Skip to main content
SpringerLink
Log in

Lipid and Inflammation in Atherosclerosis

  • Chapter
  • First Online:
Lipid Management

  • 1587 Accesses

Abstract

Lipids can be a cause of inflammation especially with regards to the development of atherosclerotic plaque and their subsequent rupture that leads to heart attacks and strokes. Here we discuss the role of biomarkers in this process as well as the effects of oxidized LDL on transformation of macrophages into foam cells and their cytotoxic effects. Moreover, we provide evidence of cholesterol crystal formation early in atherosclerosis and triggering the NLRP3 inflammasomes similar to what is known to occur with monosodium urate crystals in gout. These mechanisms eventually lead to the accumulation of free cholesterol in the extracellular space forming a necrotic core within the plaque. The core then expands with the crystallization of cholesterol from a liquid to a solid state piercing the fibrous cap and the intima to trigger systemic inflammation and subsequent rupture.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Virchow R. Cellular pathology as based upon physiological and pathological histology. Twenty lectures delivered in 1858. (Translated from the second edition of the original by F. Chance). Dover Publications, Inc, New York, 1971.

    Google Scholar 

  2. Epstein F, Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999;340(2):115–26.

    Google Scholar 

  3. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868–74.

    CAS  PubMed  Google Scholar 

  4. Ridker P, Hennekens C, Buring J, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342(12):836–43.

    CAS  PubMed  Google Scholar 

  5. Wright S, Burton C, Hernandez M, Hassing H, Montenegro J, Mundt S, et al. Infectious agents are not necessary for murine atherogenesis. J Exp Med. 2000;191(8):1437–42.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Small D. George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry. Arterioscler Thromb Vasc Biol. 1988;8(2):103–29.

    CAS  Google Scholar 

  7. 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(14):915–24.

    CAS  PubMed  Google Scholar 

  8. Wong N, Gransar H, Narula J, Shaw L, Moon J, Miranda-Peats R, et al. Myeloperoxidase, subclinical atherosclerosis, and cardiovascular disease events. JACC Cardiovasc Imaging. 2009;2(9):1093–99.

    PubMed  Google Scholar 

  9. Currie C, Poole C, Conway P. Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality. Heart. 2008;94(4):457–62.

    CAS  PubMed  Google Scholar 

  10. Sabatine M, Morrow D, Jablonski K, Rice M, Warnica J, Domanski M, et al. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation. 2007;115(12):1528–36.

    PubMed  Google Scholar 

  11. Ridker P, Cannon C, Morrow D, Rifai N, Rose L, McCabe C, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20–8.

    CAS  PubMed  Google Scholar 

  12. Ridker P, Rifai N, Rose L, Buring J, Cook N. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557–65.

    CAS  PubMed  Google Scholar 

  13. Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Artheroscler Thromb Vasc Biol. 2006;26(7):1586–93.

    CAS  Google Scholar 

  14. Ridker P, Danielson E, Fonseca F, Genest J, Gotto Jr A, Kastelein J, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195.

    CAS  PubMed  Google Scholar 

  15. Lipton B, Parthasarathy S, Ord V, Clinton S, Libby P, Rosenfeld M. Components of the protein fraction of oxidized low density lipoprotein stimulate interleukin-1 alpha production by rabbit arterial macrophage-derived foam cells. J Lipid Res. 1995;36(10):2232–42.

    CAS  PubMed  Google Scholar 

  16. Swirski F, Libby P, Aikawa E, Alcaide P, Luscinskas F, Weissleder R, et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 2007;117(1):195–205.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Tacke F, Alvarez D, Kaplan T, Jakubzick C, Spanbroek R, Llodra J, et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007;117(1):185–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Robbins C, Chudnovskiy A, Rauch P, Figueiredo J, Iwamoto Y, Gorbatov R, et al. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation. 2012;125(2): 364–74.

    PubMed Central  PubMed  Google Scholar 

  19. Hansson G, Jonasson L. The discovery of cellular immunity in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol. 2009;29(11):1714–7.

    CAS  PubMed  Google Scholar 

  20. Zhou X, Nicoletti A, Elhage R, Hansson G. Transfer of CD4+T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation. 2000;102(24):2919–22.

