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Inflammation and cholesterol

J. Nilsson*,1, M.P.S. Ares1, M. Lindholm1, G.Nordin Fredriksonl1,2 and S. Jovinge1

1 Department of Medicine, Malmö University Hospital, Lund University, Lund, Sweden
2 Deparmment of Biomedical Laboratory Science, Malmo University, Sweden

* Correspondence: Jan Nilsson, Department of Medicine, Malmö University Hospital, 205 02 Malmö, Sweden.

Abstract

Atherosclerosis develops as a result of a chronic arterial inflammation and intimal fibrosis. The disease represents in many respects a vascular repair process activated in response to injury caused by toxic breakdown products of aggregated and oxidized lipoproteins. The initial response of the artery involves expression of adhesion molecules and recruitment of leukocytes. Degenerated lipoproteins are removed from the extracellular space by macrophages. If lipoproteins continue to accumulate, the inflammatory process becomes chronic and cytokines stimulate smooth muscle to migrate into the intima. These cells proliferate and form an atherosclerotic plaque. Plaque cell death and inflammation in response to oxidized lipids and other toxic factors may cause plaques to rupture.

Key Words: Atherosclerosis • lipoproteins • immunity • macrophages • smooth muscle cells

References

  1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809[CrossRef][Medline]
  2. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001;104:503–516[CrossRef][Web of Science][Medline]
  3. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340:115–126[Free Full Text]
  4. Hansson GK, Jonasson L, Seifert PS, Stemme S. Immune mechanisms in atherosclerosis. Arteriosclerosis. 1989;9:567–578[Abstract/Free Full Text]
  5. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–925[Web of Science][Medline]
  6. Schwartz SM, Campbell GR, Campbell HL. Replication of smooth muscle cells in vascular disease. Circ Res. 1986;58:427–444[Abstract/Free Full Text]
  7. Falk. Why do plaques rupture? Circulation. 1992;86:III30–III42
  8. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–2850[Free Full Text]
  9. Ridker PM. Novel risk factors and markers for coronary disease. Adv Intern Med. 2000;45:391–418[Medline]
  10. Ridker PM. Role of inflammatory biomarkers in prediction of coronary heart disease. Lancet. 2001;358:946–948[CrossRef][Web of Science][Medline]
  11. Libby P, Ridker PM. Novel inflammatory markers of coronary risk: theory versus practice. Circulation. 1999;100:1148–1150[Free Full Text]
  12. Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem. 2001;47:403–411[Abstract/Free Full Text]
  13. Ridker P, Cushman M, Stampfer M, Tracy R, Hennekens C. Inflammation, asprin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979[Abstract/Free Full Text]
  14. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843[Abstract/Free Full Text]
  15. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98:839–844[Abstract/Free Full Text]
  16. Albert MA, Staggers J, Chew P, Ridker PM. The pravastatin inflammation CRP evaluation (PRINCE): rationale and design. Am Heart J. 2001;141:893–898[CrossRef][Web of Science][Medline]
  17. Steinberg D, Lewis A. Oxidative modification of LDL and atherogenesis. Circulation. 1997;95:1062–1071[Free Full Text]
  18. Faggiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis. 1984;4:323–340[Abstract/Free Full Text]
  19. Li H, Cybulski MI, Gimbrone MA, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993;13:197–204[Abstract/Free Full Text]
  20. Camejo G, Olofsson S-O, Lopez F, Carlsson P, Bondjers G. Identification of apo B-100 segments mediating the interaction of low density lipoproteins with arterial proteoglycans. Arteriosclerosis. 1988;8:368–377[Abstract/Free Full Text]
  21. Oorni K, Pentikainen MO, Ala-Korpela M, Kovanen PT. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J Lipid Res. 2000;41:1703–1714[Abstract/Free Full Text]
  22. Cyrus T, Witztum JL, Rader DJ, et al. Disruption of the 12/15lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999;103:1597–1604[Web of Science][Medline]
  23. Cybulsky M, Gimbrone M. Endothelial expression of a mononuclear adhesion molecule during atherogenesis. Science. 1991;251:788–791[Abstract/Free Full Text]
  24. Calara F, Dimayuga P, Nieman A, et al. An animal model to study local oxidation of LDL and its biological effects in the arterial wall. Arterioscler Thromb Vase Biol. 1998;18:884–893
  25. Tsao PS, Buirago R, Chan JR, Cooke JP. Fluid flow inhibits endothelial adhesiveness. Nitric oxide and transcriptional regulation of VCAM-1. Circulation. 1996;94:1682–1689[Abstract/Free Full Text]
  26. Alderson LM, Endemann G, Lindsay S, Pronczuk A, Hoover R, Hayes KC. LDL enhances monocyte adhesion to endothelial cells in vitro. Am J Pathol. 1986;123:334–342[Abstract]
  27. Endemann G, Pronzcuk A, Friedman G, Lindsey S, Alderson L, Hayes KC. Monocyte adherence to endothelial cells in vitro is increased by beta-VLDL. Am J Pathol. 1987;126:1–6[Abstract]
  28. Dichtl W, Nilsson L, Goncalves I, et al. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Circ Res. 1999;84:1085–1094[Abstract/Free Full Text]
  29. Spiegel S, Foster D, Kolesnick R. Signal transduction through lipid second messengers. Curr Opin Cell Biol. 1996;8:159–167[CrossRef][Web of Science][Medline]
  30. Berliner J, Navab M, Fogelman A, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation and genetics. J Clin Invest. 1995;91:2488–2496[CrossRef]
  31. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992;258:607–614[Abstract/Free Full Text]
  32. Collins T, Cybulsky MI. NF-kappaB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest. 2001;107:255–264[Web of Science][Medline]
  33. Niemann-Jönsson A, Dimayuga P, Jovinge S, et al. Accumulation of low density lipoprotein in rat arteries is associated with activation of tumor necrosis factor-{alpha} expression. Arterioscler Thromb Vase Biol. 2000;20:2205–2211
  34. Ares MPS, Kallin B, Eriksson P, Nilsson J. Oxidized low-density lipoprotein induces transcription factor AP-1 but inhibits activation of NFkB in human vascular smooth muscle cells. Arterioscler Thromb Vase Biol. 1995;15:1584–1590
  35. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA. 1995. p. 3893–3897
  36. Palinski W, Witztum JL. Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis. J Intern Med. 2000;247:371–380[CrossRef][Web of Science][Medline]
  37. Maggi E, Chiesa R, Melissano G, et al. LDL oxidation in patients with severe carotid atherosclerosis. A study of in vitro and in vivo oxidation markers. Arterioscler Thromb. 1994;14:1892–1899[Abstract/Free Full Text]
  38. Virella G, Virella I, Leman RB, Pryor MB, Lopes-Virella ME. Anti-oxidized low-density lipoprotein antibodies in patients with coronary heart disease and normal healthy volunteers. Int J Clin Lab Res. 1993;23:95–101[Web of Science][Medline]
  39. Hörkkö S, Binder CJ, Shaw PX, et al. Immunological responses to oxidized LDL. Free Radic Biol Med. 2000;28:1771–1779[CrossRef][Web of Science][Medline]
  40. Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA. 1995. p. 821–825
  41. Ameli S, Hultgrdh-Nilsson A, Regnstrom J, et al. Effect of immunization with homologous LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vase Biol. 1996;16:1074–1079
  42. Nilsson J, Calara F, Regnstrom J, et al. Immunization with homologous oxidized low density lipoprotein reduces neointimal formation after balloon in hypercholesterolemic rabbits. J Am Coll Cardiol. 1997;30:1886–1891[Abstract]
  43. Freigang S, Horkko S, Miller E, Witztum JL, Palinski W. Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vase Biol. 1998;18:1972–1982
  44. George J, Afek A, Gilburd B, et al. Hyperimmunization of apo-Edeficient mice with homologous malondialdehyde low-density lipoprotein suppresses early atherogenesis. Atherosclerosis. 1998;138:147–152[CrossRef][Web of Science][Medline]
  45. Zhou X, Caligiuri G, Hamsten A, Lefvert AK, Hansson GK. LDL immunization induces T cell-dependent antibody formation and protection against atherosclerosis. Arterioscler Thromb Vase Biol. 2001;21:108–114
  46. Holvoet P, Stassen JM, Van Cleemput J, Collen D, Vanhaecke J. Oxidized low density lipoproteins in patients with transplantassociated coronary artery disease. Arterioscler Thromb Vase Biol. 1998;18:100–107
  47. Ross R, Glomset JA. The pathogenesis of atherosclerosis. N Engl J Med. 1976;295:369–377Ross R, Glomset JA. The pathogenesis of atherosclerosis. N Engl J Med. 1976;295:420–425[Web of Science][Medline]
  48. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med. 1986;314:488–500[Web of Science][Medline]
  49. Lindner V, Lappi DA, Baird A, Majack RA, Reidy MA. Role of basic fibroblast growth factor in vascular lesion formation. Circ Res. 1991;68:106–113[Abstract/Free Full Text]
  50. Ferns GA, Raines EW, Sprugel KH, Motani AS, Reidy MA, Ross R. Inhibition of neointimal smooth muscle cell accumulation after angioplasty by an antibody to PDGF. Science. 1991;253:1129–1132[Abstract/Free Full Text]
  51. Couffinhal T, DuplAa C, Labat L, et al. Tumor necrosis factor-{alpha} stimulates ICAM-1 expression in human vascular smooth muscle cells. Arterioscler Thromb. 1993;13:407–414[Abstract/Free Full Text]
  52. Roebuck K, Rahman A, Lakshminarayanan V, Janakidevi K, Malik A. H2O2 and tumor necrosis factor-{alpha} activate intercellular adhesion molecule 1 (ICAM-1) gene transcription through dis tinct cis-regulatory elements within the ICAM-1 promoter. J Biol Chem. 1995;270:18966–18974[Abstract/Free Full Text]
  53. Nawroth P, Stern D. Tumor necrosis factor/cachectin-induced modulation of endothelial cell hemostatic properties. Onkologie. 1987;10:254–258[Web of Science][Medline]
  54. Jovinge S, Ares M, Kallin B, Nilsson J. Human monocytes/ macrophages release TNF{alpha} in response to ox-LDL. Arterioscler Thromb Vase Biol. 1997;16:1573–1579
  55. Barath P, Fishbein M, Cao J, Berenson J, Helfant R, Forrester J. Detection and localization of tumour necrosis factor in human atheroma. Am J Pathol. 1990;65:297–302
  56. Rus H, Niculescu F, Vlaicu R. Tumor necrosis factor-alpha in human arterial wall with atherosclerosis. Atherosclerosis. 1991;89:247–254[CrossRef][Web of Science][Medline]
  57. Tanaka H, Sukhova G, Schwartz D, Libby P. Proliferating arterial smooth muscle cells after balloon injury express TNF-{alpha} but not interleukin-1 or basic fibroblast growth factor. Arterioscler Thromb Vase Biol. 1996;16:12–18
  58. Jovinge S, Hultgardh-Nilsson A, Regnstrom J, Nilsson J. Smooth muscle cell migration and cytoskeletal rearrangements in response to tumor necrosis factor {alpha}. Arterioscler Thromb Vase Biol. 1997;17:490–497
  59. Tanaka H, Swanson S, Sukhova G, Schoen F, Libby P. Smooth muscle cells of the coronary arterial tunica media express tumor necrosis factor-{alpha} and proliferate during acute rejection of rabbit cardiac allografts. Am J Pathol. 1995;147:617–626[Abstract]
  60. Jovinge S, Hamsten A, Tornvall P, et al. Evidence for a role of tumor necrosis factor-{alpha} in disturbances of triglyceride and glucose metabolism predisposing to coronary heart disease. Metabolism. 1998;47:113–118[CrossRef][Web of Science][Medline]
  61. Hotamisligil GS, Spiegelman BM. Tumor necrosis factor {alpha}: a key component of the obesity-diabetes link. Diabetes. 1994;43:1271–1278[Abstract]
  62. Nilsson J, Jovinge S, Nieman A, Reneland R, Lithel H. Relation between plasma tumor necrosis factor a and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vase Biol. 1998;18:1199–1202
  63. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-{alpha}: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91[Abstract/Free Full Text]
  64. Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesitydiabetes. Central role of tumor necrosis factor-{alpha}. J Clin Invest. 1994;94:1543–1549
  65. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-{alpha} in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–2415
  66. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995;95:2111–2119
  67. Libby P, Geng YJ, Aikawa M, et al. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol. 1996;7:330–335[Web of Science][Medline]
  68. Crisby M, Kallin B, Thyberg J, et al. Cell death in atherosclerotic plaques involves both oncosis and apoptosis. Atherosclerosis. 1997;130:17–27[CrossRef][Web of Science][Medline]
  69. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103:926–933[Abstract/Free Full Text]
  70. Libby P, Aikawa M. New insights into plaque stabilisation by lipid lowering. Drugs. 1998;56:9–13 discussion 33

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