Skip to main content

Advertisement

SpringerLink
Log in

Reducing oxidized lipids to prevent cardiovascular disease

  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Opinion statement

Despite significant success in reducing plasma cholesterol, especially low-density lipoprotein cholesterol, risks for cardiovascular disease (CVD) complications remain. Among these risks are circulating levels of oxidative modified lipoproteins, primarily oxidized low-density lipoproteins (oxLDL). The evidence supporting oxLDL as a potential target for therapeutic management to reduce metabolic complications and CVD events is reviewed in this report.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Brown MS, Goldstein JL, Krieger M, et al.: Reversible accumulation of cholesteryl ester in macrophages incubated with acetylated lipoproteins. J Cell Biol 1979, 82:597–613.

    Article  CAS  PubMed  Google Scholar 

  2. Fogelman AM, Schechter I, Seager J: Malondialdehyde alteration of LDL leads to cholesteryl ester accumulation in human monocyte macrophages. Proc Natl Acad Sci U S A 1980, 77:2214–2218.

    Article  CAS  PubMed  Google Scholar 

  3. Shechter I, Fogelman AM, Haberland ME, et al.: The metabolism of native and MDA-altered LDL by human monocyte-macrophages. J Lipid Res 1981, 22:63–71.

    CAS  PubMed  Google Scholar 

  4. Morel DW, DiCorleto PE, Chisolm GM: Endothelial and smooth muscle cells alter LDL in vitro by free radical oxidation. Arteriosclerosis 1984, 4:357–364.

    CAS  PubMed  Google Scholar 

  5. Cathcart MK, McNally AK, Morel DW, et al.: Superoxide anion participation in human monocyte-mediated oxidation of LDL and conversion of LDL to a cytotoxin. J Immunol 1989, 142:1963–1969.

    CAS  PubMed  Google Scholar 

  6. Sparrow CP, Olszewski J: Cellular oxidation of LDL is caused by thiol production in media containing transition metal ions. J Lipid Res 1993, 34:1219–1228.

    CAS  PubMed  Google Scholar 

  7. Avogaro P, Bittolo Bon G, Cazzolato G: Presence of a modi- fied LDL in humans. Arteriosclerosis 1988, 8:79–87.

    CAS  PubMed  Google Scholar 

  8. Yla-Herttuala S, Palinski W, Rosenfeld ME, et al.: Evidence for the presence of oxidatively modified LDL in atherosclerotic lesions of rabbit and man. J Clin Invest 1989, 84:1086–1095.

    Article  CAS  PubMed  Google Scholar 

  9. Palinski W, Rosenfeld ME, Yla-Herttuala S, et al.: LDL undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A 1989, 86:1372–1376.

    Article  CAS  PubMed  Google Scholar 

  10. Palinski W, Horkko S, Miller E, et al.: Cloning of MAb to epitopes of oxidized lipoproteins from apoE-deficient mice. Demonstration of epitopes of oxidized LDL in human plasma. J Clin Invest 1996, 98:800–814.

    Article  CAS  PubMed  Google Scholar 

  11. Yla-Herttuala S, Palinski W, Butler SW, et al.: Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb 1994, 14:32–40.

    CAS  PubMed  Google Scholar 

  12. Salonen JT, Yla-Herttuala S, Yamamoto R, et al.: Autoantibody against LDL and progression of carotid atherosclerosis. Lancet 1992, 339:883–887.

    Article  CAS  PubMed  Google Scholar 

  13. van de Vijver LPL, Steyger R, van Poppel G, et al.: Autoantibodies against MDA-LDL in subjects with severe and minor atherosclerosis and healthy population controls. Atherosclerosis 1996, 122:245–253.

    Article  PubMed  Google Scholar 

  14. Palinski W, Miller E, Witztum JL: Immunization of LDL receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherosclerosis. Proc Natl Acad Sci U S A 1995, 92:821–825.

    Article  CAS  PubMed  Google Scholar 

  15. Palinski W, Tangirala RK, Miller E, et al.: Increased autoantibody titers against epitopes of oxidized LDL in LDL-receptor deficient mice with increased atherosclerosis. Arterioscler Thromb Vasc Biol 1995, 15:1569–1576.

    CAS  PubMed  Google Scholar 

  16. Le N-A, Li X, Kyung S, Brown WV: Evidence for the in vivo generation of oxidatively modified epitopes in patients with documented CAD. Metabolism 2000, 49:1271–1277.

    Article  CAS  PubMed  Google Scholar 

  17. Gradek Q, Harris M, Yahia N, et al.: Polyunsaturated fatty acids acutely suppress antibodies to malondialdehyde-modified LDL in patients with vascular disease. Am J Cardiol 2004, 93:881–885.

    Article  CAS  PubMed  Google Scholar 

  18. Rae TD, Schmidt PJ, Pufahl RA, et al.: Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 1999, 284:805–808.

    Article  CAS  PubMed  Google Scholar 

  19. Stocker R, Keaney JF Jr: Role of oxidative modifications in atherosclerosis. Physiol Rev 2004, 84:1381–1478.

    Article  CAS  PubMed  Google Scholar 

  20. Ushio-Fukai M, Tang Y, Fukai T, et al.: Novel role of gp91phox-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 2002, 91:1160–1167.

    Article  CAS  PubMed  Google Scholar 

  21. Fleming I, Busse R: Molecular mechanisms involved in the regulation of endothelial nitric oxide synthase. Am J Physiol 2003, 284:R1–R13.

    CAS  Google Scholar 

  22. Hazell LJ, Stocker R: Oxidation of LDL with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages. Biochem J 1993, 290:165–172.

    CAS  PubMed  Google Scholar 

  23. Cathcart MK, McNally AK, Chisolm GM: Lipoxygenase-mediated transformation of human LDL to an oxidized and cytotoxic complex. J Lipid Res 1991, 32:63–70.

    CAS  PubMed  Google Scholar 

  24. Yla-Herttuala S, Rosenfeld ME, Parthasarathy S, et al.: Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl LDL receptor mRNA colocalize with oxidation specific lipid-protein adducts. J Clin Invest 1991, 87:1146–1152.

    Article  CAS  PubMed  Google Scholar 

  25. Rabini RA, Tesei M, Galeazzi T, et al.: Increased susceptibility to peroxidation of VLDL from non-insulin-dependent diabetic patients: a possible correlation with fatty acid composition. Molec Cell Biochem 1999, 199:63–67.

    Article  CAS  PubMed  Google Scholar 

  26. McEneny J, O’Kane MJ, Moles KW, et al.: VLDL subfractions in type II diabetes mellitus: alterations in composition and susceptibility to oxidation. Diabetologia 2000, 43:485–493.

    Article  CAS  PubMed  Google Scholar 

  27. Nakajima K, Nakano T, Tanaka A: The oxidative modification hypothesis of atherosclerosis: the comparison of atherogenic effects of oxidized LDL and remnant lipoproteins in plasma. Clin Chim Acta 2006, 367:36–47.

    Article  CAS  PubMed  Google Scholar 

  28. Mabile L, Salvayre R, Bonnafe M-J, Negre-Salvayre A: Oxidizability and subsequent cytotoxicity of chylomicrons to monocytic U937 and endothelial cells are dependent on dietary fatty acid composition. Free Radic Biol Med 1995, 19:599–607.

    Article  CAS  PubMed  Google Scholar 

  29. Watson AD, Leitinger N, Navab M, et al.: Structural identification by mass spectroscopy of oxidized phospholipids in minimally oxidized LDL that induce monocyte/endothelial interactions and evidence for their presence in vivo. J Biol Chem 1997, 272:13597–13607.

    Article  CAS  PubMed  Google Scholar 

  30. Itabe H, Yamamoto H, Imanaka T, et al.: Sensitive detection of oxidatively modified LDL using a monoclonal antibody. J Lipid Res 1996, 37:45–53.

    CAS  PubMed  Google Scholar 

  31. Tsimikas S: Measures of oxidative stress. Clin Lab Med 2006, 26:571–590.

    Article  PubMed  Google Scholar 

  32. Shimada K, Mokuno H, Matsunaga E, et al.: Circulating oxidized LDL is an independent predictor for cardiac event in patients with coronary artery disease. Atherosclerosis 2004, 174:343–347.

    CAS  PubMed  Google Scholar 

  33. Kiechl S, Willeit J, Mayr M, et al.: Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes. Arterioscler Thromb Vasc Biol 2007, 27:1788–1795.

