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Upregulated LOX-1 Receptor: Key Player of the Pathogenesis of Atherosclerosis

  • Evidence-Based Medicine (L. Roever, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

In any case, in proatherogenic conditions, LOX-1 is uniquely upregulated in vascular cells and mediates the entire atherogenic process from LDL oxidation to plague arrangement. As evidence supporting the crucial role of LOX-1 in atherogenesis keeps accumulating, there is developing an enthusiasm for LOX-1 as a potential remedial target.

Recent Findings

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for binding and uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells. Following internalization of oxLDL, LOX-1 starts a vicious cycle from activation of proinflammatory signaling pathways, subsequently advancing an expanded responsive oxygen species arrangement and secretion of proinflammatory cytokines. In healthy arteries, expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is practically undetectable.

Summary

This review portrays existing evidence supporting the role of LOX-1 in mediating of proatherosclerotic impacts of oxLDL which result in endothelial dysfunction, proinflammatory recruitment of monocytes into the arterial intima, arrangement of foam cells, endothelial cell dysfunction and vascular smooth muscle cell proliferation, and platelet enactment, angiogenesis just as in plaque development. Likewise, abridges LOX-1 modulatory compounds and in vivo and in vitro examinations toward the improvement of small molecules and biologics that could be of therapeutic use.

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Abbreviations

LOX-1 :

Lectin-like oxidized low-density lipoprotein receptor-1

HUVECs:

Human umbilical vascular endothelial cells

NO:

Nitric oxide

NADPH:

Nicotinamide dinucleotide phosphate

ROS:

Reactive oxygen species

MPO:

Myeloperoxidase

eNOS:

Endothelial nitric oxide synthase

oxLDL:

Oxidized low-density lipoprotein

ApoE−/−:

Apolipoprotein E deficient

HCAECs:

Human coronary artery endothelial cells

LDLr:

Low-density lipoprotein receptor

IFN-γ:

Interferon-γ

MCP-1 :

Monocyte chemoattractant protein-1

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

COX-2:

Cyclooxygenase-2

MAPK:

Mitogen-activated protein kinase

MiR:

MicroRNA

VEGF:

Vascular endothelial growth factor

GHS R1a:

Ghrelin receptor-1

HEK:

Human embryonic kidney cells

PAFAH:

Platelet-activating factor acetlyhydrolase

cAMP:

Cyclic adenosine mono-phosphate

NFKB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

MMP-9:

Matrix metallopeptidase- 9

IL:

Interleukin

TNF-α:

Tumor necrosis factor- α

SOD:

Superoxide dismutase

CAT:

Catalase

References

  1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362(6423):801–9.

    CAS  PubMed  Google Scholar 

  2. Lusis AJ. Atherosclerosis. Nature. 2000;407(6801):233–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868–74.

    CAS  Google Scholar 

  4. Zeya B, Arjuman A, Chandra NC. Lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX-1): a chameleon receptor for oxidized LDL. Biochemistry. 2016;55(32):4437–44.

    CAS  PubMed  Google Scholar 

  5. Mehta JL, Chen J, Hermonat PL, Romeo F, Novelli G. Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovasc Res. 2006;69(1):36–45.

    CAS  PubMed  Google Scholar 

  6. Brink R. LOX-1 unlocks human plasma cell potential. Immunity. 2014;41(4):507–8.

    CAS  PubMed  Google Scholar 

  7. Lu J, Mitra S, Wang X, Khaidakov M, Mehta JL. Oxidative stress and lectin-like ox-LDL-receptor LOX-1 in atherogenesis and tumorigenesis. Antioxid Redox Signal. 2011;15(8):2301–33.

    CAS  PubMed  Google Scholar 

  8. Xu S, Ogura S, Chen J, Little PJ, Moss J, Liu P. LOX-1 in atherosclerosis: biological functions and pharmacological modifiers. Cell Mol Life Sci : CMLS. 2013;70(16):2859–72.

