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Oxidized lipids: The two faces of vascular inflammation

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Abstract

Elevated plasma levels of low-density lipoprotein and generation of oxidized low-density lipoprotein have been directly associated with the pathogenesis of atherosclerosis, and lipid oxidation products have been directly linked with induction and propagation of monocytic subendothelial accumulation and other inflammatory reactions associated with chronic vascular inflammation. However, accumulating data suggest that oxidized lipids may also exhibit anti-inflammatory potential and serve as potent inhibitors of nuclear factor-κB-dependent proinflammatory cascade. In addition, we have characterized a group of bioactive components of oxidized phospholipids with barrier-protective effects towards endothelial cells in the models of agonist-induced endothelial permeability and lipopolysaccharide-induced lung dysfunction. This review discusses the role of oxidized lipids in the progression of atherosclerosis as well as the important anti-inflammatory effects of oxidized phospholipids and their potential role in the modulation of vascular barrier integrity.

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References and Recommended Reading

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

    Article  PubMed  CAS  Google Scholar 

  2. Bochkov VN, Kadl A, Huber J, et al.: Protective role of phospholipid oxidation products in endotoxin-induced tissue damage. Nature 2002, 419:77–81.

    Article  PubMed  CAS  Google Scholar 

  3. Bochkov VN, Leitinger N: Anti-inflammatory properties of lipid oxidation products. J Mol Med 2003, 81:613–626.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Zhang W, Salomon RG: Oxidized phospholipids, isolevuglandins, and atherosclerosis. Mol Nutr Food Res 2005, 49:1050–1062.

    Article  PubMed  CAS  Google Scholar 

  6. Watson AD, Subbanagounder G, Welsbie DS, et al.: Structural identification of a novel pro-inflammatory epoxyisoprostane phospholipid in mildly oxidized low density lipoprotein. J Biol Chem 1999, 274:24787–24798.

    Article  PubMed  CAS  Google Scholar 

  7. Subbanagounder G, Leitinger N, Schwenke DC, et al.: Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position. Arterioscler Thromb Vasc Biol 2000, 20:2248–2254.

    PubMed  CAS  Google Scholar 

  8. Navab M, Imes SS, Hama SY, et al.: Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest 1991, 88:2039–2046.

    PubMed  CAS  Google Scholar 

  9. Kubes P, Suzuki M, Granger DN: Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991, 88:4651–4655.

    Article  PubMed  CAS  Google Scholar 

  10. Ehara S, Ueda M, Naruko T, et al.: Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation 2001, 103:1955–1960.

    PubMed  CAS  Google Scholar 

  11. Tsimikas S, Lau HK, Han KR, 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, 109:3164–3170.

    Article  PubMed  CAS  Google Scholar 

  12. Wu R, Shen G, Morris R, et al.: Elevated autoantibodies against oxidized palmitoyl arachidonoyl phosphocholine in patients with hypertension and myocardial infarction. J Autoimmun 2005, 24:353–360.

    Article  PubMed  CAS  Google Scholar 

  13. Arakawa H, Qian JY, Baatar D, et al.: Local expression of platelet-activating factor-acetylhydrolase reduces accumulation of oxidized lipoproteins and inhibits inflammation, shear stress-induced thrombosis, and neointima formation in balloon-injured carotid arteries in nonhyperlipidemic rabbits. Circulation 2005, 111:3302–3309.

    Article  PubMed  CAS  Google Scholar 

  14. Doria A, Shoenfeld Y, Wu R, et al.: Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003, 62:1071–1077.

    Article  PubMed  CAS  Google Scholar 

  15. Takahashi Y, Zhu H, Yoshimoto T: Essential roles of lipoxygenases in LDL oxidation and development of atherosclerosis. Antioxid Redox Signal 2005, 7:425–431.

    Article  PubMed  CAS  Google Scholar 

  16. Bochkov VN, Leitinger N, Birukov KG: Role of oxidized phospholipids in acute lung injury. Curr Resp Med Rev 2006, 2:27–37.

    Article  CAS  Google Scholar 

  17. Leitinger N: Oxidized phospholipids as triggers of inflammation in atherosclerosis. Mol Nutr Food Res 2005, 49:1063–1071.