    Article  CAS  PubMed  Google Scholar 

  34. Stocker R, Bowry VW, Frei B: Ubiquinol-10 protects human LDL more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci U S A 1991, 88:1646–1650.

    Article  CAS  PubMed  Google Scholar 

  35. Ezaki M, Witztum JL, Steinberg D: Lipoperoxides in LDL incubated with fibroblasts that overexpress 15-lipoxygenase. J Lipid Res 1995, 36:1996–2004.

    CAS  PubMed  Google Scholar 

  36. Holvoet P, Donck J, Landeloos M, et al.: Correlation between oxidized LDL and von Willebrand factor in chronic renal failure. Thromb Haemost 1996, 76:663–669.

    CAS  PubMed  Google Scholar 

  37. Esterbauer H, Striegl G, Puhl H, Rotheneder M: Continuous monitoring of in vitro oxidation of human LDL. Free Radic Res Commun 1989, 6:67–75.

    Article  CAS  PubMed  Google Scholar 

  38. Hendrickson A, McKinstry LA, Lewis JK, et al.: Ex vivo measures of LDL oxidative susceptibility predict carotid artery disease. Atherosclerosis 2005, 179:147–153.

    Article  CAS  PubMed  Google Scholar 

  39. Salonen R, Nyyssonen K, Porkkala-Sarataho E, Salonen JT: The Kupio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipid, oxidation resistance of lipoproteins, and atherosclerotic progression. Am J Cardiol 1995, 76:34C–39C.

    Article  CAS  PubMed  Google Scholar 

  40. Shishehbor MH, Brennan M-L, Aviles RJ, et al.: Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003, 108:426–431.

    Article  CAS  PubMed  Google Scholar 

  41. Heistad DD: Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 2006, 26:689–695.

    Article  CAS  PubMed  Google Scholar 

  42. Sentman ML, Brannstrom T, Westerlund S, et al.: ecSOD deficiency and atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2001, 21:1477–1482.

    Article  CAS  PubMed  Google Scholar 

  43. Yang H, Roberts LJ, Shi MJ, et al.: Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ Res 2004, 95:1075–1081.

    Article  CAS  PubMed  Google Scholar 

  44. Mackness MI, Arrol S, Durrington PN: Paraoxonase prevents accumulation of lipoperoxides in LDL. FEBS Lett 1991, 286:152–154.

    Article  CAS  PubMed  Google Scholar 

  45. Aviram M, Hardak E, Vava J, et al.: Human serum PON1 Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities. Circulation 2000, 101:2510–2517.

    CAS  PubMed  Google Scholar 

  46. Mackness B, Prington P, McElduff P, et al.: Low PON1 activity predicts coronary events in the Caerphilly Prospective Study. Circulation 2003, 107:2775–2779.

    Article  CAS  PubMed  Google Scholar 

  47. Paragh G, Balogh Z, Seres I, et al.: Effect of gemfibrozil on HDL-associated serum paraoxonase activity and lipoprotein profile in patients with hyperlipidemia. Clin Drug Invest 2000, 19:277–282.

    Article  CAS  Google Scholar 

  48. Tomas M, Senti M, Garcia-Faria F, et al.: Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2000, 20:2113–2119.

    CAS  PubMed  Google Scholar 

  49. Arthur JR: The glutathione peroxidases. Cell Mol Life Sci 2000, 57:1825–1935.

    Article  CAS  PubMed  Google Scholar 

  50. Hurt-Camejo E, Camejo G, Peilot H, et al.: Phospholipase A2 in vascular disease. Circ Res 2001, 89:298–304.

    Article  CAS  PubMed  Google Scholar 

  51. Packard CJ, O’Reilly DS, Caslake MJ, et al.: Lp-PLA2 as an independent predictor of coronary heart disease. N Engl J Med 2000, 343:1148–1155.

    Article  CAS  PubMed  Google Scholar 

  52. Caslake MJ, Packard CJ: Lp-PLA2 as a biomarker for coronary disease and stroke. Nat Clin Pract 2005, 2:529–535.

    Article  CAS  Google Scholar 

  53. Schaefer EJ, McNamara JR, Asztalos BF, et al.: Effect of atorvastatin versus other statins on fasting and postprandial hsCRP and Lp-PLA2 in patients with coronary heart disease versus control subjects. Am J Cardiol 2005, 95:1025–1032.