    CAS  PubMed  Google Scholar 

  21. Witztum J, Binder C, Chou M, Fogelstrand L, Hartvigsen K, Shaw P, et al. Natural antibodies in murine atherosclerosis. Curr Drug Targets. 2008;9(3):190–5.

    PubMed  Google Scholar 

  22. Abela G, Aziz K, Vedre A, Pathak D, Talbott J, DeJong J. Effect of cholesterol crystals on plaques and intima in arteries of patients with acute coronary and cerebrovascular syndromes. Am J Cardiol. 2009;103(7):959–68.

    CAS  PubMed  Google Scholar 

  23. Düewell P, Kono H, Rayner K, Sirois C, Vladimer G, Bauernfeind F, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–61.

    PubMed Central  PubMed  Google Scholar 

  24. Hasson GK, Libby P, SchÖnbeck U, Yan Z. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res. 2002;91(4):281–91.

    Google Scholar 

  25. Cai H, Harrison D. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000;87(10):840–4.

    CAS  PubMed  Google Scholar 

  26. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III27–32.

    Google Scholar 

  27. Cushing S, Berliner J, Valente A, Territo M, Navab M, Parhami F, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA. 1990;87(13):5134–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Ajuebor M, Flower R, Hannon R, Christie M, Bowers K, Verity A, et al. Endogenous monocyte chemoattractant protein-1 recruits monocytes in the zymosan peritonitis model. J Leukoc Biol. 1998;63(1):108–16.

    CAS  PubMed  Google Scholar 

  29. Furukawa Y, Matsumori A, Ohashi N, Shioi T, Ono K, Harada A, et al. Anti-monocyte chemoattractant protein-1/monocyte chemotactic and activating factor antibody inhibits neointimal hyperplasia in injured rat carotid arteries. Circ Res. 1999;84(3):306–14.

    CAS  PubMed  Google Scholar 

  30. Hong K, Ryu J, Han K. Monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood. 2005;105(4):1405–7.

    CAS  PubMed  Google Scholar 

  31. Ma J, Wang Q, Fei T, Han J, Chen Y. MCP-1 mediates TGF-β-induced angiogenesis by stimulating vascular smooth muscle cell migration. Blood. 2007;109(3):987–94.

    CAS  PubMed  Google Scholar 

  32. Nelken N, Coughlin S, Gordon D, Wilcox J. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991;88(4):1121.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Yu X, Dluz S, Graves D, Zhang L, Antoniades H, Hollander W, et al. Elevated expression of monocyte chemoattractant protein 1 by vascular smooth muscle cells in hypercholesterolemic primates. Proc Natl Acad Sci U S A. 1992;89(15):6953–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Deo R, Khera A, McGuire D, Murphy S, Neto J, Morrow D, et al. Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinical atherosclerosis. J Am Coll Cardiol. 2004;44(9):1812–8.

    CAS  PubMed  Google Scholar 

  35. Hoogeveen R, Morrison A, Boerwinkle E, Miles J, Rhodes C, Sharrett A, et al. Plasma MCP-1 level and risk for peripheral arterial disease and incident coronary heart disease: atherosclerosis risk in communities study. Atherosclerosis. 2005;183(2):301–7.

    CAS  PubMed  Google Scholar 

  36. Martinovic I, Abegunewardene N, Seul M, Vosseler M, Horstick G, Buerke M, et al. Elevated monocyte chemoattractant protein-1 serum levels in patients at risk for coronary artery disease. Circ J. 2005;69(12):1484–9.

    CAS  PubMed  Google Scholar 

  37. Inadera H, Egashira K, Takemoto M, Ouchi Y, Matsushima K. Increase in circulating levels of monocyte chemoattractant protein-1 with aging. J Interferon Cytokine Res. 1999;19(10):1179–82.

    CAS  PubMed  Google Scholar 

  38. Mosedale D, Smith D, Aitken S, Schofield P, Clarke S, McNab D, et al. Circulating levels of MCP-1 and eotaxin are not associated with presence of atherosclerosis or previous myocardial infarction. Atherosclerosis. 2005;183(2):268–74.

    CAS  PubMed  Google Scholar 

  39. Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen P, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE. 2010;5(7):e11765.

    PubMed Central  PubMed  Google Scholar 

  40. Fearon F, Fearon D. Inflammation and cardiovascular disease: role of the interleukin-1 receptor antagonist. Circulation. 2008;117(20):2577–9.