    Article  PubMed  CAS  Google Scholar 

  18. Subbanagounder G, Wong JW, Lee H, et al.: Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1beta. J Biol Chem 2002, 277:7271–7281.

    Article  PubMed  CAS  Google Scholar 

  19. Furnkranz A, Schober A, Bochkov VN, et al.: Oxidized phospholipids trigger atherogenic inflammation in murine arteries. Arterioscler Thromb Vasc Biol 2005, 25:633–638.

    Article  PubMed  CAS  Google Scholar 

  20. Ninio E: Phospholipid mediators in the vessel wall: involvement in atherosclerosis. Curr Opin Clin Nutr Metab Care 2005, 8:123–131.

    Article  PubMed  CAS  Google Scholar 

  21. Shashkin P, Dragulev B, Ley K: Macrophage differentiation to foam cells. Curr Pharm Des 2005, 11:3061–3072.

    Article  PubMed  CAS  Google Scholar 

  22. Jude B, Zawadzki C, Susen S, et al.: Relevance of tissue factor in cardiovascular disease. Arch Mal Coeur Vaiss 2005, 98:667–671.

    PubMed  CAS  Google Scholar 

  23. Bochkov VN, Mechtcheriakova D, Lucerna M, et al.: Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca(++)/NFAT. Blood 2002, 99:199–206.

    Article  PubMed  CAS  Google Scholar 

  24. Macdonald J, Galley HF, Webster NR: Oxidative stress and gene expression in sepsis. Br J Anaesth 2003, 90:221–232.

    Article  PubMed  CAS  Google Scholar 

  25. Ma Z, Li J, Yang L, et al.: Inhibition of LPS- and CpG DNA-induced TNF-alpha response by oxidized phospholipids. Am J Physiol Lung Cell Mol Physiol 2004, 286: L808-L816.

    Article  PubMed  CAS  Google Scholar 

  26. Walton KA, Cole AL, Yeh M, et al.: Specific phospholipid oxidation products inhibit ligand activation of toll-like receptors 4 and 2. Arterioscler Thromb Vasc Biol 2004, 23:1197–1203.

    Article  CAS  Google Scholar 

  27. Bluml S, Kirchberger S, Bochkov VN, et al.: Oxidized phospholipids negatively regulate dendritic cell maturation induced by TLRs and CD40. J Immunol 2005, 175:501–508.

    PubMed  Google Scholar 

  28. Friedl R, Pichler I, Spieckermann P, et al.: Oxidized phospatidylcholine but not native phosphatidylcholine inhibits inducible nitric oxide synthase in RAW 264.7 macrophages. Life Sci 2005, In press.

  29. Riedemann NC, Guo RF, Ward PA: Novel strategies for the treatment of sepsis. Nat Med 2003, 9:517–524.

    Article  PubMed  CAS  Google Scholar 

  30. Birukov KG, Bochkov VN, Birukova AA, et al.: Epoxycyclopentenone-containing oxidized phospholipids restore endothelial barrier function via Cdc42 and Rac. Circ Res 2004, 95:892–901.

    Article  PubMed  CAS  Google Scholar 

  31. Chang MK, Binder CJ, Miller YI, et al.: Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J Exp Med 2004, 200:1359–1370.

    Article  PubMed  CAS  Google Scholar 

  32. Cole AL, Subbanagounder G, Mukhopadhyay S, et al.: Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway. Arterioscler Thromb Vasc Biol 2003, 23:1384–1390.

    Article  PubMed  CAS  Google Scholar 

  33. Birukov KG, Leitinger N, Bochkov VN, et al.: Signal transduction pathways activated in human pulmonary endothelial cells by OxPAPC, a bioactive component of oxidized lipoproteins. Microvasc Res 2004, 67:18–28.

    Article  PubMed  CAS  Google Scholar 

  34. Yeh M, Gharavi NM, Choi J, et al.: Oxidized phospholipids increase interleukin 8 (IL-8) synthesis by activation of the c-src/signal transducers and activators of transcription (STAT)3 pathway. J Biol Chem 2004, 279:30175–30181.

