Skip to main content
SpringerLink
Log in

Atherosclerosis

  • Chapter
  • First Online:
The Immunology of Cardiovascular Homeostasis and Pathology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1003))

Abstract

In this chapter, we discuss the manner through which the immune system regulates the cardiovascular system in health and disease. We define the cardiovascular system and elements of atherosclerotic disease, the main focus in this chapter. Herein we elaborate on the disease process that can result in myocardial infarction (heart attack), ischaemic stroke and peripheral arterial disease. We have discussed broadly the homeostatic mechanisms in place that help autoregulate the cardiovascular system including the vital role of cholesterol and lipid clearance as well as the role lipid homeostasis plays in cardiovascular disease in the context of atherosclerosis. We then elaborate on the role played by the immune system in this setting, namely, major players from the innate and adaptive immune system, as well as discussing in greater detail specifically the role played by monocytes and macrophages.

This chapter should represent an overview of the role played by the immune system in cardiovascular homeostasis; however further reading of the references cited can expand the reader’s knowledge of the detail, and we point readers to many excellent reviews which summarise individual immune systems and their role in cardiovascular disease.

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 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
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

Abbreviations

ABCA1:

ATP-binding cassette transporter-A1

ABCG1:

ATP-binding cassette transporter-G1

BMI:

Body mass index

CNS:

Central nervous system

CRP:

C-reactive protein

CVD:

Cardiovascular disease

DC:

Dendritic cell

Foxp3:

Forkhead box P3

HDL:

High-density lipoprotein

ICAM-1:

Intracellular adhesion molecule-1

IHD:

Ischaemic heart disease

IL-6:

Interleukin-6

LDL:

Low-density lipoprotein

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

mRNA:

Messenger RNA

NK:

Natural killer

PAD:

Peripheral arterial disease

SBP:

Systolic blood pressure

T2DM:

Type-2 diabetes mellitus

TLR:

Toll-like receptor

TNF:

Tumour necrosis factor

Treg:

Regulatory T cell

VCAM-1:

Vascular adhesion molecule-1

VLDL:

Very low-density lipoprotein

References

  1. WHO. Global status report on noncommunicable diseases 2010. In: Alwan A, editor. Apps. Who. Int. Geneva; 2010. pp. 1–176.

    Google Scholar 

  2. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;385:117–71.

    Article  Google Scholar 

  3. Rothwell PM, Coull AJ, Silver LE, Fairhead JF, Giles MF, Lovelock CE, et al. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford vascular study). Lancet. 2005;366:1773–83.

    Article  CAS  PubMed  Google Scholar 

  4. Townsend N, Wickramasinghe K, Bhatnagar P. Coronary heart disease statistics. A compendium of health statistics. London: British Heart Foundation; 2012.

    Google Scholar 

  5. Fowkes FGR, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382:1329–40.

    Article  PubMed  Google Scholar 

  6. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ. 2004;328:1519–0.

    Google Scholar 

  7. Thun MJ, Myers DG, Day-Lally C. Age and the exposure-response relationships between cigarette smoking and premature death in cancer prevention study II. … D: Changes in …. 1997.

    Google Scholar 

  8. Holt PG, Keast D. Environmentally induced changes in immunological function: acute and chronic effects of inhalation of tobacco smoke and other atmospheric contaminants in man and experimental animals. Bacteriol Rev. 1977;41:205–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Reynolds HY. Bronchoalveolar lavage. Am Rev Respir Dis. 1987;135:250–63.

    CAS  PubMed  Google Scholar 

  10. King TE, Savici D, Campbell PA. Phagocytosis and killing of Listeria monocytogenes by alveolar macrophages: smokers versus nonsmokers. J Infect Dis. 1988;158:1309–16.

    Article  PubMed  Google Scholar 

  11. McCrea KA, Ensor JE, Nall K, Bleecker ER, Hasday JD. Altered cytokine regulation in the lungs of cigarette smokers. Am J Respir Crit Care Med. 1994;150:696–703.

    Article  CAS  PubMed  Google Scholar 

  12. Ferson M, Edwards A, Lind A, Milton GW, Hersey P. Low natural killer-cell activity and immunoglobulin levels associated with smoking in human subjects. Int J Cancer. 1979;23:603–9.

    Article  CAS  PubMed  Google Scholar 

  13. Mathews JD, Whittingham S, Hooper BM, Mackay IR, Stenhouse NS. Association of autoantibodies with smoking, cardiovascular morbidity, and death in the Busselton population. Lancet. 1973;2:754–8.

    Article  CAS  PubMed  Google Scholar 

  14. Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol. 2002;2:372–7.

    Article  CAS  PubMed  Google Scholar 

  15. Rutan GH, Kuller LH, Neaton JD, Wentworth DN, McDonald RH, Smith WM. Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the multiple risk factor intervention trial. Circulation. 1988;77:504–14.

    Article  CAS  PubMed  Google Scholar 

  16. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–74.

    Article  CAS  PubMed  Google Scholar 

  17. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–13.