    PubMed  Google Scholar 

  41. Ridker P, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162(4):597–605.

    CAS  PubMed  Google Scholar 

  42. Alexander M, Moehle C, Johnson J, Yang Z, Lee J, Jackson C, et al. Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J Clin Invest. 2012;122(1):70–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Kleinbongard P, Heusch G, Schulz R. TNF alpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther. 2010;127(3):295–314.

    CAS  PubMed  Google Scholar 

  44. Elkind MS, Cheng J, Boden-Albala B, Rundek T, Thomas J, Chen H, Rabbani LE, Sacco RL. Tumor necrosis factor receptor levels are associated with carotid atherosclerosis. Stroke. 2002;33(1):31–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Skoog T, Dicht W, Boquist S, Skoglund-Andersson C, Karpe F, Tang R, et al. Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in healthy middle-aged men. Eur Heart J. 2002;23(5):376–83.

    CAS  PubMed  Google Scholar 

  46. Del Porto F, Laganà B, Vitale M, et al. Response to anti-tumour necrosis factor alpha blockade is associated with reduction of carotid intima-media thickness in patients with active rheumatoid arthritis. Rheumatology (Oxford). 2007;46(7):1111–1115.

    CAS  Google Scholar 

  47. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J, Gonzalez-Gay M. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody. Arthritis Rheum. 2004;51(3):447–50.

    CAS  PubMed  Google Scholar 

  48. Teupser D, Weber O, Rao T, Sass K, Thiery J, Fehling H. No reduction of atherosclerosis in C-reactive protein (CRP)-deficient mice. J Biol Chem. 2011;286(8):6272–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Trion A, de Maat M, Jukema J, van der Laarse A, Maas M, Offerman E, et al. No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-Leiden/human C-reactive protein transgenic mice. Arterioscler Thromb Vasc Biol. 2005;25:1635–40.

    CAS  PubMed  Google Scholar 

  50. Tennent G, Hutchinson W, Kahan M, Hirschfield G, Gallimore J, Lewin J, et al. Transgenic human CRP is not pro-atherogenic, pro-atherothrombotic or pro-inflammatory in apoE-/- mice. Atherosclerosis. 2008;196(1):248–55.

    CAS  PubMed  Google Scholar 

  51. Koike T, Kitajima S, Yu Y, Nishijima K, Zhang J, Ozaki Y, et al. Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation. 2009;120(21):2088–94.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. CRP CHD Genetics Collaboration. Collaborative pooled analysis of data on C-reactive protein gene variants and coronary disease: judging causality by Mendelian randomisation. Eur J Epidemiol. 2008;23(8):531–40.

    Google Scholar 

  53. Wensley F, Gao P, Burgess S, Kaptoge S, Di Angelantonio E, Shah T, et al. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ. 2011;342:d548.

    PubMed  Google Scholar 

  54. Kuller L, Tracy R, Shaten J, Meilahn E. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple risk factor intervention trial. Am J Epidemiol. 1996;144(6):537–47.

    CAS  PubMed  Google Scholar 

  55. Ridker P, Cushman M, Stampfer M, Tracy R, Hennekens C. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336(14):973–9.

    CAS  PubMed  Google Scholar 

  56. Yousuf O, Mohanty B, Martin S, Joshi P, Blaha M, Nasir K, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013;62(5):397–408.

    CAS  PubMed  Google Scholar 

  57. Daugherty A, Dunn J, Rateri D, Heinecke J. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest. 1994;94(1):437–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Stocker R, Keaney J Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84(4):1381–478.

    CAS  PubMed  Google Scholar 

  59. de la Llera Moya M, McGillicuddy, Nguyen V, et al. Inflammation modulates human HDL composition and function in vivo. Atherosclerosis. 2012;222(2):390–4.

    Google Scholar 

  60. Schindhelm R, van der Zwan L, Teerlink T, Scheffer P. Myeloperoxidase: a useful biomarker for cardiovascular disease risk stratification? Clin Chem. 2009;55(8):1462–70.

    CAS  PubMed  Google Scholar 

  61. Khokha R, Murthy A, Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol. 2013;13(9):649–65.

    CAS  PubMed  Google Scholar 

  62. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regionsof human atherosclerotic plaques. J Clin Invest. 1994;94(6):2493–503.