    Article  PubMed  CAS  Google Scholar 

  35. Subbanagounder G, Leitinger N, Shih PT, et al.: Evidence that phospholipid oxidation products and/or platelet-activating factor play an important role in early atherogenesis: in vitro and In vivo inhibition by WEB 2086. Circ Res 1999, 85:311–318.

    PubMed  CAS  Google Scholar 

  36. Kadl A, Huber J, Gruber F, et al.: Analysis of inflammatory gene induction by oxidized phospholipids in vivo by quantitative real-time RT-PCR in comparison with effects of LPS. Vascul Pharmacol 2002, 38:219–227.

    Article  PubMed  CAS  Google Scholar 

  37. Leitinger N, Tyner TR, Oslund L, et al.: Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils. Proc Natl Acad Sci U S A 1999, 96:12010–12015.

    Article  PubMed  CAS  Google Scholar 

  38. Medzhitov R: Toll-like receptors and innate immunity. Nat Rev Immunol 2001, 1:135–145.

    Article  PubMed  CAS  Google Scholar 

  39. Shi W, Wang NJ, Shih DM, et al.: Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model: evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism. Circ Res 2000, 86:1078–1084.

    PubMed  CAS  Google Scholar 

  40. Reddy ST, Grijalva V, Ng C, et al.: Identification of genes induced by oxidized phospholipids in human aortic endothelial cells. Vascul Pharmacol 2002, 38:211–218.

    Article  PubMed  CAS  Google Scholar 

  41. Liao F, Andalibi A, DeBeer FC, et al.: Genetic control of inflammatory gene induction and NF-kappa B-like transcription factor activation in response to an atherogenic diet in mice. J Clin Invest 1993, 91:2572–2579.

    PubMed  CAS  Google Scholar 

  42. Feng J, Han J, Pearce SF, et al.: Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J Lipid Res 2000, 41:688–696.

    PubMed  CAS  Google Scholar 

  43. Fischer B, von Knethen A, Brune B: Dualism of oxidized lipoproteins in provoking and attenuating the oxidative burst in macrophages: role of peroxisome proliferator-activated receptor-gamma. J Immunol 2002, 168:2828–2834.

    PubMed  CAS  Google Scholar 

  44. Leitinger N: Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol 2003, 14:421–430.

    Article  PubMed  CAS  Google Scholar 

  45. Thai SF, Lewis JG, Williams RB, et al.: Effects of oxidized LDL on mononuclear phagocytes: inhibition of induction of four inflammatory cytokine gene RNAs, release of NO, and cytolysis of tumor cells. J Leukoc Biol 1995, 57:427–433.

    PubMed  CAS  Google Scholar 

  46. Ohlsson BG, Englund MC, Karlsson AL, et al.: Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumor necrosis factor-alpha and interleukin-1beta in macrophages. J Clin Invest 1996, 98:78–89.

    Article  PubMed  CAS  Google Scholar 

  47. Subbanagounder G, Deng Y, Borromeo C, et al.: Hydroxy alkenal phospholipids regulate inflammatory functions of endothelial cells. Vascul Pharmacol 2002, 38:201–209.

    Article  PubMed  CAS  Google Scholar 

  48. Salomon RG: Isolevuglandins, oxidatively truncated phospholipids, and atherosclerosis. Ann N Y Acad Sci 2005, 1043:327–342.

    Article  PubMed  CAS  Google Scholar 

  49. Llodra J, Angeli V, Liu J, et al.: Emigration of monocytederived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci U S A 2004, 101:11779–11784.

    Article  PubMed  CAS  Google Scholar 

  50. Huber J, Boechzelt H, Karten B, et al.: Oxidized cholesteryl linoleates stimulate endothelial cells to bind monocytes via the extracellular signal-regulated kinase 1/2 pathway. Arterioscler Thromb Vasc Biol 2002, 22:581–586.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Medicine, University of Chicago, 929 East 57th Street, W410, 60637, Chicago, IL, USA

    Konstantin G. Birukov MD, PhD

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Correspondence to Konstantin G. Birukov MD, PhD.

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Birukov, K.G. Oxidized lipids: The two faces of vascular inflammation. Curr Atheroscler Rep 8, 223–231 (2006). https://doi.org/10.1007/s11883-006-0077-x

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  • DOI: https://doi.org/10.1007/s11883-006-0077-x

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