Oxidant Stress in Atherosclerosis: Oxidatively Modified LDL and LOX-1

  • Ajoe John Kattoor
  • Jawahar L. MehtaEmail author


Oxidative stress, implying an imbalance between oxidant and anti-oxidant species, is present in the atherosclerotic regions and plays a significant role in the pathogenesis of atherosclerosis and its complications. Recent studies have demonstrated an association between increased oxidative stress and diabetes, hypertension, cigarette smoking and dyslipidemia, which are well known risk factors for atherosclerosis. The endothelial cells, the primary cell line to become dysfunctional early in the course of atherosclerosis internalizes ox-LDL mainly through its receptor LOX-1 which is responsible for many of the downstream effects on smooth muscle cell ans monocyte biology. Inhibition of LOX-1 by gene deletion significantly reduces atherogenesis in animal models. Many of the currently used drugs modulate atherosclerosis by their action on LOX-1 receptor. New molecules that modulate LOX-1 are currently under investigation. sLOX-1 is a potential biomarker in acute coronary injury and further studies needs to be done before it can be put to clinical use.


Conflicts of Interest





  1. 1.
    Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12(3):204–212CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Yoshimoto R, Fujita Y, Kakino A, Iwamoto S, Takaya T, Sawamura T (2011) The discovery of LOX-1, its ligands and clinical significance. Cardiovasc Drugs Ther 25(5):379–391CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917):868–874CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Parthasarathy S, Raghavamenon A, Garelnabi MO, Santanam N (2010) Oxidized low-density lipoprotein. Methods Mol Biol (Clifton, N.J.) 610:403CrossRefGoogle Scholar
  5. 5.
    Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y et al (1997) An endothelial receptor for oxidized low-density lipoprotein. Nature 386(6620):73CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Aoyama T, Sawamura T, Furutani Y, Matsuoka R, Yoshida MC, Fujiwara H et al (1999) Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. Biochem J 339(Pt 1):177–184CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kattoor AJ, Kanuri SH, Mehta JL (2018) Role of Ox-LDL and LOX-1 in atherogenesis. Curr Med ChemGoogle Scholar
  8. 8.
    Matarazzo S, Quitadamo MC, Mango R, Ciccone S, Novelli G, Biocca S (2012) Cholesterol-lowering drugs inhibit lectin-like oxidized low-density lipoprotein-1 receptor function by membrane raft disruption. Mol Pharmacol 82(2):246–254CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Pirillo A, Norata GD, Catapano AL (2013) LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm 2013:152786CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Xu S, Ogura S, Chen J, Little PJ, Moss J, Liu P (2013) LOX-1 in atherosclerosis: biological functions and pharmacological modifiers. Cell Mol Life Sci 70(16):2859–2872CrossRefGoogle Scholar
  11. 11.
    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(25):2889–2895CrossRefGoogle Scholar
  12. 12.
    Chen J, Mehta JL, Haider N, Zhang X, Narula J, Li D (2004) Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells. Circ Res 94(3):370–376CrossRefGoogle Scholar
  13. 13.
    Salvayre R, Auge N, Benoist H, Negre-Salvayre A (2002) Oxidized low-density lipoprotein-induced apoptosis. Biochim Biophys Acta 1585(2-3):213–221CrossRefGoogle Scholar
  14. 14.
    Pernow J, Shemyakin A, Böhm F (2012) New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus. Life Sci 91(13–14):507–516CrossRefGoogle Scholar
  15. 15.
    Li D, Singh RM, Liu L, Chen H, Singh BM, Kazzaz N et al (2003) Oxidized-LDL through LOX-1 increases the expression of angiotensin converting enzyme in human coronary artery endothelial cells. Cardiovasc Res 57(1):238–243CrossRefGoogle Scholar
  16. 16.
    Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K et al (1999) Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation 100(9):899–902CrossRefGoogle Scholar
  17. 17.
    Ryoo S, Bhunia A, Chang F, Shoukas A, Berkowitz DE, Romer LH (2011) OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream RhoA signaling. Atherosclerosis 214(2):279–287CrossRefGoogle Scholar
  18. 18.
    Rueckschloss U, Galle J, Holtz J, Zerkowski HR, Morawietz H (2001) 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 104(15):1767–1772CrossRefGoogle Scholar
  19. 19.
    Khaidakov M, Wang X, Mehta JL (2011) Potential involvement of LOX-1 in functional consequences of endothelial senescence. PLoS One 6(6):e20964CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yang H, Bian Y, Zhang H, Gao F, Xiao C, Liang B et al (2015) LOX-1 is implicated in oxidized low-density lipoprotein-induced oxidative stress of macrophages in atherosclerosis. Mol Med Rep 12(4):5335–5341CrossRefGoogle Scholar
  21. 21.
    Wang X, Ding Z, Lin J, Guo Z, Mehta JL (2015) LOX-1 in macrophage migration in response to ox-LDL and the involvement of calpains. Biochem Biophys Res Commun 467(1):135–139CrossRefGoogle Scholar
  22. 22.
    Eto H, Miyata M, Kume N, Minami M, Itabe H, Orihara K et al (2006) Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury. Biochem Biophys Res Commun 341(2):591–598CrossRefGoogle Scholar
  23. 23.
    Zhang Y, Chen B, Ming L, Qin H, Zheng L, Yue Z et al (2015) MicroRNA-141 inhibits vascular smooth muscle cell proliferation through targeting PAPP-A. Int J Clin Exp Pathol 8(11):14401PubMedPubMedCentralGoogle Scholar
  24. 24.
    Goyal T, Mitra S, Khaidakov M, Wang X, Singla S, Ding Z et al (2012) Current concepts of the role of oxidized LDL receptors in atherosclerosis. Curr Atheroscler Rep 14(2):150–159CrossRefGoogle Scholar
  25. 25.
    Kataoka H, Kume N, Miyamoto S, Minami M, Morimoto M, Hayashida K et al (2001 Jun) Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21(6):955–960CrossRefGoogle Scholar
  26. 26.
    Yang H, Mohamed ASS, Zhou S-H (2012) Oxidized low density lipoprotein, stem cells, and atherosclerosis. Lipids Health Dis 11(1):85CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yeung J, Li W, Holinstat M (2018) Platelet signaling and disease: targeted therapy for thrombosis and other related diseases. Pharmacol Rev 70(3):526–548CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chen M, Kakutani M, Naruko T, Ueda M, Narumiya S, Masaki T et al (2001) Activation-dependent surface expression of LOX-1 in human platelets. Biochem Biophys Res Commun 282(1):153–158CrossRefGoogle Scholar
  29. 29.
    Marwali MR, Hu C, Mohandas B, Dandapat A, Deonikar P, Chen J et al (2007) 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 322(3):1324–1332CrossRefGoogle Scholar
  30. 30.
    Sakurai K, Cominacini L, Garbin U, Fratta Pasini A, Sasaki N, Takuwa Y et al (2004) 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 44(Suppl 1):173CrossRefGoogle Scholar
  31. 31.
    Yang S, Li Y, Du D (2013) Oxidized low-density lipoprotein-induced CD147 expression and its inhibition by high-density lipoprotein on platelets in vitro. Thromb Res 132(6):702–711CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yavuzer S, Yavuzer H, Cengiz M, Erman H, Altıparmak MR, Korkmazer B et al (2015) Endothelial damage in white coat hypertension: role of lectin-like oxidized low-density lipoprotein-1. J Hum Hypertens 29(2):92–98CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Takanabe-Mori R, Ono K, Wada H, Takaya T, Ura S, Yamakage H et al (2013) Lectin-like oxidized low-density lipoprotein receptor-1 plays an important role in vascular inflammation in current smokers. J Atheroscler Thromb 20(6):585–590CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Tan KCB, Shiu SWM, Wong Y, Leng L, Bucala R (2008) Soluble lectin-like oxidized low density lipoprotein receptor-1 in type 2 diabetes mellitus. J Lipid Res 49(7):1438–1444CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Civelek S, Kutnu M, Uzun H, Erdenen F, Altunoglu E, Andican G et al (2015) Soluble lectin-like oxidized LDL receptor 1 as a possible mediator of endothelial dysfunction in patients with metabolic syndrome. J Clin Lab Anal 29(3):184–190CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hayashida K, Kume N, Murase T, Minami M, Nakagawa D, Inada T et al (2005) Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome: a novel marker for early diagnosis. Circulation 112(6):812–818CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Misaka T, Suzuki S, Sakamoto N, Yamaki T, Sugimoto K, Kunii H et al (2014) Significance of soluble lectin-like oxidized LDL receptor-1 levels in systemic and coronary circulation in acute coronary syndrome. Biomed Res Int 2014:649185CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Balin M, Celik A, Kobat MA, Baydas A (2012) 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 34(4):483–490CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu J, Liu Y, Jia K, Huo Z, Huo Q, Liu Z et al (2018) Clinical analysis of lectin-like oxidized low-density lipoprotein receptor-1 in patients with in-stent restenosis after percutaneous coronary intervention. Medicine (Baltimore) 97(17):e0366CrossRefGoogle Scholar
  40. 40.
    Ou H, Lee W, Lee I-, Chiu T, Tsai K, Lin C, et al. Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells. J Appl Physiol 2009;106(5):1674-1685.CrossRefGoogle Scholar
  41. 41.
    Kang B, Khan JA, Ryu S, Shekhar R, Seung K, Mehta JL (2010) Curcumin reduces angiotensin II-mediated cardiomyocyte growth via LOX-1 inhibition. J Cardiovasc Pharmacol 55(2):176–183PubMedGoogle Scholar
  42. 42.
    Mollace V, Ragusa S, Sacco I, Muscoli C, Sculco F, Visalli V et al (2008) The protective effect of bergamot oil extract on lecitine-like oxyLDL receptor-1 expression in balloon injury-related neointima formation. J Cardiovasc Pharmacol Ther 13(2):120–129CrossRefGoogle Scholar
  43. 43.
    Zeya B, Arjuman A, Chandra NC (2016) Lectin-like oxidized low-density lipoprotein (LDL) receptor (LOX-1): a chameleon receptor for oxidized LDL. Biochemistry 55(32):4437–4444CrossRefGoogle Scholar
  44. 44.
    Mehta JL, Chen J, Yu F, Li DY (2004) Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells. Cardiovasc Res 64(2):243–249CrossRefGoogle Scholar
  45. 45.
    Li D, Chen H, Romeo F, Sawamura T, Saldeen T, Mehta JL (2002) Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells: role of LOX-1. J Pharmacol Exp Ther 302(2):601–605CrossRefGoogle Scholar
  46. 46.
    Falconi M, Ciccone S, D’Arrigo P, Viani F, Sorge R, Novelli G et al (2013) Design of a novel LOX-1 receptor antagonist mimicking the natural substrate. Biochem Biophys Res Commun 438(2):340–345CrossRefGoogle Scholar
  47. 47.
    Thakkar S, Wang X, Khaidakov M, Dai Y, Gokulan K, Mehta JL et al (2015) Structure-based design targeted at LOX-1, a receptor for oxidized low-density lipoprotein. Sci Rep 5:16740CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ding Z, Wang X, Khaidakov M, Liu S, Mehta JL (2012) 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) 237(9):1093–1100CrossRefGoogle Scholar
  49. 49.
    Dai Y, Wu X, Dai D, Li J, Mehta JL (2018) MicroRNA-98 regulates foam cell formation and lipid accumulation through repression of LOX-1. Redox Biol 6(16):255–262CrossRefGoogle Scholar
  50. 50.
    Amati F, Diano L, Vecchione L, Norata GD, Koyama Y, Cutuli L et al (2012) LOX-1 inhibition in ApoE KO mice using a schizophyllan-based antisense oligonucleotide therapy. Mol Ther Nucleic Acids 1:e58CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sugimoto K, Ishibashi T, Sawamura T, Inoue N, Kamioka M, Uekita H et al (2009) LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. Cardiovasc Res 84(1):127–136CrossRefGoogle Scholar
  52. 52.
    Pothineni NVK, Karathanasis SK, Ding Z, Arulandu A, Varughese KI, Mehta JL (2017) LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation. J Am Coll Cardiol 69(22):2759–2768CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Division of Cardiology, Central Arkansas Veterans Healthcare SystemUniversity of Arkansas for Medical SciencesLittle RockUSA

Personalised recommendations