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Wågsäter D, Zhu C, Björkegren J, Skogsberg J, Eriksson P. MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the Ldlr(-/-) Apob(100/100) mouse. Int J Mol Med. 2011;28(2):247–53.

    PubMed  Google Scholar 

  64. Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F, et al. Peripheral blood levels of matrix metalloproteinases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 1998;32(2):368–72.

    CAS  PubMed  Google Scholar 

  65. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, Hafner G, Meyer J, Cambien F, Tiret L; AtheroGene Investigators. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation. 2003;107(12):1579–85.

    CAS  PubMed  Google Scholar 

  66. Berg K. Lp(a) lipoprotein: an overview. Chem Phys Lipids. 1994;67-68:9–16.

    CAS  PubMed  Google Scholar 

  67. Lippi G, Guidi G. Biochemical risk factors and patient's outcome: the case of lipoprotein(a). Clin Chim Acta. 1999;280(1-2):59–71.

    CAS  PubMed  Google Scholar 

  68. Tayal D, Goswami B, Koner B, Mallika V. Role of Homocysteine and Lipoprotein (A) in atherosclerosis: an update. Biomed. Res. 2011;22(4):391–405.

    CAS  Google Scholar 

  69. Schneiderman J, Sawdey M, Keeton M, Bordin G, Bernstein E, Dilley R, et al. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A. 1992;89(15):6998–7002.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Shireman P, McCarthy W, Pearce W, Patterson B, Shively V, Cipollone M, et al. Elevated levels of plasminogen-activator inhibitor type 1 in atherosclerotic aorta. J Vasc Surg. 1996;23(5):810–7.

    CAS  PubMed  Google Scholar 

  71. Eitzman D, Westrick R, Xu Z, Tyson J, Ginsburg D. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood. 2000;96(13):4212–5.

    CAS  PubMed  Google Scholar 

  72. Peng Y, Liu H, Liu F, Ouyang L, Cheng M, Gao L, et al. Atherosclerosis is associated with plasminogen activator inhibitor type-1 in chronic haemodialysis patients. Nephrology (Carlton). 2008;13(7):579–86.

    CAS  Google Scholar 

  73. Raiko JR Oikonen M, Wendelin-Saarenhovi M, Siitonen N, Kähönen M, Lehtimäki T, et al. Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2012;224(1):208–12.

    CAS  PubMed  Google Scholar 

  74. Bleijerveld O, Zhang Y, Beldar S, Hoefer I, Sze S, Pasterkamp G, et al. Proteomics of plaques and novel sources of potential biomarkers for atherosclerosis. Proteomics Clin Appl. 2013;7(7-8):490–503.

    CAS  PubMed  Google Scholar 

  75. de Kleijn D, Moll, Doevendans P, et al. Local atherosclerotic plaques are a source of prognostic biomarkers for adverse cardiovascular events. Arterioscler Thromb Vasc Biol. 2010;30(3):612–9.

    PubMed  Google Scholar 

  76. Peeters W, de Kleijn D, Vink A, van de Weg S, Schoneveld A, Sze S, et al. Adipocyte fatty acid binding protein in atherosclerotic plaques is associated with local vulnerability and is predictive for the occurrence of adverse cardiovascular events. Eur Heart J. 2011;32(14):1758–68.

    CAS  PubMed  Google Scholar 

  77. Tzoulaki I, Siontis K, Ioannidis J. Prognostic effect size of cardiovascular biomarkers in datasets from observational studies versus randomised trials: meta-epidemiology study. BMJ. 2011;343:d6829.

    PubMed Central  PubMed  Google Scholar 

  78. Ferket B, van Kempen B, Hunink M, Agarwal I, Kavousi M, Franco O, Steyerberg E, Max W, Fleischmann K. Predictive value of updating Framingham risk scores with novel risk markers in the U.S. general population. PLoS ONE. 2014;9(2):e88312.

    PubMed Central  PubMed  Google Scholar 

  79. Baras Shreibati J, Baker L, McConnell M, Hlatky M. Outcomes after coronary artery calcium and other cardiovascular ciomarker testing among asymptomatic medicare beneficiaries. Circ Cardiovasc Imaging. 2014;7:655–62.

    Google Scholar 

  80. Aziz K, Berger K, Claycombe K, Huang R, Patel R, Abela GS. Non-invasive detection and localization of vulnerable plaque and arterial thrombosis using CTA/PET. Circulation. 2008;117(16):2061–70.

    PubMed  Google Scholar 

  81. Helfand M, Buckley D, Freeman M, Fu R, Rogers K, Fleming C. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151(7):496–507.

    PubMed  Google Scholar 

  82. Kounis NG, Soufras GD, Tsigkas G, Hahalis G. White blood cell counts, leukocyte ratios, and eosinophils as inflammatory markers in patients with coronary artery disease. Clin Appl Thromb Hemost. 2014 Apr 24. [Epub ahead of print]

    Google Scholar 

  83. Holvoet P, Harris T, Tracy R, Verhamme P, Newman A, Rubin S, Simonsick E, et al. Association of high coronary heart disease risk status with circulating oxidized LDL in the well-functioning elderly: findings from the health, aging, and body composition study. Arterioscler Thromb Vasc Biol. 2003;23(8):1444–8.

    CAS  PubMed  Google Scholar 

  84. Yosida H, Kisugi R. Mechanisms of LDL oxidation. Clinica Chimica Acta. 2010;411(23–24):1875–82.

    Google Scholar 

  85. Aviram M, Hardak E, Vaya J, Mahmood S, Milo S, Hoffman A, et al. Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities. Circulation. 2000;101(21):2510–7.

    CAS  PubMed  Google Scholar 

  86. Maiolino G, Rossitto G, Caielli P, Bisogni V, Rossi GP, Calò LA. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators Inflamm. 2013;2013:1–13.

    Google Scholar 

  87. Badrnya S, Schrottmaier W, Kral J, Yaiw K, Volf I, Schabbauer G, et al. Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation. Arterioscler Thromb Vasc Biol. 2014;34(3):571–80.

    CAS  PubMed  Google Scholar 

  88. Hashizume M, Mihara M. Blockade of IL-6 and TNF-α inhibited oxLDL-induced production of MCP-1 via scavenger receptor induction. Eur J Pharmacol. 2012;689(1-3):249–54.

    CAS  PubMed  Google Scholar 

  89. Lei Z, Zhang Z, Jing Q, Qin Y, Pei G, Cao B, et al. OxLDL upregulates CXCR2 expression in monocytes via scavenger receptors and activation of p38 mitogen-activated protein kinase. Cardiovasc Res. 2002;53(2):524–32.

    CAS  PubMed  Google Scholar 

  90. Holvoet P, De Keyzer D, Jacobs D Jr. Oxidized LDL and the metabolic syndrome. Future Lipidol. 2008;3(6):637–49.

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Terkeltaub R, Banka C, Solan J, Santoro D, Brand K, Curtiss L. Oxidized LDL induces monocytic cell expression of interleukin-8, a chemokine with T-lymphocyte chemotactic activity. Arterioscler Thromb. 1994;14(1):47–53.

    CAS  PubMed  Google Scholar 

  92. Claise C, Edeas M, Chalas J, Cockx A, Abella A, Capel L, et al. Oxidized low-density lipoprotein induces the production of interleukin-8 by endothelial cells. FEBS Lett. 1996;398(2-3):223–7.

    CAS  PubMed  Google Scholar 

  93. Valente AJ, Irimpen AM, Siebenlist U, Chandrasekar. OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free Radic Biol Med. 2014;70:117–28.

    CAS  PubMed  Google Scholar 

  94. Jimi S, Saku K, Uesugi N, Sakata N, Takebayashi S. Oxidized low density lipoprotein stimulates collagen production in cultured arterial smooth muscle cells. Atherosclerosis. 1995;116(1):15–26.

    CAS  PubMed  Google Scholar 

  95. Rajavashisth T, Liao J, Galis ZS, Tripathi S, Laufs U, Tripathi J, et al. Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase. J Biol Chem. 1999;274(17):11924–9.

    CAS  PubMed  Google Scholar 

  96. Xu X, Meisel S, Ong J, Kaul S, Cercek B, Rajavashisth T, et al. Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages. Circulation. 1999;99(8):993–8.

    CAS  PubMed  Google Scholar 

  97. Loidl A, Claus R, Ingolic E, Deigner H, Hermetter A. Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells. Biochim Biophys Acta. 2004;1690(2):150–8.

