Skip to main content
SpringerLink
Log in

Key Roles of Inflammation in Atherosclerosis: Mediators Involved in Orchestrating the Inflammatory Response and Its Resolution in the Disease Along with Therapeutic Avenues Targeting Inflammation

  • Protocol
  • First Online:
Atherosclerosis

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2419))

Abstract

Inflammation is a critical driver of all stages of atherosclerosis, from lesion development to plaque rupture. Cytokines are mediators of the immune response and in atherosclerosis, the balance of anti- and pro-inflammatory cytokines is tipped in favor of the latter, resulting in persistent and unresolved inflammation. Although reducing plasma cholesterol levels mainly via the use of statins has positively impacted patient outcomes and reduced mortality rates, the presence of significant residual inflammation and cardiovascular risk posttherapy emphasizes the prevailing risk of primary and secondary events driven by inflammation independently of hyperlipidemia. Given the dominant role of inflammation in driving pathogenesis, alternative therapeutic avenues beyond targeting lowering of plasma lipids are required. This chapter will discuss the role of inflammation and pro-inflammatory cytokines in driving atherogenesis and disease progression, the therapeutic potential of targeting cytokines for atherosclerosis and promising avenues in this area.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover 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

Similar content being viewed by others

References

  1. Banyer JL, Hamilton NH, Ramshaw IA et al (2000) Cytokines in innate and adaptive immunity. Rev Immunogenet 2(3):359–373

    CAS  PubMed  Google Scholar 

  2. Ait-Oufella H, Taleb S, Mallat Z et al (2011) Recent advances on the role of cytokines in atherosclerosis. Arterioscler Thromb Vasc Biol 31:969–979

    Article  CAS  PubMed  Google Scholar 

  3. Ramji DP, Davies TS (2015) Cytokines in atherosclerosis: key players in all stages of disease and promising therapeutic targets. Cytokine Growth Factor Rev 26:673–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Moss JWE, Ramji DP (2016) Cytokines: roles in atherosclerosis disease progression and potential therapeutic targets. Future Med Chem 8(11):1317–1330

    Article  CAS  PubMed  Google Scholar 

  5. Tousoulis D, Oikonomou E, Economou EK et al (2016) Inflammatory cytokines in atherosclerosis: current therapeutic approaches. Eur Heart J 37(22):1723–1732

    Article  CAS  PubMed  Google Scholar 

  6. Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 86:515–581

    Article  CAS  PubMed  Google Scholar 

  7. Libby P (2017) Interleukin-1 beta as a target for atherosclerosis therapy: the biological basis of CANTOS and beyond. J Am Coll Cardiol 70(18):2278–2289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lichtman AH, Binder CJ, Tsimikas S et al (2013) Adaptive immunity in atherogenesis: new insights and therapeutic approaches. J Clin Invest 123:27–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nus M, Mallat Z (2016) Immune-mediated mechanisms of atherosclerosis and implications for the clinic. Expert Rev Clin Immunol 12:1217–1237

    Article  CAS  PubMed  Google Scholar 

  10. Hansson GK, Libby P, Tabas I (2015) Inflammation and plaque vulnerability. J Intern Med 278:483–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Libby P, Ridker PM, Hansson GK (2009) Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 54:2129–2138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mason JC, Libby P (2015) Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J 36:428–484

    Article  Google Scholar 

  13. McLaren JE, Michael DR, Ashlin TG et al (2011) Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res 50:331–347

    Article  CAS  PubMed  Google Scholar 

  14. Shirai T, Hilhorst M, Harrison DG et al (2015) Macrophages in vascular inflammation - from atherosclerosis to vasculitis. Autoimmunity 48(3):139–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Stewart CR, Stuart LM, Wilkinson K et al (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–161

    Article  CAS  PubMed  Google Scholar 

  16. Tall AR, Yven-Charvet L (2015) Cholesterol, inflammation and innate immunity. Nat Rev Immunol 15:104–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dinarello CA (2018) Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 281:8–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Garlanda C, Dinarello CA, Mantovani A et al (2013) The interleukin-1 family: back to the future. Immunity 39:1003–1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550

    Article  CAS  PubMed  Google Scholar 

  20. Libby P, Ordovas JM, Auger KR et al (1986) Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol 124:179–186

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Libby P, Ordovas JM, Birinyi LK et al (1986) Inducible interleukin-1 expression in human vascular smooth muscle cells. J Clin Invest 78:1432–1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wolfs IMJ, Donners MMPC, de Winther MPJ (2011) Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation. Thromb Haemost 106(5):763–771