    CAS  PubMed  Google Scholar 

  9. Pirillo A, Norata GD, Catapano AL. LOX-1, OxLDL, and atherosclerosis. Mediat Inflamm. 2013;2013:152786.

    Google Scholar 

  10. Ikeda H, Takajo Y, Murohara T, Ichiki K, Adachi H, Haramaki N, et al. Platelet-derived nitric oxide and coronary risk factors. Hypertension. 2000;35(4):904–7.

    CAS  PubMed  Google Scholar 

  11. Bath PM, Hassall DG, Gladwin AM, Palmer RM, Martin JF. Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb. 1991;11(2):254–60.

    CAS  PubMed  Google Scholar 

  12. Chen M, Masaki T, Sawamura T. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 2002;95(1):89–100.

    CAS  PubMed  Google Scholar 

  13. Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T, et al. Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation. 1999;99(24):3110–7.

    CAS  PubMed  Google Scholar 

  14. Kume N, Kita T. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in atherogenesis. Trends Cardiovasc Med. 2001;11(1):22–5.

    CAS  PubMed  Google Scholar 

  15. Mitra S, Goyal T, Mehta JL. Oxidized LDL, LOX-1 and atherosclerosis. Cardiovasc Drugs Ther. 2011;25(5):419–29.

    CAS  PubMed  Google Scholar 

  16. Pirillo A, Uboldi P, Ferri N, Corsini A, Kuhn H, Catapano AL. Upregulation of lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) expression in human endothelial cells by modified high density lipoproteins. Biochem Biophys Res Commun. 2012;428(2):230–3.

    CAS  PubMed  Google Scholar 

  17. Shiu SW, Tan KC, Wong Y, Leng L, Bucala R. Glycoxidized LDL increases lectin-like oxidized low density lipoprotein receptor-1 in diabetes mellitus. Atherosclerosis. 2009;203(2):522–7.

    CAS  PubMed  Google Scholar 

  18. Morawietz H, Duerrschmidt N, Niemann B, Galle J, Sawamura T, Holtz J. Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1. Clin Sci (Lond). 2002;103(Suppl 48):9s–12s.

    CAS  Google Scholar 

  19. Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL. Oxidative stress in atherosclerosis. Curr Atheroscler Rep. 2017;19(11):42.

    PubMed  Google Scholar 

  20. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, et al. Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem. 2000;275(17):12633–8.

    CAS  PubMed  Google Scholar 

  21. Chen XP, Xun KL, Wu Q, Zhang TT, Shi JS, Du GH. Oxidized low density lipoprotein receptor-1 mediates oxidized low density lipoprotein-induced apoptosis in human umbilical vein endothelial cells: role of reactive oxygen species. Vasc Pharmacol. 2007;47(1):1–9.

    Google Scholar 

  22. Cominacini L, Fratta Pasini A, Garbin U, Pastorino A, Rigoni A, Nava C, 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. J Am Coll Cardiol. 2003;41(3):499–507.

    CAS  PubMed  Google Scholar 

  23. Rueckschloss U, Galle J, Holtz J, Zerkowski HR, 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):1767–72.

    CAS  PubMed  Google Scholar 

  24. Ou HC, Song TY, Yeh YC, Huang CY, Yang SF, Chiu TH, et al. EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling. J Appl Physiol (Bethesda, Md : 1985). 2010;108(6):1745–56.

    CAS  Google Scholar 

  25. Shi Y, Cosentino F, Camici GG, Akhmedov A, Vanhoutte PM, Tanner FC, et al. Oxidized low-density lipoprotein activates p66Shc via lectin-like oxidized low-density lipoprotein receptor-1, protein kinase C-beta, and c-Jun N-terminal kinase kinase in human endothelial cells. Arterioscler Thromb Vasc Biol. 2011;31(9):2090–7.

    CAS  PubMed  Google Scholar 

  26. Thum T, Borlak J. 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. 2008;283(28):19456–64.

    CAS  PubMed  Google Scholar 

  27. Chen J, Liu Y, Liu H, Hermonat PL, Mehta JL. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis. Biochem J. 2006;393(Pt 1):255–65.