    Article  PubMed  Google Scholar 

  18. O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, et al. Urinary sodium and potassium excretion, mortality, and cardiovascular events. N Engl J Med. 2014;371:612–23.

    Article  PubMed  CAS  Google Scholar 

  19. Chen Z, Smith M, Du H, Guo Y, Clarke R, Bian Z, et al. Blood pressure in relation to general and central adiposity among 500,000 adult Chinese men and women. Int J Epidemiol. 2015;44:1305–19.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bautista LE, Vera LM, Arenas IA, Gamarra G. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-|[alpha]|) and essential hypertension. J Hum Hypertens. 2005;19:149–54.

    Article  CAS  PubMed  Google Scholar 

  21. Chae CU, Lee RT, Rifai N, Ridker PM. Blood pressure and inflammation in apparently healthy men. Hypertension. 2001;38:399–403.

    Article  CAS  PubMed  Google Scholar 

  22. Laviades C, Varo N, Díez J. Transforming growth factor Beta in hypertensives with cardiorenal damage. Hypertension. 2000;36:517–22.

    Article  CAS  PubMed  Google Scholar 

  23. Dörffel Y, Lätsch C, Stuhlmüller B, Schreiber S, Scholze S, Burmester GR, et al. Preactivated peripheral blood monocytes in patients with essential hypertension. Hypertension. 1999;34:113–7.

    Article  PubMed  Google Scholar 

  24. Frossard PM, Gupta A, Pravica V, Perrey C, Hutchinson IV, Lukic ML. A study of five human cytokine genes in human essential hypertension. Mol Immunol. 2002;38:969–76.

    Article  CAS  PubMed  Google Scholar 

  25. Harrison DG, Guzik TJ, Lob HE, Madhur MS. Inflammation, immunity, and hypertension. Hypertension. 2011;57(2):132–40.

    Article  CAS  PubMed  Google Scholar 

  26. Muller DN, Dechend R, Mervaala EM, Park JK, Schmidt F, Fiebeler A, et al. NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension. 2000;35:193–201.

    Article  CAS  PubMed  Google Scholar 

  27. Shagdarsuren E, Wellner M, Braesen J-H, Park J-K, Fiebeler A, Henke N, et al. Complement activation in angiotensin II-induced organ damage. Circ Res. 2005;97:716–24.

    Article  CAS  PubMed  Google Scholar 

  28. Müller DN, Shagdarsuren E, Park J-K, Dechend R, Mervaala E, Hampich F, et al. Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol. 2002;161:1679–93.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wu K-IS, Schmid-Schönbein GW. Nuclear factor kappa B and matrix metalloproteinase induced receptor cleavage in the spontaneously hypertensive rat. Hypertension. 2011;57:261–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tostes RCA, Touyz RM, He G, Chen X, Schiffrin EL. Contribution of endothelin-1 to renal activator protein-1 activation and macrophage infiltration in aldosterone-induced hypertension. Clin Sci (Lond). 2002;103(Suppl 48):25S–30S.

    Article  CAS  Google Scholar 

  31. Jennings BL, Anderson LJ, Estes AM, Yaghini FA, Fang XR, Porter J, et al. Cytochrome P450 1B1 contributes to renal dysfunction and damage caused by angiotensin II in mice. Hypertension. 2012;59:348–54.

    Article  CAS  PubMed  Google Scholar 

  32. Zubcevic J, Waki H, Raizada MK, Paton JFR. Autonomic-immune-vascular interaction: an emerging concept for neurogenic hypertension. Hypertension. 2011;57:1026–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Abboud FM, Harwani SC, Chapleau MW. Autonomic neural regulation of the immune system: implications for hypertension and cardiovascular disease. Hypertension. 2012;59:755–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ryan MJ. An update on immune system activation in the pathogenesis of hypertension. Hypertension. 2013;62:226–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161:161–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gertler MM, White PD. Coronary heart disease in young adults. A multi-disciplinary study. Science. 1954;120:1–2.

    Article  Google Scholar 

  37. Gofman JW, Delalla O, Glazier F, Freeman NK, Lindgren FT, Nichols AV, et al. The serum lipoprotein transport system in health, metabolic disorders, atherosclerosis and coronary heart disease. J Clin Lipidol. 2007;1:104–41.

    Article  PubMed  Google Scholar 

  38. Brown MS, Goldstein JL. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc Natl Acad Sci U S A. 1974;71:788–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Emerging Risk Factors Collaboration, Sarwar N, Gao P, SRK S, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–22.

    Article  CAS  Google Scholar 

  40. Emerging Risk Factors Collaboration, SRK S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829–41.

    Article  Google Scholar 

  41. Joosten MM, Pai JK, Bertoia ML, Rimm EB, Spiegelman D, Mittleman MA, et al. Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA. 2012;308:1660–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87:978–82.

    Article  CAS  PubMed  Google Scholar 

  43. Sampson MJ, Davies IR, Brown JC, Ivory K, Hughes DA. Monocyte and neutrophil adhesion molecule expression during acute hyperglycemia and after antioxidant treatment in type 2 diabetes and control patients. Arterioscler Thromb Vasc Biol. 2002;22:1187–93.