    Article  CAS  PubMed  Google Scholar 

  23. Chinetti-Gbaguidi G, Colin S, Staels B (2015) Macrophage subsets in atherosclerosis. Nat Rev Cardiol 12(1):10–17

    Article  CAS  PubMed  Google Scholar 

  24. Leitinger N, Schulman IG (2013) Phenotypic polarization of macrophages in atherosclerosis. Arterioscler Thromb Vasc Biol 33(6):1120–1126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Libby P, Warner SJ, Friedman GB (1988) Interleukin 1: a mitogen for human vascular smooth muscle cells that induces the release of growth-inhibitory prostanoids. J Clin Invest 81:487–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Khallou-Laschet J, Varthaman A, Fornasa G et al (2010) Macrophage plasticity in experimental atherosclerosis. PLoS One 5:e8852

    Article  PubMed  PubMed Central  Google Scholar 

  27. Robertson AK, Hansson GK (2006) T cells in atherogenesis: for better or for worse? Arterioscler Thromb Vasc Biol 26:2421–2432

    Article  CAS  PubMed  Google Scholar 

  28. Zhang H, Park Y, Wu J et al (2009) Role of TNF-α in vascular dysfunction. Clin Sci 116:219–230

    Article  CAS  Google Scholar 

  29. Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7(10):803–815

    Article  CAS  PubMed  Google Scholar 

  30. Frostegard J (2013) Immunity, atherosclerosis and cardiovascular disease. BMC Med 11:117. https://doi.org/10.1186/1741-7015-11-117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dinarello CA, Ikejima T, Warner SJC et al (1987) Interleukin-1 induces interleukin-1. I. Induction of circulating interleukin-1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol 139:1902–1910

    CAS  PubMed  Google Scholar 

  32. Warner SJC, Auger KR, Libby P (1987) Interleukin-1 induces interleukin-1. II. Recombinant human interleukin-1 induces interleukin-1 production by adult human vascular endothelial cells. J Immunol 139:1911–1917

    CAS  PubMed  Google Scholar 

  33. Patel MN, Carroll RG, Galvan-Pena S et al (2017) Inflammasome priming in sterile inflammatory disease. Trends Mol Med 23(2):165–180

    Article  CAS  PubMed  Google Scholar 

  34. Geng Y-J, Libby P (1995) Evidence for apoptosis in advanced human atheroma. Co-localization with interleukin-1 converting enzyme. Am J Pathol 147:251–266

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13:397–411

    Article  CAS  PubMed  Google Scholar 

  36. Prochnicki T, Mangan MS, Latz E (2016) Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res 5:1469

    Article  Google Scholar 

  37. Grebe A, Hoss F, Latz E (2018) NLRP3 inflammasome and the IL-1 pathway in atherosclerosis. Circ Res 122:1722–1740

    Article  CAS  PubMed  Google Scholar 

  38. Zimmer S, Grebe A, Latz E (2015) Danger signaling in atherosclerosis. Circ Res 116:323–340

    Article  CAS  PubMed  Google Scholar 

  39. Duewell P, Kono H, Rayner KJ et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tschopp J, Schroder K (2010) NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 10(3):210–215

    Article  CAS  PubMed  Google Scholar 

  41. Biasucci LM, Liuzzo G, Fantuzzi G et al (1999) Increasing levels of interleukin(1L)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina patients are associated with increased risk of in-hospital coronary events. Circulation 99:2079–2084

    Article  CAS  PubMed  Google Scholar 

  42. Haslinger-Löffler B (2008) Multiple effects of HMG-CoA reductase inhibitors (statins) besides their lipid-lowering function. Kidney Int 74(5):553–555. https://doi.org/10.1038/ki.2008.323

    Article  CAS  PubMed  Google Scholar 

  43. Bergheanu SC, Bodde MC, Jukema JW (2017) Pathophysiology and treatment of atherosclerosis: current view and future perspective on lipoprotein modification treatment. Neth Hear J 25(4):231–242. https://doi.org/10.1007/s12471-017-0959-2

    Article  CAS  Google Scholar 

  44. Antonopoulos A, Margaritis M, Lee R et al (2012) Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des 18(11):1519–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Calderon RM, Cubeddu LX, Goldberg RB et al (2010) Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 85(4):349–356

    Article  PubMed  PubMed Central  Google Scholar 

  46. Campbell CY, Rivera JJ, Blumenthal RS (2007) Residual risk in statin-treated patients: future therapeutic options. Curr Cardiol Rep 9(6):499–505. https://doi.org/10.1007/BF02938395

    Article  PubMed  Google Scholar 

  47. Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473(7347):317–325. https://doi.org/10.1038/nature10146

    Article  CAS  PubMed  Google Scholar 

  48. Sampson UK, Fazio S, Linton MF (2012) Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 14(1):1–10. https://doi.org/10.1007/s11883-011-0219-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ray KK, Wright S, Kallend D et al (2020) Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 382(16):1507–1519

    Article  CAS  PubMed  Google Scholar 

  50. Jia L, Betters JL, Yu L (2011) Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol 73:239–259. https://doi.org/10.1146/annurev-physiol-012110-142233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cannon CP, Blazing MA, Giugliano RP et al (2015) Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 25:2387–2397

    Article  Google Scholar 

  52. Tsujita K, Sugiyama S, Sumida H et al (2015) Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention. J Am Coll Cardiol 66(5):495–507

    Article  PubMed  Google Scholar 

  53. Bohula EA, Giugliano RP, Leiter LA et al (2018) Inflammatory and cholesterol risk in the FOURIER trial. Circulation 138(2):131–140

    Article  CAS  PubMed  Google Scholar 

  54. Ballantyne CM, Laufs U, Ray KK et al (2020) Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol 27(6):593–603

    Google Scholar 

  55. Pinkosky SL, Filippov S, Srivastava RA et al (2013) AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res 54:134–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pinkosky SL, Newton RS, Day EA et al (2016) Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun 7:13457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ballantyne CM, Banach M, Mancini GBJ et al (2018) Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis 277:195–203

    Google Scholar 

  58. Laufs U, Banach M, Mancini GBJ et al (2019) Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc 8:e011662

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ridker PM, Libby P, MacFayden JG et al (2018) Modulation of the interleukin-6 signaling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 39(38):3499–3507

    Article  CAS  PubMed  Google Scholar 

  60. Ridker PM, Cannon CP, Morrow D et al (2005) C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352(1):20–28

    Article  CAS  PubMed  Google Scholar 

  61. Puri R, Nissen SE, Libby P et al (2013) C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy. Circulation 128(22):2395–2403

    Article  CAS  PubMed  Google Scholar 

  62. Bevilacqua MP, Pober JS, Majeau GR et al (1984) Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med 160:618–623

    Article  CAS  PubMed  Google Scholar 

  63. Bevilacqua MP, Pober JS, Wheeler ME et al (1985) Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest 76:2003–2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Galea J, Armstrong J, Gadsdon P et al (1996) Interleukin-1 beta in coronary arteries of patients with ischemic heart disease. Arterioscler Thromb Vasc Biol 16:1000–1006

    Article  CAS  PubMed  Google Scholar 

  65. Shimokawa H, Ito A, Fukumoto Y et al (1996) Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. J Clin Invest 97:769–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kirii H, Niwa T, Yamada Y et al (2003) Lack of interleukin-1β decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 23(4):656–660

    Article  CAS  PubMed  Google Scholar 

  67. Morton AC, Arnold ND, Gunn J et al (2005) Interleukin-1 receptor antagonist alters the response to vessel wall injury in a porcine coronary artery model. Cardiovasc Res 68:493–501

    Article  CAS  PubMed  Google Scholar 

  68. Elhage R, Maret A, Pieraggi MT et al (1998) Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice. Circulation 97:242–244

    Article  CAS  PubMed  Google Scholar 

  69. Devlin CM, Kuriakose G, Hirsch E et al (2002) Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci U S A 99:6280–6285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Isoda K, Sawada S, Ishigami N et al (2004) Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 24:1068–1073

    Article  CAS  PubMed  Google Scholar 

  71. Nicklin MJ, Hughes DE, Barton JL et al (2000) Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med 191:303–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bhaskar V, Yin J, Mirza AM et al (2011) Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice. Atherosclerosis 216(2):313–320

    Article  CAS  PubMed  Google Scholar 

  73. Alexander MR, Moehle CW, Johnson JL et al (2012) Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J Clin Invest 122:70–79