    CAS  PubMed  Google Scholar 

  28. Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol. 2009;27:165–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

    CAS  PubMed  Google Scholar 

  30. Mattaliano MD, Huard C, Cao W, Hill AA, Zhong W, Martinez RV, et al. LOX-1-dependent transcriptional regulation in response to oxidized LDL treatment of human aortic endothelial cells. Am J Physiol Cell Physiol. 2009;296(6):C1329–37.

    CAS  PubMed  Google Scholar 

  31. Li D, Chen H, Romeo F, Sawamura T, Saldeen T, Mehta JL. 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):601–5.

    CAS  PubMed  Google Scholar 

  32. Zhu H, Xia M, Hou M, et al. Ox-LDL plays dual effect in modulating expression of inflammatory molecules through LOX-1 pathway in human umbilical vein endothelial cells. Front Biosci. 2005;10:2585–94.

    PubMed  Google Scholar 

  33. Pirillo A, Reduzzi A, Ferri N, Kuhn H, Corsini A, Catapano AL. Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) by 15-lipoxygenase-modified LDL in endothelial cells. Atherosclerosis. 2011;214(2):331–7.

    CAS  PubMed  Google Scholar 

  34. Lievens D, Eijgelaar WJ, Biessen EA, Daemen MJ, Lutgens E. The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thromb Haemost. 2009;102(2):206–14.

    CAS  PubMed  Google Scholar 

  35. Li D, Liu L, Chen H, Sawamura T, Mehta JL. LOX-1, an oxidized LDL endothelial receptor, induces CD40/CD40L signaling in human coronary artery endothelial cells. Arterioscler Thromb Vasc Biol. 2003;23(5):816–21.

    CAS  PubMed  Google Scholar 

  36. Bobryshev YV, Ivanova EA, Chistiakov DA, Nikiforov NG, Orekhov AN. Macrophages and their role in atherosclerosis: pathophysiology and transcriptome analysis. Biomed Res Int. 2016;2016:9582430.

    PubMed  PubMed Central  Google Scholar 

  37. Sakurai K, Cominacini L, Garbin U, Fratta Pasini A, Sasaki N, Takuwa Y, et al. 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):S173–80.

    CAS  PubMed  Google Scholar 

  38. Schaeffer DF, Riazy M, Parhar KS, Chen JH, Duronio V, Sawamura T, et al. LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasma. J Lipid Res. 2009;50(8):1676–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Li D, Mehta JL. Intracellular signaling of LOX-1 in endothelial cell apoptosis. Circ Res. 2009;104(5):566–8.

    CAS  PubMed  Google Scholar 

  40. Moriwaki H, Kume N, Kataoka H, Murase T, Nishi E, Sawamura T, et al. Expression of lectin-like oxidized low density lipoprotein receptor-1 in human and murine macrophages: upregulated expression by TNF-alpha. FEBS Lett. 1998;440(1–2):29–32.

    CAS  PubMed  Google Scholar 

  41. Ishiyama J, Taguchi R, Yamamoto A, Murakami K. Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells. Atherosclerosis. 2010;209(1):118–24.

    CAS  PubMed  Google Scholar 

  42. Li L, Sawamura T, Renier G. Glucose enhances human macrophage LOX-1 expression: role for LOX-1 in glucose-induced macrophage foam cell formation. Circ Res. 2004;94(7):892–901.

    CAS  PubMed  Google Scholar 

  43. Bobryshev YV. Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur Heart J. 2005;26(17):1700–4.

    PubMed  Google Scholar 

  44. Perrin-Cocon L, Coutant F, Agaugue S, Deforges S, Andre P, Lotteau V. Oxidized low-density lipoprotein promotes mature dendritic cell transition from differentiating monocyte. J Immunol (Baltimore, Md : 1950). 2001;167(7):3785–91.

    CAS  Google Scholar 

  45. Nickel T, Hanssen H, Sisic Z, Pfeiler S, Summo C, Schmauss D, et al. Immunoregulatory effects of the flavonol quercetin in vitro and in vivo. Eur J Nutr. 2011;50(3):163–72.

    CAS  PubMed  Google Scholar 

  46. Nickel T, Schmauss D, Hanssen H, Sicic Z, Krebs B, Jankl S, et al. oxLDL uptake by dendritic cells induces upregulation of scavenger-receptors, maturation and differentiation. Atherosclerosis. 2009;205(2):442–50.

    CAS  PubMed  Google Scholar 

  47. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):Iii27–32.

    PubMed  Google Scholar 

  48. Xu F, Sun Y, Chen Y, Sun Y, Li R, Liu C, et al. Endothelial cell apoptosis is responsible for the formation of coronary thrombotic atherosclerotic plaques. Tohoku J Exp Med. 2009;218(1):25–33.

    PubMed  Google Scholar 

  49. Chen J, Mehta JL, 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):370–6.

    CAS  PubMed  Google Scholar 

  50. Imanishi T, Hano T, Sawamura T, Takarada S, Nishio I. Oxidized low density lipoprotein potentiation of Fas-induced apoptosis through lectin-like oxidized-low density lipoprotein receptor-1 in human umbilical vascular endothelial cells. Circ J. 2002;66(11):1060–4.

    CAS  PubMed  Google Scholar 

  51. Hong D, Bai YP, Gao HC, Wang X, Li LF, Zhang GG, et al. Ox-LDL induces endothelial cell apoptosis via the LOX-1-dependent endoplasmic reticulum stress pathway. Atherosclerosis. 2014;235(2):310–7.

    CAS  PubMed  Google Scholar 

  52. Cominacini L, Rigoni A, Pasini AF, Garbin U, Davoli A, Campagnola M, et al. The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide. J Biol Chem. 2001;276(17):13750–5.

    CAS  PubMed  Google Scholar 

  53. Blair A, Shaul PW, Yuhanna IS, Conrad PA, Smart EJ. Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J Biol Chem. 1999;274(45):32512–9.

    CAS  PubMed  Google Scholar 

  54. Akhmedov A, Rozenberg I, Paneni F, Camici GG, Shi Y, Doerries C, et al. Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo. Eur Heart J. 2014;35(40):2839–48.

    CAS  PubMed  Google Scholar 

  55. Mehta JL, Sanada N, Hu CP, Chen J, Dandapat A, Sugawara F, et al. Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. Circ Res. 2007;100(11):1634–42.

    CAS  PubMed  Google Scholar 

  56. Keman K, Rahardjo B, Madakusuma D. OS076. The effect of lectin-like oxidized low density lipoprotein receptor monoclonal antibody (LOX-1 MAb) on the expression of eNOS in preeclamptic HUVECs model. Pregnancy Hypertens. 2012;2(3):218–9.

    CAS  PubMed  Google Scholar 

  57. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386(6620):73–7.

    CAS  PubMed  Google Scholar 

  58. Silverstein RL, Nachman RL. Angiogenesis and atherosclerosis. The mandate broadens. Circulation. 1999;100(8):783–5.

    CAS  PubMed  Google Scholar 

  59. Slevin M, Krupinski J, Badimon L. Controlling the angiogenic switch in developing atherosclerotic plaques: possible targets for therapeutic intervention. J Angiogenes Res. 2009;1:4–4.

    PubMed  PubMed Central  Google Scholar 

  60. Pitsilos S, Hunt J, Mohler ER, Prabhakar A, Poncz M, Dawicki J, et al. Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters. Thromb Haemost. 2003;90(6):1112–20.

    CAS  PubMed  Google Scholar 

  61. Matsunaga T, Chilian WM, March K. Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease. Am J Phys Heart Circ Phys. 2005;288(5):H2042–6.

    CAS  Google Scholar 

  62. Dandapat A, Hu C, Sun L, Mehta JL. Small concentrations of oxLDL induce capillary tube formation from endothelial cells via LOX-1-dependent redox-sensitive pathway. Arterioscler Thromb Vasc Biol. 2007;27(11):2435–42.

    CAS  PubMed  Google Scholar 

  63. Khaidakov M, Mitra S, Wang X, Ding Z, Bora N, Lyzogubov V, et al. Large impact of low concentration oxidized LDL on angiogenic potential of human endothelial cells: a microarray study. PLoS One. 2012;7(10):–e47421.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Dai Y, Zhang Z, Cao Y, Mehta JL, Li J. MiR-590-5p inhibits oxidized- LDL induced angiogenesis by targeting LOX-1. Sci Rep. 2016;6:22607.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Camaré C, Trayssac M, Garmy-Susini B, Mucher E, Sabbadini R, Salvayre R, et al. Oxidized LDL-induced angiogenesis involves sphingosine 1-phosphate: prevention by anti-S1P antibody. Br J Pharmacol. 2015;172(1):106–18.

    PubMed  Google Scholar 

  66. Camare C, Auge N, Pucelle M, et al. The neutral sphingomyelinase-2 is involved in angiogenic signaling triggered by oxidized LDL. Free Radic Biol Med. 2016;93:204–16.

    CAS  PubMed  Google Scholar 

  67. Hu C, Dandapat A, Sun L, Khan JA, Liu Y, Hermonat PL, et al. 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):10226–31.

    CAS  PubMed  Google Scholar 

  68. Mulligan-Kehoe MJ, Simons M. Vasa vasorum in normal and diseased arteries. Circulation. 2014;129(24):2557–66.

    PubMed  Google Scholar 

  69. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med. 2003;349(24):2316–25.

    CAS  PubMed  Google Scholar 

  70. Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation. 2006;113(18):2245–52.

    PubMed  Google Scholar 

  71. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852–66.

    CAS  PubMed  Google Scholar 

  72. Hu C, Dandapat A, Sun L, Chen J, Marwali MR, Romeo F, et al. 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):287–93.

    CAS  PubMed  Google Scholar 

  73. Aukrust P, Halvorsen B, Ueland T, Michelsen AE, Skjelland M, Gullestad L, et al. Activated platelets and atherosclerosis. Expert Rev Cardiovasc Ther. 2010;8(9):1297–307.

    PubMed  Google Scholar 

  74. Chen M, Kakutani M, Naruko T, Ueda M, Narumiya S, Masaki T, et al. Activation-dependent surface expression of LOX-1 in human platelets. Biochem Biophys Res Commun. 2001;282(1):153–8.

    CAS  PubMed  Google Scholar 

  75. Marwali MR, Hu CP, Mohandas B, Dandapat A, Deonikar P, Chen J, et al. 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):1324–32.

    CAS  PubMed  Google Scholar 

  76. Kakutani M, Masaki T, Sawamura T. A platelet–endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1. Proc Natl Acad Sci. 2000;97(1):360–4.

    CAS  PubMed  Google Scholar 

  77. Chistiakov DA, Orekhov AN, Bobryshev YV. Endothelial barrier and its abnormalities in cardiovascular disease. Front Physiol. 2015;6:365.

    PubMed  PubMed Central  Google Scholar 

  78. Kume N, Moriwaki H, Kataoka H, Minami M, Murase T, Sawamura T, et al. Inducible expression of LOX-1, a novel receptor for oxidized LDL, in macrophages and vascular smooth muscle cells. Ann N Y Acad Sci. 2000;902:323–7.

    CAS  PubMed  Google Scholar 

  79. Rudijanto A. The expression and down stream effect of lectin like-oxidized low density lipoprotein 1 (LOX-1) in hyperglycemic state. Acta Med Indones. 2007;39(1):36–43.

    PubMed  Google Scholar 

  80. Favari E, Chroni A, Tietge UJ, Zanotti I, Escola-Gil JC, Bernini F. Cholesterol efflux and reverse cholesterol transport. Handb Exp Pharmacol. 2015;224:181–206.

    CAS  PubMed  Google Scholar 

  81. Yoshida H, Kondratenko N, Green S, Steinberg D, Quehenberger O. Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor. Biochem J. 1998;334 ( Pt 1:9–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Inoue K, Arai Y, Kurihara H, Kita T, Sawamura T. Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice. Circ Res. 2005;97(2):176–84.

    CAS  PubMed  Google Scholar 

  83. Ding Z, Liu S, Wang X, Deng X, Fan Y, Shahanawaz J, et al. Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc Res. 2015;107(4):556–67.

    PubMed  Google Scholar 

  84. Kuge Y, Kume N, Ishino S, Takai N, Ogawa Y, Mukai T, et al. Prominent lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1) expression in atherosclerotic lesions is associated with tissue factor expression and apoptosis in hypercholesterolemic rabbits. Biol Pharm Bull. 2008;31(8):1475–82.

    CAS  PubMed  Google Scholar 

  85. Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016;118(4):692–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Eto H, Miyata M, Kume N, Minami M, Itabe H, Orihara K, et al. Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury. Biochem Biophys Res Commun. 2006;341(2):591–8.

    CAS  PubMed  Google Scholar 

  87. Hinagata J, Kakutani M, Fujii T, et al. Oxidized LDL receptor LOX-1 is involved in neointimal hyperplasia after balloon arterial injury in a rat model. Cardiovasc Res. 2006;69(1):263–71.

    CAS  PubMed  Google Scholar 

  88. Kataoka H, Kume N, Miyamoto S, Minami M, Morimoto M, Hayashida K, et al. 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):955–60.

    CAS  PubMed  Google Scholar 

  89. Murugesan G, Fox PL. Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein. J Clin Invest. 1996;97(12):2736–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Aoyama T, Chen M, Fujiwara H, Masaki T, Sawamura T. LOX-1 mediates lysophosphatidylcholine-induced oxidized LDL uptake in smooth muscle cells. FEBS Lett. 2000;467(2–3):217–20.

    CAS  PubMed  Google Scholar 

  91. Klouche M, Rose-John S, Schmiedt W, Bhakdi S. Enzymatically degraded, nonoxidized LDL induces human vascular smooth muscle cell activation, foam cell transformation, and proliferation. Circulation. 2000;101(15):1799–805.

    CAS  PubMed  Google Scholar 

  92. Chen XP, Zhang TT, Du GH. Lectin-like oxidized low-density lipoprotein receptor-1, a new promising target for the therapy of atherosclerosis? Cardiovasc Drug Rev. 2007;25(2):146–61.

    CAS  PubMed  Google Scholar 

  93. Lee WJ, Ou HC, Hsu WC, Chou MM, Tseng JJ, Hsu SL, et al. Ellagic acid inhibits oxidized LDL-mediated LOX-1 expression, ROS generation, and inflammation in human endothelial cells. J Vasc Surg. 2010;52(5):1290–300.

    PubMed  Google Scholar 

  94. Gu L, Bai W, Li S, Zhang Y, Han Y, Gu Y, et al. Celastrol prevents atherosclerosis via inhibiting LOX-1 and oxidative stress. PLoS One. 2013;8(6):–e65477.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Taye A, Saad AH, Kumar AH, Morawietz H. Effect of apocynin on NADPH oxidase-mediated oxidative stress-LOX-1-eNOS pathway in human endothelial cells exposed to high glucose. Eur J Pharmacol. 2010;627(1–3):42–8.

    CAS  PubMed  Google Scholar 

  96. Xu S, Liu Z, Huang Y, Le K, Tang F, Huang H, et al. Tanshinone II-A inhibits oxidized LDL-induced LOX-1 expression in macrophages by reducing intracellular superoxide radical generation and NF-kappaB activation. Transl Res. 2012;160(2):114–24.

    CAS  PubMed  Google Scholar 

  97. Mehta JL, Hu B, Chen J, Li D. 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.

    CAS  PubMed  Google Scholar 

  98. Lu L, Liu H, Peng J, Gan L, Shen L, Zhang Q, et al. Regulations of the key mediators in inflammation and atherosclerosis by aspirin in human macrophages. Lipids Health Dis. 2010;9:16.

    PubMed  PubMed Central  Google Scholar 

  99. Song Q, Zhang Y, Han X, et al. Potential mechanisms underlying the protective effects of salvianic acid a against atherosclerosis in vivo and vitro. Biomed Pharmacother. 2019;109:945–56.

    CAS  PubMed  Google Scholar 

  100. Liu TT, Zeng Y, Tang K, Chen X, Zhang W, Xu XL. Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice. Atherosclerosis. 2017;262:39–50.

    CAS  PubMed  Google Scholar 

  101. Liu Z, Xu S, Huang X, Wang J, Gao S, Li H, et al. Cryptotanshinone, an orally bioactive herbal compound from Danshen, attenuates atherosclerosis in apolipoprotein E-deficient mice: role of lectin-like oxidized LDL receptor-1 (LOX-1). Br J Pharmacol. 2015;172(23):5661–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Li Q, Zhao W, Zeng X, Hao Z. Ursolic acid attenuates atherosclerosis in ApoE(−/−) mice: role of LOX-1 mediated by ROS/NF-kappaB pathway. Molecules. 2018;23(5):1101–12.

    PubMed Central  Google Scholar 

  103. Liu SL, Li YH, Shi GY, Chen YH, Huang CW, Hong JS, et al. A novel inhibitory effect of naloxone on macrophage activation and atherosclerosis formation in mice. J Am Coll Cardiol. 2006;48(9):1871–9.

    CAS  PubMed  Google Scholar 

  104. Mohana T, Navin AV, Jamuna S, Sakeena Sadullah MS, Niranjali Devaraj S. Inhibition of differentiation of monocyte to macrophages in atherosclerosis by oligomeric proanthocyanidins -in-vivo and in-vitro study. Food Chem Toxicol. 2015;82:96–105.

    CAS  PubMed  Google Scholar 

  105. Zheng J, Liu B, Lun Q, et al. Longxuetongluo capsule inhibits atherosclerosis progression in high-fat diet-induced ApoE−/− mice by improving endothelial dysfunction. 2016;255:156–63.

  106. Minatti J, Wazlawik E, Hort MA, Zaleski FL, Ribeiro-do-Valle RM, Maraschin M, et al. Green tea extract reverses endothelial dysfunction and reduces atherosclerosis progression in homozygous knockout low-density lipoprotein receptor mice. Nutr Res. 2012;32(9):684–93.

    CAS  PubMed  Google Scholar 

  107. Van der Veken B, De Meyer GRY, Martinet W. Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice. Vasc Pharmacol. 2018;100:34–40.

    Google Scholar 

  108. Wang L, Li G, Chen Q, Ke D. Octanoylated ghrelin attenuates angiogenesis induced by oxLDL in human coronary artery endothelial cells via the GHSR1a-mediated NF-kappaB pathway. Metabolism. 2015;64(10):1262–71.

    CAS  PubMed  Google Scholar 

  109. Biocca S, Iacovelli F, Matarazzo S, Vindigni G, Oteri F, Desideri A, et al. Molecular mechanism of statin-mediated LOX-1 inhibition. Cell Cycle. 2015;14(10):1583–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhang H, Guo C, Zhang A, Fan Y, Gu T, Wu D, et al. Effect of S-aspirin, a novel hydrogen-sulfide-releasing aspirin (ACS14), on atherosclerosis in apoE-deficient mice. Eur J Pharmacol. 2012;697(1–3):106–16.

    CAS  PubMed  Google Scholar 

  111. Becher T, Schulze TJ, Schmitt M, Trinkmann F, el-Battrawy I, Akin I, et al. Ezetimibe inhibits platelet activation and uPAR expression on endothelial cells. Int J Cardiol. 2017;227:858–62.