    Article  CAS  PubMed  Google Scholar 

  44. Ceriello A, Falleti E, Motz E, Taboga C, Tonutti L, Ezsol Z, et al. Hyperglycemia-induced circulating ICAM-1 increase in diabetes mellitus: the possible role of oxidative stress. Horm Metab Res. 1998;30:146–9.

    Article  CAS  PubMed  Google Scholar 

  45. Chen NG, Azhar S, Abbasi F, Carantoni M, Reaven GM. The relationship between plasma glucose and insulin responses to oral glucose, LDL oxidation, and soluble intercellular adhesion molecule-1 in healthy volunteers. Atherosclerosis. 2000;152:203–8.

    Article  CAS  PubMed  Google Scholar 

  46. Marfella R, Esposito K, Giunta R, Coppola G, De Angelis L, Farzati B, et al. Circulating adhesion molecules in humans: role of hyperglycemia and hyperinsulinemia. Circulation. 2000;101:2247–51.

    Article  CAS  PubMed  Google Scholar 

  47. Ceriello A, Quagliaro L, Piconi L, Assaloni R, Da Ros R, Maier A, et al. Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes. 2004;53:701–10.

    Article  CAS  PubMed  Google Scholar 

  48. Jafar N, Edriss H, Nugent K. The effect of short-term hyperglycemia on the innate immune system. Am J Med Sci. 2016;351:201–11.

    Article  PubMed  Google Scholar 

  49. Turina M, Fry DE, Polk HC. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med. 2005;33:1624–33.

    Article  PubMed  Google Scholar 

  50. WHO. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia. Bull. World Health Organ. Geneva: WHO Press; 2006 pp. 1–50.

    Google Scholar 

  51. Deresinski S. Infections in the diabetic patient: Strategies for the clinician. Infect. Dis. Rep. 1995;1:1–12.

    Google Scholar 

  52. Carton JA, Maradona JA, Nuño FJ, Fernandez-Alvarez R, Pérez-Gonzalez F, Asensi V. Diabetes mellitus and bacteraemia: a comparative study between diabetic and non-diabetic patients. Eur J Med. 1992;1:281–7.

    CAS  PubMed  Google Scholar 

  53. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol. 1999;26:259–65.

    Article  CAS  PubMed  Google Scholar 

  54. Katz S, Klein B, Elian I, Fishman P, Djaldetti M. Phagocytotic activity of monocytes from diabetic patients. Diabetes Care. 1983;6:479–82.

    Article  CAS  PubMed  Google Scholar 

  55. West KM. Epidemiology of diabetes and its vascular lesions. New York: Elsevier North-Holland Inc; 1978. p. 234–48.

    Google Scholar 

  56. Barrett-Connor E. Epidemiology, obesity, and non-insulin-dependent diabetes mellitus. Epidemiol Rev. 1989;11:172–81.

    Article  CAS  PubMed  Google Scholar 

  57. Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: findings from a national cohort of US adults. Am J Epidemiol. 1997;146:214–22.

    Article  CAS  PubMed  Google Scholar 

  58. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–607.

    Article  CAS  PubMed  Google Scholar 

  59. WHO. Waist circumference and waist-hip ratio: report of a WHO expert consultation, Geneva, 8–11 December 2008. Geneva, CH: World Health Organization; 2014. pp. 23–6.

    Google Scholar 

  60. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev. 2010;72:219–46. doi:10.1146/annurev-physiol-021909-135846.

    CAS  Google Scholar 

  63. Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract. 2005;69:29–35.

    Article  CAS  PubMed  Google Scholar 

  64. Festa A, D’Agostino R, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, et al. The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord. 2001;25:1407–15.

    Article  CAS  PubMed  Google Scholar 

  65. Bulló M, García-Lorda P, Megias I, Salas-Salvadó J. Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res. 2003;11:525–31.

    Article  PubMed  Google Scholar 

  66. Winer DA, Luck H, Tsai S, Winer S. The intestinal immune system in obesity and insulin resistance. CMET. 2016;23:413–26.

    CAS  Google Scholar 

  67. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med. 2009;15:921–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15:914–20.

    Article  CAS  PubMed  Google Scholar 

  72. Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med. 2011;17:610–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wensveen FM, Jelenčić V, Valentić S, Šestan M, Wensveen TT, Theurich S, et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol. 2015;16:376–85.

    Article  CAS  PubMed  Google Scholar 

  74. Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18:1407–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation. 2004;110:1245–50.

    Article  PubMed  Google Scholar 

  76. Qatanani M, Lazar MA. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 2007;21:1443–55.

    Article  CAS  PubMed  Google Scholar 

  77. Odegaard JI, Chawla A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab. 2008;4:619–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tobias P, Curtiss LK. Thematic review series: the immune system and atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis. J Lipid Res. 2005;46:404–11.

    Article  CAS  PubMed  Google Scholar 

  79. Harrison DG, Guzik TJ, Goronzy J, Weyand C. Is hypertension an immunologic disease? Curr Cardiol Rep. 2008;10:464–9.

    Article  PubMed  Google Scholar 

  80. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet. 1994;344:1383–9.

