrossRefGoogle Scholar
  6. 6.
    Zembowicz A, Tang JL, Wu KK. 1995. Transcriptional induction of endothelial nitric oxide synthase type III by lysophosphatidylcholine. J Biol Chem 270:17006–17010.PubMedCrossRefGoogle Scholar
  7. 7.
    Hirata K, Miki N, Kuroda Y, Sakoda T, Kawashima S, Yokoyama M. 1995. Low concentration of oxidized low-density lipoprotein and lysophosphatidylcholine upregulate constitutive nitric oxide synthase mRNA expression in bovine aortic endothelial cells. Circ Res 76:958–962.PubMedCrossRefGoogle Scholar
  8. 8.
    Zembowicz A, Jones SL, Wu KK. 1995. Induction of cyclooxygenase-2 in human umbilical vein endothelial cells by lysophosphatidylcholine. J Clin Invest 96:1688–1692.PubMedCrossRefGoogle Scholar
  9. 9.
    Li DY, Yang BC, Mehta JL. 1998. Ox-LDL enhances anoxia-reoxygenation-mediated apoptosis in human coronary endothelial cells: Role of PKC, PTK, Bcl-2 and Fas. Am J Physiol 275:H568–H576.PubMedGoogle Scholar
  10. 10.
    Bickel PE, Freeman M. 1992. Rabbit aortic smooth muscle cells express inducible macrophage scav-enger receptor messenger RNA that is absent from endothelial cells. J Clin Invest 90:1450–1457.PubMedCrossRefGoogle Scholar
  11. 11.
    Kume N, Arai H, Kawai C, Kita T. 1991. Receptors for modified low-density lipoproteins in human endothelials cells: different recognition for acetylated low-density lipoprotein and oxidized low-density lipoprotein. Biochem Biophys Acta 1091:63–67.PubMedCrossRefGoogle Scholar
  12. 12.
    van Berkel TJC, De Rijke YB, Kruijt JK. 1991. Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. J Biol Chem 266:2282–2289.PubMedGoogle Scholar
  13. 13.
    De Rijke YB, van Berkel TJC. 1994. Rat liver Kupffer and endothelial cells express different binding proteins for modified low density lipoproteins. J Biol Chem 269:824–827.PubMedGoogle Scholar
  14. 14.
    Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y,Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. 1997. An endothelial receptor for oxidized low-density lipoprotein. Nature 386:73–77.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen M, Kakutani M, Minami M, Kataoka H, Kume N, Narumiya S, Kita T, Masaki T, Sawamura T. 2000. Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol 20:1107–1115.PubMedCrossRefGoogle Scholar
  16. 16.
    Mehta JL, Li DY. 1998. Identification and autoregulation of receptor for OX-LDL in cultured human coronary artery endothelial cells. Biochem Biophys Res Commun 248:511–514.PubMedCrossRefGoogle Scholar
  17. 17.
    Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL. 1999. Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res 84:1043–1049.PubMedCrossRefGoogle Scholar
  18. 18.
    Nagase M, Hirose S, Sawamura T, Masaki T, Fujita T. 1997. Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats. Biochem Biophys Res Commun 237:496–498.PubMedCrossRefGoogle Scholar
  19. 19.
    Chen M, Kakutani M, Naruko T, Ueda M, Narumiya S, Masaki T, Sawamura T. 2001. Activation-dependent surface expression of LOX-1 in human platelets. Biochem Biophys Res Commun Mar 23;282:153–158CrossRefGoogle Scholar
  20. 20.
    Kataoka H, Kume N, Miyamoto S, Minami M, Morimoto M, Hayashida K, Hashimoto N, Kita T. 2001. Oxidized LDL modulates Bax/Bcl-2 through the lectin-like Ox-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21:955–960PubMedCrossRefGoogle Scholar
  21. 21.
    Yoshida H, Kondratenko N, Green S, Steinberg D, Quehenberger O. 1998. Identification of the lectin-like receptor of oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor. Biochem J 334:9–13.PubMedGoogle Scholar
  22. 22.
    Moriwaki H, Kume N, Sawamura T, Aoyama T, Hoshikawa H, Ochi H, Nishi E, Masaki T, Kita T. 1998. Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipopro-tein. Arterioscler Thromb Vasc Biol 18:1541–1547.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen M, Inoue K, Narumiya S, Masaki T, Sawamura T. 2001. Requirements of basic amino acid residues within the lectin-like domain of LOX-1 for the binding of oxidized low-density lipopro-tein. FEBS Lett 499:215–219.PubMedCrossRefGoogle Scholar
  24. 24.
    Aoyama T, Fujiwara H, Masaki T, Sawamura T. 1999. Induction of lectin-like oxidized LDL recep-tor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells. J Mol Cell Cardiol 31:2101–2114.PubMedCrossRefGoogle Scholar
  25. 25.
    Tipping PG, Hancock WW. 1993. Production of tumor necrosis factor and interleukin-1 by macrophages from human atheromatous plaques. Am J Pathol 142:1721–1728.PubMedGoogle Scholar
  26. 26.
    Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. 1990. Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected by in situ hybridization. Am J Pathol 137:503–509.PubMedGoogle Scholar
  27. 27.
    Lee RT, Libby P. 1997. The unstable atheroma. Arterioscler Thromb Vasc Biol 17:1859–1867.PubMedCrossRefGoogle Scholar
  28. 28.
    Kume N, Murase T, Moriwaki H, Aoyama T, Sawamura T, Masaki T, Kita T. 1998. Inducible expres-sion of lectin-like oxidized LDL receptor-1 in vascular endothelial cells. Circ Res 83:322–327.PubMedCrossRefGoogle Scholar
  29. 29.
    Pitas RE. 1990. Expression of the acetylated low density lipoprotein receptor by rabbit fibroblasts and smooth muscle cells: up-regulation by phorbol esters. J Biol Chem 265:12722–12727.PubMedGoogle Scholar
  30. 30.
    Li H, Freeman MW, Libby P. 1995. Regulation of smooth muscle scavenger receptor expression in vivo by atherogenic diets and in vitro by cytokines. J Clin Invest 95:122–133.PubMedCrossRefGoogle Scholar
  31. 31.
    Hsu HY, Nicholson AC, Hajjar DP. 1996. Inhibition of macrophage scavenger activity by tumor necrosis factor-OC is transcriptionally an post-transcriptionally regulated. J Biol Chem 271:7767–7773.PubMedCrossRefGoogle Scholar
  32. 32.
    Murase T, Kume N, Korenaga R, Ando J, Sawamura T, Masaki T, Kita T. 1998. Fluid shear stress transcriptionally induces lectin-like oxidized LDL receptor-1 in vascular endothelial cells. Circ Res 83:328–333.PubMedCrossRefGoogle Scholar
  33. 33.
    Chobanian AV, Hauderschild CC, Nickerson C, Hope S. 1992. Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Hypertension 20:473–477.PubMedCrossRefGoogle Scholar
  34. 34.
    Pitt B. 1994. Angiotensin-converting enzyme inhibitors in patients with coronary atherosclerosis. Am Heart J 128:1328–1332.PubMedCrossRefGoogle Scholar
  35. 35.
    Li DY, Yang BC, Phillips MI, Mehta JL. 1999. Proapoptotic effects of Ang II in human coronary artery endothelial cells: role of AT receptor and PKC activation. Am J Physiol 276:H786–H792.PubMedGoogle Scholar
  36. 36.
    Raij L. 2001. Hypertension and cardiovascular risk factors: role of the angiotensin II-nitric oxide interaction. Hypertension 37:767–773.PubMedCrossRefGoogle Scholar
  37. 37.
    Lassegue B, Sorescu D, Szocs K,Yin Q, Akers M, Zhang Y, Grant SL, Lambeth JD, Griendling KK. 2001. Novel gp91(phox) homologues in vascular smooth muscle cells: noxl mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res 88:888–894.PubMedCrossRefGoogle Scholar
  38. 38.
    Dzau VJ. 2001. Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 37:1047–1052.PubMedCrossRefGoogle Scholar
  39. 39.
    Li D, Saldeen T, Romeo F, Mehta JL. 2000. Oxidized LDL upregulates angiotensin II type 1 recep-tor expression in cultured human coronary artery endothelial cells: the potential role of transcrip-tion factor NF-kappaB. Circulation 102:1970–1976.PubMedCrossRefGoogle Scholar
  40. 40.
    Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, Zerkowski HR, Sawamura T, Holtz J. 1999. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation 100:899–902.PubMedCrossRefGoogle Scholar
  41. 41.
    Strehlow K, Wassmann S, Bohm M, Nickenig G. 2000. Angiotensin ATI receptor over-expression in hypercholesterolaemia. Ann Med 32:386–389.PubMedCrossRefGoogle Scholar
  42. 42.
    Yang BC, Phillips MI, Mohuczy D, Meng H, Shen L, Mehta P, Mehta JL. 1998. Increased angiotensin II type 1 receptor expression in hypercholesterolemic atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 18:1433–1439.PubMedCrossRefGoogle Scholar
  43. 43.
    Li D, Mehta JL. 2000. 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-1 mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol 20:1116–1122.PubMedCrossRefGoogle Scholar
  44. 44.
    Li D, Mehta JL. 2000. Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells. Circulation 101:2889–2895.PubMedCrossRefGoogle Scholar
  45. 45.
    Walsh K, Isner JM. 2000. Apoptosis in inflammatory-fibroproliferative disorders of the vessel wall. Cardiovasc Res 45:756–765.PubMedCrossRefGoogle Scholar
  46. 46.
    Sam F, Sawyer DB, Chang DL, Eberli FR, Ngoy S, Jain M, Amin J, Apstein CS, Colucci WS. 2000. Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol Heart Circ Physiol 279:H422–428.PubMedGoogle Scholar
  47. 47.
    Li D, Chen H, Mhatre A, Romeo F, Saldeen T, Mehta JL. 2000. Statins inhibit ox-LDL-induced expression of adhesion molecules and monocyte adhesion to human coronary endothelial cells: Role of mitogen-activated protein kinase and NF-KB. Circulation 102:1229Google Scholar
  48. 48.
    Mehta JL, Li DY, Chen HJ, Joseph J, Romeo F. 2001. Inhibition of LOX-1 by statins may relate to upregulation of eNOS. Biochemical Biophysical Research Communications 289:857–861.CrossRefGoogle Scholar
  49. 49.
    Voraberger G, Schafer R, Strotowa C. 1991. Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5’-regulatory region. Induction by cytokines and phorbol ester. J Immunol 147:2777–2786.PubMedGoogle Scholar
  50. 50.
    Iademarco MF, McQuillan JJ, Rosen GD, Dean DC. 1992. Characterization of the promoter for vascular cell adhesion molecule-1 (VCAM-1). J Biol Chem 267:16323–16329.PubMedGoogle Scholar
  51. 51.
    Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, Rigoni A, Pastorino AM, Lo Cascio V, Sawamura T. 2000. Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-KB through an increased production of intracellular reactive oxygen species. J Biol Chem 275:12633–12638.PubMedCrossRefGoogle Scholar
  52. 52.
    Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, Pastorino AM, Lo Cascio V, Sawamura T. 2001. The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL recep-tor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem 276:13750–13755.PubMedGoogle Scholar
  53. 53.
    Kusuhara M, Chait A, Cader A, Berk BC. 1997. Oxidized LDL stimulates mitogen-activated protein kinases in smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol 17:141–148.PubMedCrossRefGoogle Scholar
  54. 54.
    Han KH, Tangirala RK, Green SR, Quehenberger O. 1998. Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes: a regulatory role for plasma LDL. Arterioscler Thromb Vasc Biol 18:1983–1991.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang GP, Deng ZD, Ni J, Qu ZL. 1997. Oxidized low density lipoprotein and very low density lipoprotein enhance expression of monocyte chemoattractant protein-1 in rabbit peritoneal exudates macrophages. Atherosclerosis 133:31–36.PubMedCrossRefGoogle Scholar
  56. 56.
    Li DY, Chen HJ, Mehta JL. 2001. Statins inhibit oxidized-LDL-mediated LOX-1 expression, uptake of ox-LDL and reduction in PKB phosphorylation. Cardiovasc Res, 52:130–135PubMedCrossRefGoogle Scholar
  57. 57.