    PubMed  Google Scholar 

  112. Wojcicka G, Zareba M, Warpas A, et al. The effect of exenatide (a GLP-1 analog) and sitagliptin (a DPP-4 inhibitor) on plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and concentration in normal and fructose-fed rats. Eur J Pharmacol. 2019;850:180–9.

    CAS  PubMed  Google Scholar 

  113. Lee HS, Kim SD, Lee WM, Endale M, Kamruzzaman SM, Oh WJ, et al. A noble function of BAY 11-7082: inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations. Eur J Pharmacol. 2010;627(1–3):85–91.

    CAS  PubMed  Google Scholar 

  114. Alarcon M, Fuentes E, Olate N, Navarrete S, Carrasco G, Palomo I. Strawberry extract presents antiplatelet activity by inhibition of inflammatory mediator of atherosclerosis (sP-selectin, sCD40L, RANTES, and IL-1beta) and thrombus formation. Platelets. 2015;26(3):224–9.

    CAS  PubMed  Google Scholar 

  115. Lien L-M, Lin K-H, Huang L-T, Tseng MF, Chiu HC, Chen RJ, et al. Licochalcone A prevents platelet activation and thrombus formation through the inhibition of PLCγ2-PKC, Akt, and MAPK pathways. Int J Mol Sci. 2017;18(7):1500.

    PubMed Central  Google Scholar 

  116. Qin L, Yang YB, Yang YX, Zhu N, Liu Z, Ni YG, et al. Inhibition of macrophage-derived foam cell formation by ezetimibe via the caveolin-1/MAPK pathway. Clin Exp Pharmacol Physiol. 2016;43(2):182–92.

    CAS  PubMed  Google Scholar 

  117. Yao W, Huang L, Sun Q, Yang L, Tang L, Meng G, et al. The inhibition of macrophage foam cell formation by tetrahydroxystilbene glucoside is driven by suppressing vimentin cytoskeleton. Biomed Pharmacother. 2016;83:1132–40.

    CAS  PubMed  Google Scholar 

  118. Plotkin JD, Elias MG, Dellinger AL, Kepley CL. NF-kappaB inhibitors that prevent foam cell formation and atherosclerotic plaque accumulation. Nanomedicine. 2017;13(6):2037–48.

    CAS  PubMed  Google Scholar 

  119. Wang Z, Wang S, Wang Z, Yun T, Wang C, Wang H. Tofacitinib ameliorates atherosclerosis and reduces foam cell formation in apoE deficient mice. Biochem Biophys Res Commun. 2017;490(2):194–201.

    CAS  PubMed  Google Scholar 

  120. Zhang Z, Zhang D, Du B, Chen Z. Hyperoside inhibits the effects induced by oxidized low-density lipoprotein in vascular smooth muscle cells via oxLDL-LOX-1-ERK pathway. Mol Cell Biochem. 2017;433(1–2):169–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Yu YH, Xu XQ, Wang Y, Sun SZ, Chen Y. Intervention of Tongxinluo capsule against vascular lesion of atherosclerosis and its effect on lectin-like oxidized low density lipoprotein receptor-1 expression in rabbits. Chin J Integr Med. 2006;12(1):32–6.

    PubMed  Google Scholar 

  122. Zhang Z, Zhang M, Li Y, Liu S, Ping S, Wang J, et al. Simvastatin inhibits the additive activation of ERK1/2 and proliferation of rat vascular smooth muscle cells induced by combined mechanical stress and oxLDL through LOX-1 pathway. Cell Signal. 2013;25(1):332–40.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India for providing necessary support to carry out this study.

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  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP), Industrial Area, Hajipur, Dist: Vaishali, Bihar, 844102, India

    Sanjiv Singh & Avtar Singh Gautam

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Singh, S., Gautam, A.S. Upregulated LOX-1 Receptor: Key Player of the Pathogenesis of Atherosclerosis. Curr Atheroscler Rep 21, 38 (2019). https://doi.org/10.1007/s11883-019-0801-y

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