    Google Scholar 

  81. Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, Erbel RM, Libby P, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365:2078–87.

    Article  CAS  PubMed  Google Scholar 

  82. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504.

    Article  CAS  PubMed  Google Scholar 

  83. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.

    Article  Google Scholar 

  84. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–57.

    Article  Google Scholar 

  85. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279:1615–22.

    Article  CAS  PubMed  Google Scholar 

  86. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med. 1996;335:1001–9.

    Article  CAS  PubMed  Google Scholar 

  87. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, 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;333:1301–7.

    Article  CAS  PubMed  Google Scholar 

  88. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437–45.

    Article  CAS  PubMed  Google Scholar 

  89. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart J-C, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.

    Article  CAS  PubMed  Google Scholar 

  90. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.

    Article  CAS  PubMed  Google Scholar 

  91. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670–1681.

    Google Scholar 

  92. Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370:1829–39.

    Article  CAS  Google Scholar 

  93. Stamler J, Vaccaro O, Neaton JD, Wentworth D, The Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors, and 12-Yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care. 1993;16:434–44.

    Article  CAS  PubMed  Google Scholar 

  94. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987;84:2995–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Parthasarathy S, Quinn MT, Steinberg D. Is oxidized low density lipoprotein involved in the recruitment and retention of monocyte/macrophages in the artery wall during the initiation of atherosclerosis? Basic Life Sci. 1988;49:375–80.

    CAS  PubMed  Google Scholar 

  96. Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A. 1984;81:3883–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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;320:915–24.

    Article  CAS  PubMed  Google Scholar 

  98. Carpenter KL, Wilkins GM, Fussell B, Ballantine JA, Taylor SE, Mitchinson MJ, et al. Production of oxidized lipids during modification of low-density lipoprotein by macrophages or copper. Biochem J. 1994;304(Pt 2):625–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Folcik VA, Nivar-Aristy RA, Krajewski LP, Cathcart MK. Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. J Clin Invest. 1995;96:504–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Berliner J, Leitinger N, Watson A, Huber J, Fogelman A, Navab M. Oxidized lipids in atherogenesis: formation, destruction and action. Thromb Haemost. 1997;78:195–9.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. Navab M, Hama SY, Reddy ST, Ng CJ, Van Lenten BJ, Laks H, et al. Oxidized lipids as mediators of coronary heart disease. Curr Opin Lipidol. 2002;13:363–72.

    Article  CAS  PubMed  Google Scholar 

  103. Birukov KG. Oxidized lipids: the two faces of vascular inflammation. Curr Atheroscler Rep. 2006;8:223–31.

    Article  CAS  PubMed  Google Scholar 

  104. Jovinge S, Ares MP, Kallin B, Nilsson J. Human monocytes/macrophages release TNF-alpha in response to Ox-LDL. Arterioscler Thromb Vasc Biol. 1996;16:1573–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  106. Bekkering S, Quintin J, Joosten LAB, van der Meer JWM, Netea MG, Riksen NP. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler Thromb Vasc Biol. 2014;34:1731–8.

    Article  CAS  PubMed  Google Scholar 

  107. Fuhrman B, Partoush A, Volkova N, Aviram M. Ox-LDL induces monocyte-to-macrophage differentiation in vivo: possible role for the macrophage colony stimulating factor receptor (M-CSF-R). Atherosclerosis. 2008;196:598–607.

    Article  CAS  PubMed  Google Scholar 

  108. Brand K, Banka CL, Mackman N, Terkeltaub RA, Fan ST, Curtiss LK. Oxidized LDL enhances lipopolysaccharide-induced tissue factor expression in human adherent monocytes. Arterioscler Thromb. 1994;14:790–7.

    Article  CAS  PubMed  Google Scholar 

  109. Foster GA, Xu L, Chidambaram AA, Soderberg SR, Armstrong EJ, Wu H, et al. CD11c/CD18 signals very late antigen-4 activation to initiate foamy monocyte recruitment during the onset of hypercholesterolemia. J Immunol. 2015;195(11):5380–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gower RM, Wu H, Foster GA, Devaraj S, Jialal I, Ballantyne CM, et al. CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to vascular cell adhesion molecule-1. Arterioscler Thromb Vasc Biol. 2011;31:160–6.

    Article  CAS  PubMed  Google Scholar 

  111. Jackson WD, Weinrich TW, Woollard KJ. Very-low and low-density lipoproteins induce neutral lipid accumulation and impair migration in monocyte subsets. Nature Publishing Group; 2016; pp. 1–12.

    Google Scholar 

  112. Berliner JA, Heinecke JW. The role of oxidized lipoproteins in atherogenesis. Free Radic Biol Med. 1996;20:707–27.

    Article  CAS  PubMed  Google Scholar 

  113. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham study. Am J Med. 1977;62:707–14.

    Article  CAS  PubMed  Google Scholar 

  114. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000.