    CAS  PubMed  Google Scholar 

  98. Schwartz C, Valente A, Sprague E, Kelley J, Nerem R. The pathogenesis of atherosclerosis: an overview. Clin Cardiol. 1991;14(2 Suppl 1):I1–16.

    Google Scholar 

  99. Cathcart M, Morel D, Chisolm G 3rd. Monocytes and neutrophils oxidize low density lipoprotein making it cytotoxic. J Leukoc Biol. 1985;38(2):341–50.

    CAS  PubMed  Google Scholar 

  100. Sata M, Walsh K. Oxidized LDL activates fas-mediated endothelial cell apoptosis. J Clin Invest. 1998;102(9):1682–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Hardwick S, Hegyi L, Clare K, Law N, Carpenter K, Mitchinson M, et al. Apoptosis in human monocyte-macrophages exposed to oxidized low density lipoprotein. J Pathol. 1996;179(3):294–302.

    CAS  PubMed  Google Scholar 

  102. Thorin E, Hamilton C, Dominiczak M, Reid J. Chronic exposure of cultured bovine endothelial cells to oxidized LDL abolishes prostacyclin release. Arterioscler Thromb. 1994;14(3):453–9.

    CAS  PubMed  Google Scholar 

  103. Li L, Chen J, Liao D, Yu L. Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells by reducing P-selectin synthesis in vitro. Endothelium. 1998;6(1):1–8.

    CAS  PubMed  Google Scholar 

  104. Kugiyama K, Sakamoto T, Misumi I, Sugiyama S, Ohgushi M, Ogawa H, et al. Transferable lipids in oxidized low-density lipoprotein stimulate plasminogen activator inhibitor-1 and inhibit tissue-type plasminogen activator release from endothelial cells. Circ Res. 1993;73(2):335–43.

    CAS  PubMed  Google Scholar 

  105. Gräfe M, Auch-Schwelk W, Hertel H, Terbeek D, Steinheider G, Loebe M, et al. Human cardiac microvascular and macrovascular endothelial cells respond differently to oxidatively modified LDL. Atherosclerosis. 1998;137(1):87–95.

    PubMed  Google Scholar 

  106. Allison B, Nilsson L, Karpe F, Hamsten A, Eriksson P. Effects of native, triglyceride-enriched, and oxidatively modified LDL on plasminogen activator inhibitor-1 expression in human endothelial cells. Arterioscler Thromb Vasc Biol. 1999;19(5):1354–60.

    CAS  PubMed  Google Scholar 

  107. James RW, Leviev I, Righetti A. Smoking is associated with reduced serum paraoxonase activity and concentration in patients with coronary artery disease. Circulation. 2000;101(19):2252–7.

    CAS  PubMed  Google Scholar 

  108. Yang S, Li Y, Du D. Oxidized low-density lipoprotein-induced CD147 expression and its inhibition by high-density lipoprotein on platelets in vitro. Thromb Res. 2013;132(6):702–11.

    CAS  PubMed  Google Scholar 

  109. Tsimikas S, Brilakis E, Miller E, McConnell J, Lennon R, Kornman K, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005;353(1):46–57.

    CAS  PubMed  Google Scholar 

  110. Ylä-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb. 1994;14(1):32–40.

    PubMed  Google Scholar 

  111. 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. 2014;65:932–6.

    Google Scholar 

  112. Ravandi A, Boekholdt S, Mallat Z, Talmud P, Kastelein J, Wareham N, et al. Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study. J Lipid Res. 2011;52(10):1829–36.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Tsimikas S, Brilakis E, Lennon R, Miller E, Witztum J, McConnell J, et al. Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J Lipid Res. 2007;48(2):425–33.

    CAS  PubMed  Google Scholar 

  114. Wilson P, Ben-Yehuda O, McNamara J, Massaro J, Witztum J, Reaven PD. Autoantibodies to oxidized LDL and cardiovascular risk: the Framingham Offspring Study. Atherosclerosis. 2006;189(2):364–8.

    CAS  PubMed  Google Scholar 

  115. Martinon F, Pe´trilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–41.

    CAS  PubMed  Google Scholar 

  116. Abela GS, Aziz K. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events: a novel insight into plaque rupture by scanning electron microscopy. Scanning. 2006; 28(1):1–10.

    CAS  PubMed  Google Scholar 

  117. Patel R, Janoudi A, Vedre A, Aziz K, Tamhane U, Rubinstein J, et al. Plaque rupture and thrombosis is reduced by lowering cholesterol levels and crystallization with ezetimibe and is correlated with FDG-PET. Arterioscler Thromb Vasc Biol. 2011;31(9):2007–14.

    CAS  PubMed  Google Scholar 

  118. Geng Y, Phillips J, Mason R, Casscells S. Cholesterol crystallization and macrophage apoptosis: implication for atherosclerotic plaque instability and rupture. Biochem Pharm. 2003;66(8):1485–92.

    CAS  PubMed  Google Scholar 

  119. Matsumoto T, Takashima H, Ohira N, Tarutani Y, Yasuda Y, Yamane T, et al. Plasma level of oxidized low-density lipoprotein is an independent determinant of coronary macrovasomotor and microvasomotor responses induced by bradykinin. Am Coll Cardiol. 2004;44(2):451–7.

    CAS  Google Scholar 

  120. Seiler C, Hess O, Buechi M, Suter T, Krayenbuehl H. Influence of serum cholesterol and other coronary risk factors on vasomotion of angiographically normal coronary arteries. Circulation. 1993;88(5 pt 1):2139–48.

    CAS  PubMed  Google Scholar 

  121. Muller J, Abela G, Nesto R, Tofler G. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994;23(3):809–13.

    CAS  PubMed  Google Scholar 

  122. Schaar J, Muller J, Falk E, Virmani R, Fuster V, Serruys P, et al. Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece. Eur Heart J. 2004;25(12):1077–82.

    PubMed  Google Scholar 

  123. Lundber B. Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis. 1985;56(1):93–110.

    Google Scholar 

  124. Abela G. Cholesterol crystals piercing the arterial plaque and intima triggers local and systemic inflammation. J Clin Lipidol. 2010;4(3):156–64.

    PubMed  Google Scholar 

  125. Abela G, Vedre A, Janoudi A, Huang R, Durga S, Tamhane U. Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am J Cardiol. 2011;107(12):1710–7.

    CAS  PubMed  Google Scholar 

  126. Abela G, Shamoun F, Vedre A, Pathak D, Shah I, Dhar G, et al. The effect of ethanol on cholesterol crystals during tissue preparation for scanning electron microscopy. J Am Coll Cardiol (Letter to Editor) 2012;59(1):93.

    PubMed  Google Scholar 

  127. Vedre A, Aziz K, Huang R, Abela GS. Aspirin prevents cholesterol crystallization: a potential mechanism of plaque stabilization. J Am Coll Cardiol. 2008;51(Suppl A):318.

    Google Scholar 

  128. Kolodgie F, Gold H, Burke A, Fowler D, Kruth H, Weber D, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med. 2003;349(24):2316–25.

    CAS  PubMed  Google Scholar 

  129. Vedre A, Pathak D, Crimp M, Lum C, Koochesfahani M, Abela G. Physical factors that trigger cholesterol crystallization leading to plaque rupture. Atherosclerosis. 2009;203(1):89–96.

    CAS  PubMed  Google Scholar 

  130. Ota H, Reeves MJ, Zhu DC, Majid A, Collar A, Yuan C, et al. Sex differences of high-risk carotid atherosclerotic plaque with less than 50 % stenosis in asymptomatic patients: an in vivo 3T MRI study. Am J Neuroradiol. 2013;34(5):1049–55.

    CAS  PubMed  Google Scholar 

  131. Arbustini E, Dal Bello B, Morbini P, Burke A, Bocciarelli M, Specchia G, et al. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart. 1999;82(3):269–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Dey S, Flather M, Devlin G, Brieger D, Gurfinkel E, Steg P, et al. Global Registry of Acute Coronary Events investigators. Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. Heart. 2009;95(1):20–6.

    CAS  PubMed  Google Scholar 

  133. Maehara A, Mintz GS, Bui AB, Walter OR, Castagna MT, Canos D, et al. Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound. J Am Coll Cardiol. 2002;40(5):904–10.

    PubMed  Google Scholar 

  134. Schoenhagen P, Stone G, Nissen S, Grines C, Griffin J, Clemson B, et al. Coronary plaque morphology and frequency of ulceration distant from culprit lesions in patients with unstable and stable presentation. Atheroscler Thromb Vasc Biol. 2003;23(10):1895–900.

    CAS  Google Scholar 

  135. Kubo T, Imanishi T, Kashiwagi M, Ikejima H, Tsujioka H, Kuroi A, et al. Multiple coronary lesion instability in patients with acute myocardial infarction as determined by optical coherence tomography. Am J Cardiol. 2010;105(3):318–22.

    PubMed  Google Scholar 

  136. Ishibashi F, Aziz K, Abela G, Waxman S. Update on coronary angioscopy: review of a 20-year experience and potential application for detection of vulnerable plaque. J Interv Cardiol. 2006;19(1):17–25.

    PubMed  Google Scholar 

  137. Shepherd J, Cobbe S, Ford I, Isles C, Lorimer A, MacFarlane P, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–7.

    CAS  PubMed  Google Scholar 

  138. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet. 2009;373(9678):1849–60.

    PubMed  Google Scholar 

  139. Fernández-Jarne E, Martínez-Losa E, Serrano-Martínez M, Prado-Santamaría M, Brugarolas-Brufau C, Martínez-González M. Type of alcoholic beverage and first acute myocardial infarction: a casecontrol study in a Mediterranean country. Clin Cardiol. 2003;26(7):313–8.

    PubMed  Google Scholar 

  140. Schwartz G, Olsson A, Ezekowitz M, Ganz P, Oliver M, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study. JAMA. 2001;285(13):1711–8.

    CAS  PubMed  Google Scholar 

  141. Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) Randomized Trial. J Am Coll Cardiol. 2009; 54(6):558–65.

    CAS  PubMed  Google Scholar 

  142. Anderson J, Adams C, Antman E, Bridges C, Califf R, Casey D Jr, et al. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(23):e663–828.

    PubMed  Google Scholar 

  143. Mihos C, Pineda A, Santana O. Cardiovascular effects of statins, beyond lipid-lowering properties. Pharmacol Res. 2014;88:12–9.

    Google Scholar 

  144. Nurmi K, Virkanen J, Rajama J, Niemi K, Kovanen P, Eklund K. Ethanol Inhibits Activation of NLRP3 and AIM2 Inflammasomes in human macrophages—a novel anti-inflammatory action of alcohol. PLoS ONE. 8(11):e78537.

    Google Scholar 

  145. Imhof A, Woodward M, Doering A, Helbecque N, Loewel H, Amouyel P, Lowe GD, Koenig W. Overall alcohol intake, beer, wine, and systemic markers of inflammation in western Europe: results from three MONICA samples (Augsburg, Glasgow, Lille). Eur Heart J. 2004;25(23):2092–100.

    CAS  PubMed  Google Scholar 

  146. Abela GS. The role of cholesterol crystals in myocardial infarction and stroke: a review. Clin Lipidol. 2010;5(1):57–69.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Michigan State University and Sparrow Hospital, 48864, Okemos, MI, USA

    Imad Ahmado MD

  2. University of Cincinnati, 45208, Cincinnati, OH, USA

    Oliver G. Abela MD

  3. Michigan State University & Sparrow Hospital, 48842, Holt, MI, USA

    Muhamad Adeeb Saffia MD

  4. Michigan State University, 48824, East Lansing, MI, USA

    Abed Janoudi PhD

  5. Department of Medicine, Division of Cardiology, Michigan State University, B208 Clinical Center, 48824, East Lansing, MI, USA

    George S. Abela MSc, MD

Authors
  1. Imad Ahmado MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver G. Abela MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhamad Adeeb Saffia MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abed Janoudi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. George S. Abela MSc, MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Imad Ahmado MD .

Editor information

Editors and Affiliations

  1. University of Southern California Lipid Clinic, Los Angeles, California, USA

    Hussein Yassine

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Ahmado, I., Abela, O., Saffia, M., Janoudi, A., Abela, G. (2015). Lipid and Inflammation in Atherosclerosis. In: Yassine, H. (eds) Lipid Management. Springer, Cham. https://doi.org/10.1007/978-3-319-11161-2_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-11161-2_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-11160-5

  • Online ISBN: 978-3-319-11161-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation