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Review article: Biomedical intelligence

Vol. 144 No. 5152 (2014)

Oxidised phospholipids as biomarkers in human disease

  • Maria Philippova
  • Therese Resink
  • Paul Erne
  • Valerie Bochkov
DOI
https://doi.org/10.4414/smw.2014.14037
Cite this as:
Swiss Med Wkly. 2014;144:w14037
Published
15.12.2014

Summary

Oxidised phospholipids (OxPLs) are generated from (poly)unsaturated diacyl- and alk(en)ylacyl glycerophospholipids under conditions of oxidative stress. OxPLs exert a wide variety of biological effects on diverse cell types in vitro and in vivo and are thought to play a role in the development of several chronic diseases including atherosclerosis, a classical lipid-associated and inflammatory disorder. OxPLs are recognised as culprit molecular components responsible for the pathophysiological actions of oxidised low-density lipoproteins. There is growing interest in the potential use of OxPLs as biomarkers of human pathologies. Here we offer a brief overview of current detection methods and knowledge on relationships between levels of circulating OxPLs and disease progression, with particular emphasis on cardiovascular disease.

References

  1. Vance JE. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res. 2008;49(7):1377–87.
  2. Bochkov VN, Oskolkova OV, Birukov KG, Levonen AL, Binder CJ, Stockl J. Generation and biological activities of oxidized phospholipids. Antioxidants & redox signaling. 2010;12(8):1009–59.
  3. Binder CJ. Naturally occurring IgM antibodies to oxidation-specific epitopes. Adv Exp Med Biol. 2012;750:2–13.
  4. Fuchs B. Mass spectrometry and inflammation-MS methods to study oxidation and enzyme-induced changes of phospholipids. Anal Bioanal Chem. 2014;406(5):1291–306.
  5. Spickett CM, Dever G. Studies of phospholipid oxidation by electrospray mass spectrometry: from analysis in cells to biological effects. BioFactors. 2005;24(1–4):17–31.
  6. Itabe H, Yamamoto H, Imanaka T, Shimamura K, Uchiyama H, Kimura J, et al. Sensitive detection of oxidatively modified low density lipoprotein using a monoclonal antibody. J Lipid Res. 1996;37(1):45–53.
  7. Horkko S, Bird DA, Miller E, Itabe H, Leitinger N, Subbanagounder G, et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest. 1999;103(1):117–28.
  8. Friedman P, Horkko S, Steinberg D, Witztum JL, Dennis EA. Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids. Importance of Schiff base formation and aldol condensation. J Biol Chem. 2002;277(9):7010–20.
  9. Chang MK, Bergmark C, Laurila A, Horkko S, Han KH, Friedman P, et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci U S A. 1999;96(11):6353–8.
  10. Shaw PX, Horkko S, Chang MK, Curtiss LK, Palinski W, Silverman GJ, et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest. 2000;105(12):1731–40.
  11. Kotani K, Maekawa M, Kanno T, Kondo A, Toda N, Manabe M. Distribution of immunoreactive malondialdehyde-modified low-density lipoprotein in human serum. Biochim Biophys Acta. 1994;1215(1–2):121–5.
  12. Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell. 2001;104(4):503–16.
  13. Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nature medicine 2002;8(11):1211–7.
  14. Berliner JA, Leitinger N, Tsimikas S. The role of oxidized phospholipids in atherosclerosis. J Lipid Res. 2009;50(Suppl):S207–12.
  15. Briley-Saebo KC, Shaw PX, Mulder WJ, Choi SH, Vucic E, Aguinaldo JG, et al. Targeted molecular probes for imaging atherosclerotic lesions with magnetic resonance using antibodies that recognize oxidation-specific epitopes. Circulation. 2008;117(25):3206–15.
  16. van Dijk RA, Kolodgie F, Ravandi A, Leibundgut G, Hu PP, Prasad A, et al. Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions. J Lipid Res. 2012;53(12):2773–90.
  17. Bochkov VN. Inflammatory profile of oxidized phospholipids. Thromb Haemost. 2007;97(3):348–54.
  18. Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005;353(1):46–57.
  19. Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, et al. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res. 2013;54(10):2815–30.
  20. Tsimikas S, Witztum JL. The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol. 2008;19(4):369–77.
  21. Toshima S, Hasegawa A, Kurabayashi M, Itabe H, Takano T, Sugano J, et al. Circulating oxidized low density lipoprotein levels. A biochemical risk marker for coronary heart disease. Arterioscler Thromb Vasc Biol. 2000;20(10):2243–7.
  22. Nishi K, Itabe H, Uno M, Kitazato KT, Horiguchi H, Shinno K, et al. Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler Thromb Vasc Biol. 2002;22(10):1649–54.
  23. Tsimikas S, Kiechl S, Willeit J, Mayr M, Miller ER, Kronenberg F, et al. Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study. J Am Coll Cardiol. 2006;47(11):2219–28.
  24. Kiechl S, Willeit J, Mayr M, Viehweider B, Oberhollenzer M, Kronenberg F, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10–year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol. 2007;27(8):1788–95.
  25. Tsimikas S, Willeit P, Willeit J, Santer P, Mayr M, Xu Q, et al. Oxidation-specific biomarkers, prospective 15–year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol. 2012;60(21):2218–29.
  26. Tsimikas S, Mallat Z, Talmud PJ, Kastelein JJ, Wareham NJ, Sandhu MS, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events. J Am Coll Cardiol. 2010;56(12):946–55.
  27. Crisby M, Henareh L, Agewall S. Relationship Between Oxidized LDL, IgM, and IgG Autoantibodies to ox-LDL Levels With Recurrent Cardiovascular Events in Swedish Patients With Previous Myocardial Infarction. Angiology 2013.
  28. Tsimikas S, Clopton P, Brilakis ES, Marcovina SM, Khera A, Miller ER, et al. Relationship of oxidized phospholipids on apolipoprotein B-100 particles to race/ethnicity, apolipoprotein(a) isoform size, and cardiovascular risk factors: results from the Dallas Heart Study. Circulation. 2009;119(13):1711–9.
  29. Bertoia ML, Pai JK, Lee JH, Taleb A, Joosten MM, Mittleman MA, et al. Oxidation-specific biomarkers and risk of peripheral artery disease. J Am Coll Cardiol. 2013;61(21):2169–79.
  30. Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, et al. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation. 2001;103(15):1955–60.
  31. Ehara S, Ueda M, Naruko T, Haze K, Matsuo T, Ogami M, et al. Pathophysiological role of oxidized low-density lipoprotein in plaque instability in coronary artery diseases. J Diabetes Complications. 2002;16(1):60–4.
  32. Kayo S, Ohsawa M, Ehara S, Naruko T, Ikura Y, Hai E, et al. Oxidized low-density lipoprotein levels circulating in plasma and deposited in the tissues: comparison between Helicobacter pylori-associated gastritis and acute myocardial infarction. Am Heart J. 2004;148(5):818–25.
  33. Tsimikas S, Bergmark C, Beyer RW, Patel R, Pattison J, Miller E, et al. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J Am Coll Cardiol. 2003;41(3):360–70.
  34. Uno M, Kitazato KT, Nishi K, Itabe H, Nagahiro S. Raised plasma oxidised LDL in acute cerebral infarction. J Neurol Neurosurg Psychiatry. 2003;74(3):312–6.
  35. Uno M, Harada M, Takimoto O, Kitazato KT, Suzue A, Yoneda K, et al. Elevation of plasma oxidized LDL in acute stroke patients is associated with ischemic lesions depicted by DWI and predictive of infarct enlargement. Neurological research. 2005;27(1):94–102.
  36. Uno M, Kitazato KT, Suzue A, Matsuzaki K, Harada M, Itabe H, et al. Inhibition of brain damage by edaravone, a free radical scavenger, can be monitored by plasma biomarkers that detect oxidative and astrocyte damage in patients with acute cerebral infarction. Free Radic Biol Med. 2005;39(8):1109–16.
  37. Leibundgut G, Arai K, Orsoni A, Yin H, Scipione C, Miller ER, et al. Oxidized phospholipids are present on plasminogen, affect fibrinolysis, and increase following acute myocardial infarction. J Am Coll Cardiol. 2012;59(16):1426–37.
  38. Tsimikas S, Lau HK, Han KR, Shortal B, Miller ER, Segev A, et al. Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation. 2004;109(25):3164–70.
  39. Fefer P, Tsimikas S, Segev A, Sparkes J, Otsuma F, Kolodgie F, et al. The role of oxidized phospholipids, lipoprotein (a) and biomarkers of oxidized lipoproteins in chronically occluded coronary arteries in sudden cardiac death and following successful percutaneous revascularization. Cardiovasc Revasc Med. 2012;13(1):11–9.
  40. Segev A, Strauss BH, Witztum JL, Lau HK, Tsimikas S. Relationship of a comprehensive panel of plasma oxidized low-density lipoprotein markers to angiographic restenosis in patients undergoing percutaneous coronary intervention for stable angina. Am Heart J. 2005;150(5):1007–14.
  41. Naruko T, Ueda M, Ehara S, Itoh A, Haze K, Shirai N, et al. Persistent high levels of plasma oxidized low-density lipoprotein after acute myocardial infarction predict stent restenosis. Arterioscler Thromb Vasc Biol. 2006;26(4):877–83.
  42. Ravandi A, Leibundgut G, Hung MY, Patel M, Hutchins PM, Murphy RC, et al. Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans. J Am Coll Cardiol. 2014;63(19):1961–71.
  43. Frey B, Haupt R, Alms S, Holzmann G, Konig T, Kern H, et al. Increase in fragmented phosphatidylcholine in blood plasma by oxidative stress. J Lipid Res. 2000;41(7):1145–53.
  44. Tsimikas S, Witztum JL, Miller ER, Sasiela WJ, Szarek M, Olsson AG, et al. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation. 2004;110(11):1406–12.
  45. Fraley AE, Schwartz GG, Olsson AG, Kinlay S, Szarek M, Rifai N, et al. Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial. J Am Coll Cardiol. 2009;53(23):2186–96.
  46. Yoshida H, Shoda T, Yanai H, Ikewaki K, Kurata H, Ito K, et al. Effects of pitavastatin and atorvastatin on lipoprotein oxidation biomarkers in patients with dyslipidemia. Atherosclerosis. 2013;226(1):161–4.
  47. Choi SH, Chae A, Miller E, Messig M, Ntanios F, DeMaria AN, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol. 2008;52(1):24–32.
  48. Ky B, Burke A, Tsimikas S, Wolfe ML, Tadesse MG, Szapary PO, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol. 2008;51(17):1653–62.
  49. Rodenburg J, Vissers MN, Wiegman A, Miller ER, Ridker PM, Witztum JL, et al. Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin. J Am Coll Cardiol. 2006;47(9):1803–10.
  50. Faghihnia N, Tsimikas S, Miller ER, Witztum JL, Krauss RM. Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet. J Lipid Res. 2010;51(11):3324–30.
  51. Ahmadi N, Tsimikas S, Hajsadeghi F, Saeed A, Nabavi V, Bevinal MA, et al. Relation of oxidative biomarkers, vascular dysfunction, and progression of coronary artery calcium. Am J Cardiol. 2010;105(4):459–66.
  52. Tsimikas S, Aikawa M, Miller FJ, Jr., Miller ER, Torzewski M, Lentz SR, et al. Increased plasma oxidized phospholipid:apolipoprotein B-100 ratio with concomitant depletion of oxidized phospholipids from atherosclerotic lesions after dietary lipid-lowering: a potential biomarker of early atherosclerosis regression. Arterioscler Thromb Vasc Biol. 2007;27(1):175–81.
  53. Inami S, Okamatsu K, Takano M, Takagi G, Sakai S, Sano J, et al. Effects of statins on circulating oxidized low-density lipoprotein in patients with hypercholesterolemia. Japanese Heart J. 2004;45(6):969–75.
  54. Penny WF, Ben-Yehuda O, Kuroe K, Long J, Bond A, Bhargava V, et al. Improvement of coronary artery endothelial dysfunction with lipid-lowering therapy: heterogeneity of segmental response and correlation with plasma-oxidized low density lipoprotein. J Am Coll Cardiol. 2001;37(3):766–74.
  55. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005;112(20):3066–72.
  56. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA: the journal of the American Medical Association. 2001;286(3):327–34.
  57. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev. 2002;23(5):599–622.
  58. Mertens A, Verhamme P, Bielicki JK, Phillips MC, Quarck R, Verreth W, et al. Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation. 2003;107(12):1640–6.
  59. Yoshida H, Ishikawa T, Nakamura H. Vitamin E/lipid peroxide ratio and susceptibility of LDL to oxidative modification in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol. 1997;17(7):1438–46.
  60. Mastorikou M, Mackness M, Mackness B. Defective metabolism of oxidized phospholipid by HDL from people with type 2 diabetes. Diabetes. 2006;55(11):3099–103.
  61. Lopes-Virella MF, Baker NL, Hunt KJ, Lachin J, Nathan D, Virella G, et al. Oxidized LDL immune complexes and coronary artery calcification in type 1 diabetes. Atherosclerosis. 2011;214(2):462–7.
  62. Ujihara N, Sakka Y, Takeda M, Hirayama M, Ishii A, Tomonaga O, et al. Association between plasma oxidized low-density lipoprotein and diabetic nephropathy. Diabetes Res Clin Pract. 2002;58(2):109–14.
  63. Trevisan R, Dodesini AR, Lepore G. Lipids and renal disease. Journal of the American Society of Nephrology: JASN 2006;17(4 Suppl 2):S145–7.
  64. Magil AB, Frohlich JJ, Innis SM, Steinbrecher UP. Oxidized low-density lipoprotein in experimental focal glomerulosclerosis. Kidney Int. 1993;43(6):1243–50.
  65. Maggi E, Bellazzi R, Falaschi F, Frattoni A, Perani G, Finardi G, et al. Enhanced LDL oxidation in uremic patients: an additional mechanism for accelerated atherosclerosis? Kidney Int. 1994;45(3):876–83.
  66. Ward RA, McLeish KR. Oxidant stress in hemodialysis patients: what are the determining factors? Artif Organs. 2003;27(3):230–6.
  67. Lee YK, Lee DH, Kim JK, Park MJ, Yan JJ, Song DK, et al. Lysophosphatidylcholine, oxidized low-density lipoprotein and cardiovascular disease in Korean hemodialysis patients: analysis at 5 years of follow-up. J Korean Med Sci. 2013;28(2):268–73.
  68. Bossola M, Tazza L, Luciani G, Tortorelli A, Tsimikas S. OxPL/apoB, lipoprotein(a) and OxLDL biomarkers and cardiovascular disease in chronic hemodialysis patients. J Nephrol. 2011;24(5):581–8.
  69. Koppaka V, Paul C, Murray IV, Axelsen PH. Early synergy between Abeta42 and oxidatively damaged membranes in promoting amyloid fibril formation by Abeta40. J Biol Chem. 2003;278(38):36277–84.
  70. Ross BM, Mamalias N, Moszczynska A, Rajput AH, Kish SJ. Elevated activity of phospholipid biosynthetic enzymes in substantia nigra of patients with Parkinson’s disease. Neuroscience. 2001;102(4):899–904.
  71. Rinaldi L, Grassivaro F, Gallo P. Lipids in Multiple Sclerosis. In: Lajtha A, Tettamanti G, Goracci G. Handbook of Neurochemistry and Molecular Neurobiologyed.: Springer US, 2010:593–602.
  72. Qin J, Goswami R, Balabanov R, Dawson G. Oxidized phosphatidylcholine is a marker for neuroinflammation in multiple sclerosis brain. J Neurosci Res. 2007;85(5):977–84.
  73. Miketova P, Kaemingk K, Hockenberry M, Pasvogel A, Hutter J, Krull K, et al. Oxidative changes in cerebral spinal fluid phosphatidylcholine during treatment for acute lymphoblastic leukemia. Biol Res Nurs. 2005;6(3):187–95.
  74. Caron JE, Krull KR, Hockenberry M, Jain N, Kaemingk K, Moore IM. Oxidative stress and executive function in children receiving chemotherapy for acute lymphoblastic leukemia. Pediatric blood & cancer. 2009;53(4):551–6.
  75. Stenzel SL, Krull KR, Hockenberry M, Jain N, Kaemingk K, Miketova P, et al. Oxidative stress and neurobehavioral problems in pediatric acute lymphoblastic leukemia patients undergoing chemotherapy. J Pediatr Hematol Oncol. 2010;32(2):113–8.
  76. Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133(2):235–49.
  77. Birukova AA, Starosta V, Tian X, Higginbotham K, Koroniak L, Berliner JA, et al. Fragmented oxidation products define barrier disruptive endothelial cell response to OxPAPC. Translational research: J Lab Clin Med. 2013;161(6):495–504.
  78. Starosta V, Wu T, Zimman A, Pham D, Tian X, Oskolkova O, et al. Differential regulation of endothelial cell permeability by high and low doses of oxidized 1–palmitoyl-2–arachidonyl-sn-glycero-3–phosphocholine. Am J Respir Cell Mol Biol. 2012;46(3):331–41.
  79. Ma Z, Li J, Yang L, Mu Y, Xie W, Pitt B, et al. Inhibition of LPS- and CpG DNA-induced TNF-alpha response by oxidized phospholipids. Am J Physiol Lung Cell Mol Physiol. 2004;286(4):L808–16.
  80. Nonas S, Miller I, Kawkitinarong K, Chatchavalvanich S, Gorshkova I, Bochkov VN, et al. Oxidized phospholipids reduce vascular leak and inflammation in rat model of acute lung injury. Am J Respir Crit Care Med. 2006;173(10):1130–8.
  81. Cruz D, Watson AD, Miller CS, Montoya D, Ochoa MT, Sieling PA, et al. Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy. J Clin Invest. 2008;118(8):2917–28.
  82. Navaneethan U, Gutierrez NG, Venkatesh PG, Jegadeesan R, Zhang R, Jang S, et al. Lipidomic profiling of bile in distinguishing benign from malignant biliary strictures: a single-blinded pilot study. Am J Gastroenterol. 2014;109(6):895–902.

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