    Article  Google Scholar 

  115. Mineo C, Shaul PW. Novel biological functions of high-density lipoprotein cholesterol. Circ Res. 2012;111:1079–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Baldán A, Bojanic DD, Edwards PA. The ABCs of sterol transport. J Lipid Res. 2009;50(Suppl):S80–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Yvan-Charvet L, Wang N, Tall AR. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol. 2010;30:139–43.

    Article  CAS  PubMed  Google Scholar 

  118. Barter PJ, Nicholls S, Rye K-A, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004;95:764–72.

    Article  CAS  PubMed  Google Scholar 

  119. De Nardo D, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer M, et al. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat Immunol. 2014;15:152–60.

    Article  PubMed  CAS  Google Scholar 

  120. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380:572–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science. 2016;351:1166–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJP, Komajda M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–22.

    Article  CAS  PubMed  Google Scholar 

  123. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  CAS  Google Scholar 

  124. Schwartz GG, Olsson AG, Ballantyne CM, Barter PJ, Holme IM, Kallend D, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158:896–901.e3.

    Article  CAS  PubMed  Google Scholar 

  125. Lambert JE, Parks EJ. Postprandial metabolism of meal triglyceride in humans. BBA Mol Cell Biol Lipids. 2012;1821:721–6.

    Article  CAS  Google Scholar 

  126. Redgrave TG. Chylomicron metabolism. Biochem Soc Trans. 2004;32:79–82.

    Article  CAS  PubMed  Google Scholar 

  127. López-Miranda J, Marín C. Chapter 17: dietary, physiological, and genetic impacts on postprandial lipid metabolism. Fat Detect Taste Texture Post Ingestive Effects. 2010:1–59.

    Google Scholar 

  128. Hartigh den LJ, Altman R, Norman JE, Rutledge JC. Postprandial VLDL lipolysis products increase monocyte adhesion and lipid droplet formation via activation of ERK2 and NFκB. Am J Physiol Heart Circ Physiol. 2014;306:H109–20.

    Article  CAS  Google Scholar 

  129. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979;60:473–85.

    Article  CAS  PubMed  Google Scholar 

  130. Nordestgaard BG, Benn M, Schnohr P, Tybjærg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308.

    Article  CAS  PubMed  Google Scholar 

  131. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384:626–35.

    Article  CAS  PubMed  Google Scholar 

  132. Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L, et al. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med. 2014;160:398–406.

    Article  PubMed  Google Scholar 

  133. Harcombe Z, Baker JS, Cooper SM, Davies B, Sculthorpe N, DiNicolantonio JJ, et al. Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis. Open Heart. 2015;2:e000196.

    Article  PubMed  PubMed Central  Google Scholar 

  134. de Souza RJ, Mente A, Maroleanu A, Cozma AI, Ha V, Kishibe T, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ. 2015;351:h3978–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Siri-Tarino PW, Sun Q, FB H, Krauss RM. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am J Clin Nutr. 2010;91:535–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Estruch R, Ros E, Salas-Salvadó J, Covas M-I, Corella D, Arós F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–90.

    Article  CAS  PubMed  Google Scholar 

  137. Li R, Wu Y, Manso AM, Gu Y, Liao P, Israeli S, et al. β1 integrin gene excision in the adult murine cardiac myocyte causes defective mechanical and signaling responses. Am J Pathol. 2012;180:952–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lal H, Verma SK, Smith M, Guleria RS, Lu G, Foster DM, et al. Stretch-induced MAP kinase activation in cardiac myocytes: differential regulation through beta1-integrin and focal adhesion kinase. J Mol Cell Cardiol. 2007;43:137–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lal H, Verma SK, Golden HB, Foster DM, Smith M, Dostal DE. Stretch-induced regulation of angiotensinogen gene expression in cardiac myocytes and fibroblasts: opposing roles of JNK1/2 and p38alpha MAP kinases. J Mol Cell Cardiol. 2008;45:770–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Verma SK, Lal H, Golden HB, Gerilechaogetu F, Smith M, Guleria RS, et al. Rac1 and RhoA differentially regulate angiotensinogen gene expression in stretched cardiac fibroblasts. Cardiovasc Res. 2011;90:88–96.

    Article  CAS  PubMed  Google Scholar 

  141. Burgess ML, Carver WE, Terracio L, Wilson SP, Wilson MA, Borg TK. Integrin-mediated collagen gel contraction by cardiac fibroblasts. Effects of angiotensin II. Circ Res. 1994;74:291–8.

    Article  CAS  PubMed  Google Scholar 

  142. Dostal DE, Feng H, Nizamutdinov D, Golden HB, Afroze SH, Dostal JD, et al. Mechanosensing and regulation of cardiac function. J Clin Exp Cardiolog. 2014;5:314.

    PubMed  PubMed Central  Google Scholar 

  143. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation. 2008;118:863–71.

    Article  PubMed  Google Scholar 

  144. Kishi T. Heart failure as an autonomic nervous system dysfunction. J Cardiol. 2012;59:117–22.

    Article  PubMed  Google Scholar 

  145. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res. 2014;114:1004–21.

    Article  CAS  PubMed  Google Scholar 

  146. Esler MD, Krum H, Schlaich M, Schmieder RE, Böhm M, Sobotka PA, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126:2976–82.

    Article  CAS  PubMed  Google Scholar 

  147. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393–401.

    Article  CAS  PubMed  Google Scholar 

  148. Khansari DN, Murgo AJ, Faith RE. Effects of stress on the immune system. Immunol Today. 1990;11(5):170.

    Article  CAS  PubMed  Google Scholar 

  149. Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130:601–30.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, Zaltsman A, et al. Chronic variable stress activates hematopoietic stem cells. Nat Med. 2014;20:754–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo J-L, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204:3037–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010;121:2437–45.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Emami H, Singh P, MacNabb M, Vucic E, Lavender Z, Rudd JHF, et al. Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. JACC Cardiovasc Imaging. 2015;8:121–30.

    Article  PubMed  Google Scholar 

  155. van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968;128:415–35.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Tsujioka H, Imanishi T, Ikejima H, Kuroi A, Takarada S, Tanimoto T, et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J Am Coll Cardiol. 2009;54:130–8.

    Article  PubMed  Google Scholar 

  157. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487:325–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Gerrity RG. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol. 1981;103:181–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Gerrity RG. The role of the monocyte in atherogenesis: II. Migration of foam cells from atherosclerotic lesions. Am J Pathol. 1981;103:191–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Cros J, Cagnard N, Woollard KJ, Patey N, Zhang S-Y, Senechal B, et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity. 2010;33:375–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol. 2010:1–10.

    Google Scholar 

  162. Combadière C, Potteaux S, Rodero M, Simon T, Pezard A, Esposito B, et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008;117:1649–57.

    Article  PubMed  CAS  Google Scholar 

  163. Tacke F, Alvarez D, Kaplan TJ, 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;117:185–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lesnik P, Haskell CA, Charo IF. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J Clin Invest. 2003;111:333–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13:709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wong KL, Tai JJ-Y, Wong W-C, Han H, Sem X, Yeap W-H, et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood. 2011;118:e16–31.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Yona S, Kim K-W, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91.

    Article  CAS  PubMed  Google Scholar 

  169. Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14:392–404.

    Article  CAS  PubMed  Google Scholar 

  170. Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, Dorf M, et al. Inflammatory chemokine transport and presentation in HEV a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med. 2001;194:1361–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Luscinskas FW, Ding H, Tan P, Cumming D, Tedder TF, Gerritsen ME. L- and P-selectins, but not CD49d (VLA-4) integrins, mediate monocyte initial attachment to TNF-alpha-activated vascular endothelium under flow in vitro. J Immunol. 1996;157:326–35.

    CAS  PubMed  Google Scholar 

  172. An G, Wang H, Tang R, Yago T, McDaniel JM, McGee S, et al. P-selectin glycoprotein ligand-1 is highly expressed on Ly-6Chi monocytes and a major determinant for Ly-6Chi monocyte recruitment to sites of atherosclerosis in mice. Circulation. 2008;117:3227–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82.

    Article  CAS  PubMed  Google Scholar 

  174. Grage-Griebenow E, Flad HD, Ernst M. Heterogeneity of human peripheral blood monocyte subsets. J Leukoc Biol. 2001;69:11–20.

    CAS  PubMed  Google Scholar 

  175. Jakubzick C, Gautier EL, Gibbings SL, Sojka DK, Schlitzer A, Johnson TE, et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity. 2013;39:599–610.

    Article  CAS  PubMed  Google Scholar 

  176. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330:841–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336:86–90.

    Article  CAS  PubMed  Google Scholar 

  178. Hoeffel G, Wang Y, Greter M, See P, Teo P, Malleret B, et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med. 2012;209:1167–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity. 2014;40:91–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Bain CC, Bravo-Blas A, Scott CL, Gomez Perdiguero E, Geissmann F, Henri S, et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 2014;15:929–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P, et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity. 2015;42:665–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518:547–51.

    Article  PubMed  CAS  Google Scholar 

  183. Ensan S, Li A, Besla R, Degousee N, Cosme J, Roufaiel M, et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. Nat Immunol. 2016;17:159–68.

    Article  CAS  PubMed  Google Scholar 

  184. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145:341–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest. 1994;93:1885–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb Vasc Biol. 1994;14:133–40.

    Article  CAS  Google Scholar 

  187. Reddick RL, Zhang SH, Maeda N. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. Arterioscler Thromb. 1994;14:141–7.

    Article  CAS  PubMed  Google Scholar 

  188. Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993;92:883–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992;71:343–53.

    Article  CAS  PubMed  Google Scholar 

  190. Zhang FX, Kirschning CJ, Mancinelli R, Xu XP, Jin Y, Faure E, et al. Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem. 1999;274:7611–4.

    Article  CAS  PubMed  Google Scholar 

  191. Woollard KJ. Immunological aspects of atherosclerosis. Clin Sci. 2013;125:221–35.

    Article  CAS  PubMed  Google Scholar 

  192. Randolph GJ. Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res. 2014;114:1757–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell. 2012;151:138–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Horiuchi S, Sakamoto Y, Sakai M. Scavenger receptors for oxidized and glycated proteins. Amino Acids. 2003;25:283–92.

    Article  CAS  PubMed  Google Scholar 

  195. Hazen SL. Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity. J Biol Chem. 2008;283:15527–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J Clin Invest. 2009;119:136–45.

    CAS  PubMed  Google Scholar 

  197. Randolph GJ. Emigration of monocyte-derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis. Curr Opin Lipidol. 2008;19:462–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15:551–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Tabas I. Nonoxidative modifications of lipoproteins in atherogenesis. Annu Rev Nutr. 1999;19:123–39.

    Article  CAS  PubMed  Google Scholar 

  200. Skålén K, Gustafsson M, Rydberg EK, Hultén LM, Wiklund O, Innerarity TL, et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002;417:750–4.

    Article  PubMed  CAS  Google Scholar 

  201. Libby P, Clinton SK. Cytokines as mediators of vascular pathology. Nouv Rev Fr Hematol. 1992;34(Suppl):S47–53.

    PubMed  Google Scholar 

  202. Munro JM, Cotran RS. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Investig. 1988;58:249–61.

    CAS  PubMed  Google Scholar 

  203. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340:115–26.

    Article  CAS  PubMed  Google Scholar 

  204. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–43.

    Article  CAS  PubMed  Google Scholar 

  205. de Villiers WJ, Smith JD, Miyata M, Dansky HM, Darley E, Gordon S. Macrophage phenotype in mice deficient in both macrophage-colony-stimulating factor (op) and apolipoprotein E. Arterioscler Thromb Vasc Biol. 1998;18:631–40.

    Article  PubMed  Google Scholar 

  206. Robbins CS, Hilgendorf I, Weber GF, Theurl I, Iwamoto Y, Figueiredo J-L, et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med. 2013;19:1166–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Zhu S-N, Chen M, Jongstra-Bilen J, Cybulsky MI. GM-CSF regulates intimal cell proliferation in nascent atherosclerotic lesions. J Exp Med. 2009;206:2141–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol. 2000;20:2587–92.

    Article  CAS  PubMed  Google Scholar 

  209. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317–25.

    Article  CAS  PubMed  Google Scholar 

  211. Boyle JJ. Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage. Curr Opin Lipidol. 2012;

    Google Scholar 

  212. Boyle JJ, Johns M, Kampfer T, Nguyen AT, Game L, Schaer DJ, et al. Activating transcription factor 1 directs Mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circ Res. 2012;110:20–33.

    Article  CAS  PubMed  Google Scholar 

  213. Finn AV, Nakano M, Polavarapu R, Karmali V, Saeed O, Zhao X, et al. Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol. 2012;59:166–77.

    Article  CAS  PubMed  Google Scholar 

  214. Boyle JJ, Harrington HA, Piper E, Elderfield K, Stark J, Landis RC, et al. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol. 2009;174:1097–108.

    Article  PubMed  PubMed Central  Google Scholar 

  215. Steinman RM. Decisions about dendritic cells: past, present, and future. Annu Rev Immunol. 2012;30:1–22.

    Article  CAS  PubMed  Google Scholar 

  216. Paulson KE, Zhu S-N, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res. 2010;106:383–90.

    Article  CAS  PubMed  Google Scholar 

  217. Cybulsky MI, Cheong C, Robbins CS. Macrophages and dendritic cells partners in atherogenesis. Circ Res. 2016;118:637–52.

    Article  CAS  PubMed  Google Scholar 

  218. Soehnlein O, Weber C, Lindbom L. Neutrophil granule proteins tune monocytic cell function. Trends Immunol. 2009;30:538–46.

    Article  CAS  PubMed  Google Scholar 

  219. van Leeuwen M, Gijbels MJJ, Duijvestijn A, Smook M, van de Gaar MJ, Heeringa P, et al. Accumulation of myeloperoxidase-positive neutrophils in atherosclerotic lesions in LDLR−/− mice. Arterioscler Thromb Vasc Biol. 2008;28:84–9.

    Article  PubMed  CAS  Google Scholar 

  220. Ionita MG, van den Borne P, Catanzariti LM, Moll FL, de Vries J-PPM, Pasterkamp G, et al. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler Thromb Vasc Biol. 2010;30:1842–8.

    Article  CAS  PubMed  Google Scholar 

  221. Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, et al. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation. 2002;106:2894–900.

    Article  PubMed  Google Scholar 

  222. Lee TD, Gonzalez ML, Kumar P, Chary-Reddy S, Grammas P, Pereira HA. CAP37, a novel inflammatory mediator. Am J Pathol. 2002;160:841–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Edfeldt K, Agerberth B, Rottenberg ME, Gudmundsson GH, Wang X-B, Mandal K, et al. Involvement of the antimicrobial peptide LL-37 in human atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:1551–7.

    Article  CAS  PubMed  Google Scholar 

  224. Barnathan ES, Raghunath PN, Tomaszewski JE, Ganz T, Cines DB, Higazi A a-R. Immunohistochemical localization of defensin in human coronary vessels. Am J Pathol. 1997;150:1009–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Hemdahl A-L, Gabrielsen A, Zhu C, Eriksson P, Hedin U, Kastrup J, et al. Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol. 2006;26:136–42.

    Article  CAS  PubMed  Google Scholar 

  226. Wedmore CV, Williams TJ. Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature. 1981;289:646–50.

    Article  CAS  PubMed  Google Scholar 

  227. Soehnlein O, Xie X, Ulbrich H, Kenne E, Rotzius P, Flodgaard H, et al. Neutrophil-derived heparin-binding protein (HBP/CAP37) deposited on endothelium enhances monocyte arrest under flow conditions. J Immunol. 2005;174:6399–405.

    Article  CAS  PubMed  Google Scholar 

  228. Soehnlein O, Zernecke A, Eriksson EE, Rothfuchs AG, Pham CT, Herwald H, et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood. 2008;112:1461–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Chertov O, Ueda H, Xu LL, Tani K, Murphy WJ, Wang JM, et al. Identification of human neutrophil-derived cathepsin G and azurocidin/CAP37 as chemoattractants for mononuclear cells and neutrophils. J Exp Med. 1997;186:739–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Gombart AF, Krug U, O’Kelly J, An E, Vegesna V, Koeffler HP. Aberrant expression of neutrophil and macrophage-related genes in a murine model for human neutrophil-specific granule deficiency. J Leukoc Biol. 2005;78:1153–65.

    Article  CAS  PubMed  Google Scholar 

  231. Leclercq A, Houard X, Philippe M, Ollivier V, Sebbag U, Meilhac O, et al. Involvement of intraplaque hemorrhage in atherothrombosis evolution via neutrophil protease enrichment. J Leukoc Biol. 2007;82:1420–9.

    Article  CAS  PubMed  Google Scholar 

  232. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226–35.

    Article  CAS  PubMed  Google Scholar 

  233. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2045–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Aubry M-C, Riehle DL, Edwards WD, Maradit-Kremers H, Roger VL, Sebo TJ, et al. B-lymphocytes in plaque and adventitia of coronary arteries in two patients with rheumatoid arthritis and coronary atherosclerosis. Cardiovasc Pathol. 2004;13:233–6.

    Article  PubMed  Google Scholar 

  235. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986;6:131–8.

    Article  CAS  PubMed  Google Scholar 

  236. Reardon CA, Blachowicz L, White T, Cabana V, Wang Y, Lukens J, et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2001;21(6):1011.

    Article  CAS  PubMed  Google Scholar 

  237. Dansky HM, Charlton SA. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1997;94(9):4642–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  239. Ketelhuth DFJ, Hansson GK. Adaptive response of T and B cells in atherosclerosis. Circ Res. 2016;118:668–78.

    Article  CAS  PubMed  Google Scholar 

  240. Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest. 2002;109:745–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Major AS, Fazio S, Linton MF. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol. 2002;22:1892–8.

    Article  CAS  PubMed  Google Scholar 

  242. Kyaw T, Tay C, Krishnamurthi S, Kanellakis P. B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circulation. 2011;109(8):830–40.

    Article  CAS  Google Scholar 

  243. Rosenfeld SM, Perry HM, Gonen A, Prohaska TA, Srikakulapu P, Grewal S, et al. B-1b cells secrete atheroprotective IgM and attenuate atherosclerosis. Circ Res. 2015;117:e28–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Kyaw T, Tay C, Khan A, Dumouchel V, Cao A, To K, et al. Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J Immunol. 2010;185:4410–9.

    Article  CAS  PubMed  Google Scholar 

  245. Clement M, Guedj K, Andreata F, Morvan M, Bey L, Khallou-Laschet J, et al. Control of the T follicular helper-germinal center B-cell axis by CD8+ regulatory T cells limits atherosclerosis and tertiary lymphoid organ development. Circulation. 2015;131:560–70.

    Article  CAS  PubMed  Google Scholar 

  246. Hedrick CC. Lymphocytes in atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35:253–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London, UK

    Mohammed Shamim Rahman & Kevin Woollard

Authors
  1. Mohammed Shamim Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin Woollard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin Woollard .

Editor information

Editors and Affiliations

  1. Hammersmith Campus, Imperial College London National Heart and Lung Institute, London, United Kingdom

    Susanne Sattler

  2. Hammersmith Campus, Imperial College London National Heart and Lung Institute, London, United Kingdom

    Teresa Kennedy-Lydon

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Rahman, M.S., Woollard, K. (2017). Atherosclerosis. In: Sattler, S., Kennedy-Lydon, T. (eds) The Immunology of Cardiovascular Homeostasis and Pathology. Advances in Experimental Medicine and Biology, vol 1003. Springer, Cham. https://doi.org/10.1007/978-3-319-57613-8_7

Download citation

Publish with us

Policies and ethics

Search

Navigation