    Tang X, Downes CP, Whetton AD, Owen-Lynch PJ. 2000. Role of phosphatidylinositol 3-kinase and specific protein kinase B isoforms in the suppression of apoptosis mediated by the Abelson protein-tyrosine kinase. J Biol Chem 275:3142–3148.Google Scholar
  58. 58.
    Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, Komatsu R, Matsuo T, Itabe H, Takano T, Tsukamoto Y, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE. 2001. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation 103:1955–1960.PubMedCrossRefGoogle Scholar
  59. 59.
    Chen H, Li D, Sawamura T, Inoue K, Mehta JL. 2000. Upregulation of LOX-1 expression in aorta of hypercholesterolemic rabbits: modulation by losartan. Biochem Biophys Res Commun 276:1100–1104.PubMedCrossRefGoogle Scholar
  60. 60.
    Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T, Sawamura T, Masaki T, Hashimoto N, Kita T. 1999. Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation 99:3110–3117.PubMedCrossRefGoogle Scholar
  61. 61.
    Oka K, Sawamura T, Kikuta K, Itokawa S, Kume N, Kita T, Masaki T. 1998. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci USA 95:9535–9540.PubMedCrossRefGoogle Scholar
  62. 62.
    Nagase M, Hirose S, Sawamura T, Masaki T, Fujita. 1997. Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats. Biochem Biophys Res Commun 237:496–498.PubMedCrossRefGoogle Scholar
  63. 63.
    Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. 1990. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323:22–27.PubMedCrossRefGoogle Scholar
  64. 64.
    Conti CR, Mehta JL. 1987. Acute myocardial ischemia: Role of atherosclerosis, in situ thrombosis, platelet activation, coronary vasospasm, and altered arachidonic acid metabolism. Circulation 75.-V84–V95.PubMedGoogle Scholar
  65. 65.
    Chen LY, Mehta P, Mehta JL. 1996. Oxidized LDL decreases L-arginine uptake and nitric oxide synthase protein expression in human platelets: relevance of the effect of oxidized LDL on platelet function. Circulation 93:1740–1746.PubMedCrossRefGoogle Scholar
  66. 66.
    Kakatani M, Sawamura T, Chen M. 2000. Role of Lox-1 in thrombosis. Circulation 102:11–191.CrossRefGoogle Scholar
  67. 67.
    Harrison GJ, Jordan LR, Selley ML, Willis RJ. 1995. Low-density lipoproteins inhibit histamine and NaNO2 relaxation of the coronary vasculature and reduce contractile function in isolated rat hears. Heart Vessels 10:249–257.PubMedCrossRefGoogle Scholar
  68. 68.
    Dayuan Li, MD,PhD, Victor Williams, MD, Ling Liu, MD, Hongjiang Chen, MD, Tatsuya Sawamura, MD,PhD, Francesco Romeo, MD, Jawahar L. Mehta, MD,PhD. 2001. Expression of LOX-1 during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction in rats. Circulation 104:II-11.Google Scholar
  69. 69.
    Williams V, Li DY, Liu L, Chen HJ, Sawamura T, Antakli T, Mehta JL. 2001. The role of LOX-1, an oxidized LDL Receptor, in myocardial ischemia-reperfusion injury in rats. Circulation 104:II-92.CrossRefGoogle Scholar
  70. 70.
    Kita T, Kume N, Yokode M, Ishii K, Arai H, Horiuchi H, Moriwaki H, Minami M, Kataoka H, Wakatsuki Y. 1999. Oxidized LDL and expression of monocyte adhesion molecules. Diabetes Res Clin Pract 45:123–126.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Jacob Joseph
    • 1
  • Dayuan Li
    • 2
  • Hongjiang Chen
    • 3
  • Jawahar L. Mehta
    • 4
  1. 1.Division of Cardiovascular Medicine, Department of Internal MedicineUniversity of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare SystemLittle RockUSA
  2. 2.Supported by a Merit Review Award from the VA Central OfficeWashington D.C.
  3. 3.a contract with the Department of DefenseWashington
  4. 4.a Scientist Development Grant from the American Heart AssociationDallas

Personalised recommendations