    Article  CAS  PubMed  Google Scholar 

  54. Tsimihodomos V, Kostoula A, Kakafika A, et al.: Effect of fenofibrate on serum inflammatory markers in patients with high triglyceride values. J Cardiovasc Pharmacol Ther 2004, 9:27–33.

    Article  Google Scholar 

  55. Zalewski A, Macphee CH: Role of Lp-PLA2 in atherosclerosis. Arterioscler Thromb Vasc Biol 2005, 25:923–931.

    Article  CAS  PubMed  Google Scholar 

  56. Nielsen NS, Pedersen A, Sandström B, et al.: Different effects of diets rich in olive oil, rapeseed oil and sunflower-seed oil on postprandial lipid and lipoprotein concentrations and on lipoprotein oxidation susceptibility. Br J Nutr 2002, 87:489–499.

    Article  CAS  PubMed  Google Scholar 

  57. Kaikkonen J, Porkkala-Sarataho E, Tuomainen TP, et al.: Exhaustive exercise increases plasma/serum total oxidation resistance in moderately trained men and women, whereas their VLDL+LDL lipoprotein fraction is more susceptible to oxidation. Scand J Clin Lab Invest 2002, 62:599–608.

    Article  CAS  PubMed  Google Scholar 

  58. Shern-Brewer R, Santanam N, Wetzstein C, et al.: Exercise and cardiovascular disease: a new perspective. Arterioscler Thromb Vasc Biol 1998, 18:1181–1187.

    CAS  PubMed  Google Scholar 

  59. Parthasarathy S, Santanam N, Ramachandran S, Meilhac O: Potential role of oxidized lipids and lipoproteins in antioxidant defense. Free Radic Res 2000, 33:197–215.

    Article  CAS  PubMed  Google Scholar 

  60. Silaste ML, Rantala M, Alfthan G, et al.: Changes in dietary fat intake alter plasma levels of oxidized low-density lipoprotein and lipoprotein(a). Arterioscler Thromb Vasc Biol 2004, 24:498–503.

    Article  CAS  PubMed  Google Scholar 

  61. Nielsen NS, Marckmann P, Høy C: Effect of meal fat quality on oxidation resistance of postprandial VLDL and LDL particles and plasma triacylglycerol level. Br J Nutr 2000, 84:855–863.

    CAS  PubMed  Google Scholar 

  62. Parthasarathy S, Khoo JC, Miller E, et al.: LDL rich in oleic acid is protected against oxidative modification: implications for dietary prevention of atherosclerosis. Proc Natl Acad Sci U S A 1990, 87:3894–3898.

    Article  CAS  PubMed  Google Scholar 

  63. Fito M, Guxens M, Corella D, et al.: Effect of a traditional Mediterranean diet on lipoprotein oxidation. Arch Intern Med 2007, 167:1195–1203.

    Article  PubMed  Google Scholar 

  64. Kris-Etherton PM, Lichtenstein AH, Howard BV, et al.: Antioxidant vitamin supplements and cardiovascular disease. Circulation 2004, 110:637–641.

    Article  CAS  PubMed  Google Scholar 

  65. Wen Y, Killalea S, Norris LA, et al.: Vitamin E supplementation in hyperlipidaemic patients: effect of increasing doses on in vitro and in vivo LDL oxidation. Eur J Clin Invest 1999, 29:1027–1034.

    Article  CAS  PubMed  Google Scholar 

  66. Hodis HN, Mack WJ, LaBree L, et al.: Alpha-tocopherol supplementation in healthy individuals reduces LDL oxidation but not atherosclerosis. Circulation 2002, 106:1453–1459.

    Article  CAS  PubMed  Google Scholar 

  67. Zilversmit DB: Atherogenesis: a postprandial phenomenon. Circulation 1979, 60:473–485.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Emory Lipid Research Laboratory, Emory University and Atlanta Veterans’ Affairs Medical Center, 1670 Clairmont Road, Room 4A187, Decatur, GA, 30033, USA

    Ngoc-Anh Le

Authors
  1. Ngoc-Anh Le
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ngoc-Anh Le.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Le, NA. Reducing oxidized lipids to prevent cardiovascular disease. Curr Treat Options Cardiovasc Med 10, 263–272 (2008). https://doi.org/10.1007/s11936-008-0047-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11936-008-0047-4

Keywords

Search

Navigation