    Article  CAS  PubMed  Google Scholar 

  74. Menu P, Pellegrin M, Aubert J-F et al (2011) Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis 2(3):e137–e145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shemesh S, Kamari Y, Shaish A et al (2012) Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice. Atherosclerosis 222(2):329–336

    Article  CAS  PubMed  Google Scholar 

  76. Kamari Y, Werman-Venkert R, Shaish A et al (2007) Differential role and tissue specificity of interleukin-1alpha gene expression in atherogenesis and lipid metabolism. Atherosclerosis 195:31–38

    Article  CAS  PubMed  Google Scholar 

  77. Kamari Y, Shaish A, Shemesh S et al (2011) Reduced atherosclerosis and inflammatory cytokines in apolipoprotein-E-deficient mice lacking bone marrow-derived interleukin-1α. Biochem Biophys Res Commun 405(2):197–203

    Article  CAS  PubMed  Google Scholar 

  78. Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131

    Article  CAS  PubMed  Google Scholar 

  79. Ridker PM, Everett BM, Pradhan A et al (2018) Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 380(8):752–762

    Article  PubMed  PubMed Central  Google Scholar 

  80. Westlake SL, Colebatch AN, Baird J et al (2010) The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review. Rheumatology 49(2):295–307

    Article  CAS  PubMed  Google Scholar 

  81. Choi HK, Hernan MA, Seeger JD et al (2002) Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 359(9313):1173–1177

    Article  CAS  PubMed  Google Scholar 

  82. Micha R, Imamura F, Wyler Von Ballmoos M et al (2011) Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 108(9):1362–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Morton AC, Rothman AM, Greenwood JP et al (2015) The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart study. Eur Heart J 36(6):377–384

    Article  CAS  PubMed  Google Scholar 

  84. Abbate A, Kontos MC, Abouzaki NA et al (2015) Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am J Cardiol 115(3):288–292

    Article  CAS  PubMed  Google Scholar 

  85. Abbate A, Kontos MC, Grizzard JD et al (2010) Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol 105(10):1371–1377

    Article  CAS  PubMed  Google Scholar 

  86. Abbate A, Trankle CR, Buckley LF et al (2020) Interleukin-1 blockade inhibits the acute inflammatory response in patients with ST-segment-elevation myocardial infarction. J Am Heart Assoc 9:e014941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nidorf SM, Eikelboom JW, Budgeon CA et al (2013) Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 61(4):404–410

    Article  CAS  PubMed  Google Scholar 

  88. O’Donoghue ML, Braunwald E, White HD et al (2014) Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA 312(10):1006–1015

    Article  PubMed  Google Scholar 

  89. O’Donoghue ML, Glaser R, Cavender MA et al (2016) Effect of iosmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA 315(15):1591–1599

    Article  PubMed  Google Scholar 

  90. Tardif J-C, Kouz S, Waters DD et al (2019) Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 381(26):2497–2505

    Article  CAS  PubMed  Google Scholar 

  91. Nidorf SM, Fiolet ATL, Mosterd A et al (2020) Colchicine in patients with chronic coronary disease. N Engl J Med 383(19):1838–1847

    Article  CAS  PubMed  Google Scholar 

  92. Nidorf SM, Eikelboom JW, Thompson PL (2014) Targeting cholesterol crystal-induced inflammation for the secondary prevention of cardiovascular disease. J Cardiovasc Pharmacol Therapeut 19(1):45–52

    Article  CAS  Google Scholar 

  93. Martinez GJ, Celermajer DS, Patel S (2018) The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis 269:262–271

    Article  CAS  PubMed  Google Scholar 

  94. Huber SA, Sakkinen P, Conze D et al (1999) Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 19:2364–2367

    Article  CAS  PubMed  Google Scholar 

  95. Schieffer B, Selle T, Hilfiker A et al (2004) Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis. Circulation 110:3493–3500

    Article  CAS  PubMed  Google Scholar 

  96. Zhang K, Huang XZ, Li XN et al (2012) Interleukin 6 destabilizes atherosclerotic plaques by downregulating prolyl-4-hydroxylase α1 via a mitogen-activated protein kinase and c-Jun pathway. Arch Biochem Biophys 528:127–133

    Article  CAS  PubMed  Google Scholar 

  97. Schuett H, Oestreich R, Waetzig GH et al (2012) Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol 32:281–290

    Article  CAS  PubMed  Google Scholar 

  98. Madan M, Bishayi B, Hoge M et al (2008) Atheroprotective role of interleukin-6 in diet- and/or pathogen-associated atherosclerosis using an ApoE heterozygote murine model. Atherosclerosis 197:504–514

    Article  CAS  PubMed  Google Scholar 

  99. Whitman SC, Ravisankar P, Daugherty A (2002) Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res 90:E34–E38

    Article  CAS  PubMed  Google Scholar 

  100. Bhat OM, Kumar PU, Giridharan NV et al (2015) Interleukin-18-induced atherosclerosis involves CD36 and NF-κB crosstalk in Apo E-/- mice. J Cardiol 66(1):28–35

    Article  PubMed  Google Scholar 

  101. Pejnovic N, Vratimos A, Lee SH et al (2009) Increased atherosclerotic lesions and Th17 in interleukin-18 deficient apolipoprotein E-knockout mice fed high-fat diet. Mol Immunol 47(1):37–45

    Article  CAS  PubMed  Google Scholar 

  102. Canault M, Peiretti F, Mueller C et al (2004) Exclusive expression of transmembrane TNF-alpha in mice reduces the inflammatory response in early lipid lesions of aortic sinus. Atherosclerosis 172:211–218

    Article  CAS  PubMed  Google Scholar 

  103. Ohta H, Wada H, Niwa T et al (2005) Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in apoE-deficient mice. Atherosclerosis 180:11–17

    Article  CAS  PubMed  Google Scholar 

  104. Xiao N, Yin M, Zhang L et al (2009) Tumor necrosis factor-alpha deficiency retards early fatty-streak lesion by influencing the expression of inflammatory factors in apoE-null mice. Mol Genet Metab 96(4):239–244

    Article  CAS  PubMed  Google Scholar 

  105. Xanthoulea S, Thelen M, Pottgens C et al (2011) Absence of p55 TNF receptor reduces atherosclerosis, but has no major effect on angiotensin II induced aneurysms in LDL receptor deficient mice. PLoS 4(7):e6113

    Article  Google Scholar 

  106. Mackesy DZ, Goalstone ML (2014) ERK5: novel mediator of insulin and TNF-stimulated VCAM-1 expression in vascular cells. J Diab 6:595–602

    Article  CAS  Google Scholar 

  107. Rajasingh J, Bord E, Luedemann C et al (2006) IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression. FASEB J 20:2112–2114

    Article  CAS  PubMed  Google Scholar 

  108. Lisinski TJ, Furie MB (2002) Interleukin-10 inhibits proinflammatory activation of endothelium in response to Borrelia burgdorferi or lipopolysaccharide but not interleukin-1 beta or tumor necrosis factor alpha. J Leukoc Biol 72:503–511

    Article  CAS  PubMed  Google Scholar 

  109. Gallagher H, Williams JO, Ferekidis N et al (2019) Dihomo-γ-linolenic acid inhibits several key cellular processes associated with atherosclerosis. Biochem Biophys Acta Mol Basis Dis 1865(9):2538–2550

    Article  CAS  Google Scholar 

  110. Takai S, Jin D, Kawashima H et al (2009) Anti-atherosclerotic effects of dihomo-gamma-linolenic acid in ApoE-deficient mice. J Atheroscler Thromb 16(4):480–489

    Article  CAS  PubMed  Google Scholar 

  111. Bhatt DL, Steg PG, Miller M et al (2019) Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 380(1):11–22

    Article  CAS  PubMed  Google Scholar 

  112. Budoff MJ, Bhatt DL, Kinninger A et al (2020) Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J 41:3925–3932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank the British Heart Foundation for financial support (grants PG/16/25/32097 and FS/17/75/33257).

Author information

Authors and Affiliations

  1. Cardiff School of Biosciences, Cardiff University, Cardiff, UK

    Yee-Hung Chan & Dipak P. Ramji

Authors
  1. Yee-Hung Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dipak P. Ramji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yee-Hung Chan .

Editor information

Editors and Affiliations

  1. School of Biosciences, Cardiff University, Cardiff, UK

    Dipak Ramji

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Chan, YH., Ramji, D.P. (2022). Key Roles of Inflammation in Atherosclerosis: Mediators Involved in Orchestrating the Inflammatory Response and Its Resolution in the Disease Along with Therapeutic Avenues Targeting Inflammation. In: Ramji, D. (eds) Atherosclerosis. Methods in Molecular Biology, vol 2419. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1924-7_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1924-7_2

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1923-0

  • Online ISBN: 978-1-0716-1924-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation