Advertisement

Internal and Emergency Medicine

, Volume 12, Issue 1, pp 13–22 | Cite as

An exploratory look at NETosis in atherosclerosis

  • Chiara MozziniEmail author
  • Ulisse Garbin
  • Anna Maria Fratta Pasini
  • Luciano Cominacini
IM - REVIEW

Abstract

Current evidence suggests the likelihood of a link between venous thromboembolism (VTE) and atherosclerosis, although they have been traditionally considered as different pathological entities. The contribution of neutrophils to human atherogenesis has been underestimated, if compared to their contribution established in VTE. This is due to the major importance attributed to macrophages in plaque destabilization. Nevertheless, the role of neutrophils in atherogenesis deserves increasing attention. In particular, neutrophil extracellular traps (NETs) are net-like chromatin fibres that are released from dying neutrophils. The death of neutrophils with NETs formation is called NETosis. During activation, neutrophils produce reactive oxygen species (ROS), through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The main function of NETs is trapping and killing pathogens. Nevertheless, NETs formation has been observed in various chronic inflammatory diseases, autoimmune diseases, vasculitis, lung diseases, cancer and VTE. Recent studies suggest that NETs formation might contribute also to atherosclerosis progression. New data report the presence of NETs in the luminal portion of human atherosclerotic vessels and coronary specimens obtained from patients after acute myocardial infarction. Programmed death mechanisms in atherosclerosis such as apoptosis, efferocytosis and also NETosis, share common features and triggers. If defective, they can lead the cells to a switch from programmed death to necrosis, resulting in the release of pro-atherogenic factors, accumulation of cell debris and progression of the disease. This review provides evidence on the emerging role of neutrophils focusing on NETosis and oxidative stress burden in orchestrating common mechanisms in atherosclerosis and thrombosis.

Keywords

NETosis Atherosclerosis Venous thromboembolism Coronary artery disease Oxidative stress 

Abbreviations

MP

Microparticles

MPO

Myeloperoxidase

NADPH

Nicotinamide adenine dinucleotide phosphate

NE

Neutrophil elastase

NETs

Neutrophil extracellular traps

Nrf2

Nuclear erythroid-related factor 2

ROS

Reactive oxygen species

TF

Tissue factor

VTE

Venous thromboembolism

Notes

Compliance with ethical standards

Conflict of interests

None.

Ethical approval

The study was conducted in accordance with the ethical standards laid down in the Helsinki Declaration of 1975 and its late amendments. The local ethics committee approved the study.

Human and animal rights statement

No human nor animal data have been collected in this paper.

Informed consent

None.

References

  1. 1.
    Prandoni P, Bilora F, Marchiori A, Bernardi E, Petrobelli F, Lensing AWA, Prins MH, Girolami A (2003) An association between atherosclerosis and venous thrombosis. N Engl J Med 348:1435–1441CrossRefPubMedGoogle Scholar
  2. 2.
    Prandoni P, Villalta S, Bagatela P, Rossi L, Marchiori A, Piccoli A, Bernardi E, Girolami A (1997) The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica 82:423–428PubMedGoogle Scholar
  3. 3.
    Schulman S, Lindmarker P, Holmstrom M (2006) Post-thrombotic syndrome, recurrence and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 4:734–742CrossRefPubMedGoogle Scholar
  4. 4.
    Hong C, Zhu F, Du D (2005) Coronary artery calcification and risk factors for atherosclerosis in patients with venous thromboembolism. Atherosclerosis 183:169–174CrossRefPubMedGoogle Scholar
  5. 5.
    Lowe G (2008) Common risk factors for both arterial and venous thrombosis. Br J Haematol 5:488–495CrossRefGoogle Scholar
  6. 6.
    Reich LM, Folsom AM, Key NS, Boland LL, Heckbert RS, Rosamond WD, Cusham M (2006) Prospective study of subclinical atherosclerosis as a risk factor for venous thromboembolism. J Thromb Haemost 4:1909–1913CrossRefPubMedGoogle Scholar
  7. 7.
    Van der Hagen PB, Folsom AR, Jenny NS, Heckbert RS, Rosamond WD, Cusham M (2006) Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study. J Thromb Haemost 4:1903–1908CrossRefPubMedGoogle Scholar
  8. 8.
    Prandoni P (2007) Venous thromboembolism and atherosclerosis: is there a link? J Thromb Haemost 5:270–275CrossRefPubMedGoogle Scholar
  9. 9.
    Prandoni P (2009) Venous and arterial thrombosis: two aspects of the same disease? Clin Epidemiol 1:1–6CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Brinkman V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535CrossRefGoogle Scholar
  11. 11.
    Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A (2010) Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 191(3):677–691CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS (2014) Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle-cells disease. Blood 12:3818–3827CrossRefGoogle Scholar
  14. 14.
    Stoiber W, Obermayer A, Steinbacher P, Krautgartner WD (2015) The role of reactive oxygen species (ROS) in the formation of extracellular traps in humans. Biomolecules 5:702–723CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Almyroudis NG, Grimm MJ, Davidson BA, Rohm M, Urban CF, Segal BH (2013) NETosis and NADPH oxidase: at the intersection of host defence, inflammation, and injury. Front Immunol 4(45):1–7Google Scholar
  16. 16.
    Bianchi M, Niemiec MJ, Siler U, Urban CF, Reichenbach J (2011) Restoration of anti-Aspergillus defence by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent. J Allergy Clin. Immunol 127:1243–1252CrossRefPubMedGoogle Scholar
  17. 17.
    Röhm M, Grimm MJ, D’Auria AC, Almyroudis NG, Segal BH, Urban CF (2014) NADPH oxidase promotes neutrophil extracellular trap formation in pulmonary aspergillosis. Infect Immun 82:1766–1777CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hakkim A, Furnfohr BG, Amann K, Laube B, Abed UA, Brinkmann V (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA 107:9813–9818CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yipp BG, Kubes P (2013) NETosis: how vital is it? Blood 122(16):2784–2794CrossRefPubMedGoogle Scholar
  20. 20.
    Marcos V, Zhou Z, Yildirim AO, Bohla A, Hector A, Vitkov L, Wiedenbauer E-M, Krautgartner WD, Stoiber W, Belohradsky BH (2010) CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. Nature Med 16:1018–1023CrossRefPubMedGoogle Scholar
  21. 21.
    Sangaletti S, Tripodo C, Chiodoni C, Guarnotta C, Cappetti B, Casalini P, Piconese S, Parenza M, Guiducci C, Vitali C (2012) Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 120:3007–3018CrossRefPubMedGoogle Scholar
  22. 22.
    Brinkmann V, Zychlinsky A (2012) Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol 198:773–783CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, Scadden DT, Wagner DD (2012) Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 109:13076–13081CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Demers M, Wagner DD (2014) NETosis: a new factor in tumour progression and cancer-associated thrombosis. Semin Thromb Haemost 40(3):277–283CrossRefGoogle Scholar
  25. 25.
    The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) (2014) ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 35:3033–3080CrossRefGoogle Scholar
  26. 26.
    Virchow R (1856) Gesammalte abhandlungen zur wissenschaftlichen medtzin. Medinger Sohn & Co, Frankfurt, pp 219–732Google Scholar
  27. 27.
    Wakefield TW, Myers DD, Henke PK (2008) Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 28:387–391CrossRefPubMedGoogle Scholar
  28. 28.
    Ali T, Humphries J, Burnand K, Sawyer B, Bursill C, Channon K, Greaves D, Rollins B, Charo IF, Smith A (2006) Monocyte recruitment in venous thrombus resolution. J Vasc Surg 43:601–608CrossRefPubMedGoogle Scholar
  29. 29.
    Saha P, Humphries J, Modarai B, Mattock K, Waltham M, Evans C, Ahmad A, Patel A, Premaratmne S, Lyons O, Smith A (2011) Leukocytes and the natural history of deep vein thrombosis. Arterioscler ThrombVasc Biol 31:506–512CrossRefGoogle Scholar
  30. 30.
    Fuchs TA, Brill A, Deuerschmied D, Schatzberg D, Monestier M, Myers DD, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 107:15880–15885CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gupta AK, Joshi MB, Philippova M, Erne P, Hasler P, Hahn S, Resink TJ (2010) Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Lett 584:3193–3197CrossRefPubMedGoogle Scholar
  32. 32.
    Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD (2012) Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 10:136–144CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wolberg AS, Aleman MM, Leiderman K, Machlus KR (2012) Pro-coagulant activity in haemostasis and thrombosis: Virchow’s triad revisited. Anaesth Analg 114:275–285CrossRefGoogle Scholar
  34. 34.
    Massberg S, Grahl L, von Bruehl ML (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine protease. Nat Med 16(8):887–896CrossRefPubMedGoogle Scholar
  35. 35.
    von Bruhl ML, Stark K, Steinhart A (2012) Monocytes, neutrophils and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209(4):819–835CrossRefGoogle Scholar
  36. 36.
    Fuchs T, Bhandari A, Wagner DD (2011) Histones induce rapid and profound thrombocytopenia in mice. Blood 118:3708–3714CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nomura S, Shimizu M (2015) Clinical significance of pro-coagulant micro-particles. J Intensive Care 3:1–2CrossRefGoogle Scholar
  38. 38.
    Wolberg AS, Monroe DM, Roberts HR, Hoffman MR (1999) Tissue factor de-encryption: ionophore treatment induces changes in tissue factor activity by phosphatidylserine-dependent and independent mechanisms. Blood Coagul Fibrinolysis 10:201–210CrossRefPubMedGoogle Scholar
  39. 39.
    Zhou L (2014) Micro-particles: new light shed on the understanding of venous thromboembolism. Acta Pharmacol Sin 35:1103–1110CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Geddings GE (2013) Tumour-derived tissue factor–positive micro-particles and venous thrombosis in cancer patients. Blood 122(11):1873–1880CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Bernal-Mizrachi L, Jimenez JJ, Pastor J, Mauro LM, Horstman LL (2003) High levels of circulating endothelial microparticles in patients with acute coronary syndrome. Am Heart J 145:962–970CrossRefPubMedGoogle Scholar
  42. 42.
    Ogata N, Imaizumi M, Nomura S, Shouzu A, Arichi A, Matsuoka M (2005) Increased levels of platelet-derived micro-particles in patients with diabetic retinopathy. Diabetes Res Clin Pract 68:193–201CrossRefPubMedGoogle Scholar
  43. 43.
    Sabatier F, Darmon P, Hugel B, Combes V, Sanmarco M, Velut JG (2002) Type 1 and 2 diabetic patients display different patterns of cellular micro-particles. Diabetes 51:2840–2845CrossRefPubMedGoogle Scholar
  44. 44.
    Koga H, Sugiyama K, Watanabe K, Fukushima H, Tanaka T (2005) Elevated levels of VE-cadherin- positive endothelial micro-particles in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 45:1622–1630CrossRefPubMedGoogle Scholar
  45. 45.
    As Leroyer, Isobe H, Leseche G, Castier Y, Wassef M, Mallat Z (2007) Cellular origins and thrombogenic activity of micro-particles isolated from human atherosclerotic plaques. J Am Coll Cardiol 49:772–777CrossRefGoogle Scholar
  46. 46.
    Urban CF, Reichard U, Brinkmann V, Zychlinsky A (2006) Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 8(4):668–676CrossRefPubMedGoogle Scholar
  47. 47.
    Guimarães-Costa AB, Nascimento MT, Wardini AB, Pinto-da-Silva LH, Saraiva EM (2012) ETosis: a microbicidal mechanism beyond cell death. J Parasitol Res 2012:92–97CrossRefGoogle Scholar
  48. 48.
    Becatti M, Emmi G, Silvestri E, Bruschi G, Ciucciarelli L, Squarito D, Vaglio A, Taddei N, Abbate R, Emmi L, Goldoni M, Fiorillo C, Prisco D (2016) Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Beçhet disease. Circulation 133:302–311PubMedGoogle Scholar
  49. 49.
    Darrah E, Andrade F (2013) NETs: the missing link between cell death and systemic autoimmune disease? Front Immunol 3(428):1–17Google Scholar
  50. 50.
    Kahlenberg JM, Carmona-Rivera C, Smith CK, Kaplan MJ (2013) Neutrophil extracellular trap-associated protein activation of NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol 190(3):1217–1226CrossRefPubMedGoogle Scholar
  51. 51.
    Demers M, Wagner DD (2014) NETosis: a new factor in tumour progression and cancer-associated thrombosis. Semin Thromb Hemost 40(3):277–283CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Cedervall J, Olsson AK (2015) NETosis in cancer. Oncoscience 2(11):900–901PubMedPubMedCentralGoogle Scholar
  53. 53.
    Pedersen F, Marwitz S, Holz O, Kirsten A, Bahmer T, Waschki B, Magnussen H, Rabe KF, Goldmann T, Uddin M, Watz H (2015) Neutrophil extracellular trap formation and extracellular DNA in sputum of stable COPD patients. Respir Med 109(10):1360–1362CrossRefPubMedGoogle Scholar
  54. 54.
    Grabcanovic-Musija F, Obermayer A, Stoiber W, Krautgartner WD, Steinbacher P, Winterberg N, Bathke AC, Klappacher M, Studnicka M (2015) Neutrophil extracellular trap (NET) formation characterises stable and exacerbated COPD and correlates with airflow limitation. Respir Res 22(16):59CrossRefGoogle Scholar
  55. 55.
    Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation and cancer: how are they linked? Free Rad Biol Med 49:1603–1616CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Lawlwss MW, O’Byrne KJ, Gray SG (2009) Oxidative stress induced lung cancer and COPD: opportunities for epigenetic therapy. J Cell Mol Med 13:2800–2821CrossRefGoogle Scholar
  57. 57.
    Menegazzo L, Ciciliot S, Poncina N, Mazzucato M, Persano M, Bonora B, Albiero M, Vigili de Kreutzenberg S, Avogaro A, Fadini GP (2015) NETosis is induced by high glucose and associated with type 2 diabetes. Acta Diabetol 52(3):497–503CrossRefPubMedGoogle Scholar
  58. 58.
    Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, Kahn CR, Wagner DD (2015) Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med 21(7):815–819CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Rodriguez-Espinosa O, Rojas-Espinosa O, Moreno-Altamirano MM, Lopez-Villegas EO, Sanchez-Garcia FJ (2015) Metabolic requirements for neutrophil extracellular traps (NETs) formation. Immunology 145:213–222CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Mozzini C, Garbin U, Stranieri C, Pasini A, Solani E, Tinelli IA, Cominacini L, Fratta Pasini AM (2015) Endoplasmic reticulum stress and Nrf2 repression in circulating cells of type 2 diabetic patients without the recommended glycemic goals. Free Radic Res 49(3):244–252CrossRefPubMedGoogle Scholar
  61. 61.
    Li P, Li M, Lindbeerg MR, Kennett MJ, Xiong N, Wang Y (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 207(9):1853–1862CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Fadini GP, Menegazzo L, Scattolini V, Gintoli M, Albiero M, Avogaro A (2016) A perspective on NETosis in diabetes and cardiometabolic disorders. Nutr Metab Cardiovasc Dis 26(1):1–8CrossRefPubMedGoogle Scholar
  63. 63.
    Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM (2000) Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 20:1262–1275CrossRefPubMedGoogle Scholar
  64. 64.
    Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R (2010) Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 30:1282–1292CrossRefPubMedGoogle Scholar
  65. 65.
    Kolodgie FD, Burke AP, Farb A, Gold HK, Yuan J, Narula J, Finn AV, Virmani R (2001) The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol 16:285–292CrossRefPubMedGoogle Scholar
  66. 66.
    Massberg S, Grahl L, von Bruehl ML (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16:887–896CrossRefPubMedGoogle Scholar
  67. 67.
    Borissoff JI, Joosen IA, Versteylen MO, Brill A, Fuchs TA, Savchennko A, Gallant M, Martinod K, Cate H, Hofstra L, Crijins HJ, Wagner DD, Kietselaer BLJH (2013) Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a pro-thrombotic state. Arterioscler Thromb Vasc Biol 33(8):2032–2040CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Megens RT, Vijayan S, Lievens D, Döring Y, van Zandvoort MA, Grommes J, Weber C, Soehnlein O (2012) Presence of luminal neutrophil extracellular traps in atherosclerosis. Thromb Haemost 107:597–598CrossRefPubMedGoogle Scholar
  69. 69.
    De Boer OJ, Li X, Teeling P, Mackaay C, Ploegmakers HJ, van der Loos CM, Daemen MJ, de Winter RJ, van der Wal AC (2013) Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction. Thromb Haemost 109:290–297CrossRefPubMedGoogle Scholar
  70. 70.
    Mangold A, Alias S, Schertz T, Hofbuer T, Jakowitsch J, Panzenbock A, Simon D, Laimer D, Bangert C, Kammerlander A, Mascherbauer J, Winter MP, Distelmaier K, Adibrecht C, Preissner KT, Lang IM (2015) Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res 116(7):1182–1192CrossRefPubMedGoogle Scholar
  71. 71.
    Stakos DA, Kambas K, Kostantinidis T, Mitroulis I, Apostolidou E, Arelaki S, Tsironidou V, Giatromanolaki A, Skendros P, Kostantinides S, Ritis S (2015) Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 36(22):1405–1414CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Nahrendorf M, Swirski FK (2015) Neutrophil-macrophage communication in inflammation and atherosclerosis. Science 349(6245):237–238CrossRefPubMedGoogle Scholar
  73. 73.
    Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V (2015) Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349(6245):316–320CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Farrera C, Fadeel B (2013) Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol 191:2647–2656CrossRefPubMedGoogle Scholar
  75. 75.
    Nakazawa D, Shida H, Kusunoki Y, Miyoshi A, Nishio S, Tomaru U, Atsumi T, Ishizu A (2016) The responses of macrophages in interaction with neutrophils that undergo NETosis. J Autoimmun 67:19–28CrossRefPubMedGoogle Scholar
  76. 76.
    Doring Y, Weber C, Soehnlein O (2013) Footprints of neutrophil extracellular traps as predictors of cardiovascular risk. Arterioscler Thromb Vasc Biol 33:1735–1736CrossRefPubMedGoogle Scholar
  77. 77.
    Borissoff JI, Spronk HMH, Cate H (2011) The haemostatic system as a modulator of atherosclerosis. N Engl J Med 364:1746–1760CrossRefPubMedGoogle Scholar
  78. 78.
    Cominacini L, Garbin U, Mozzini C, Stranieri C, Pasini A, Solani E, Tinelli IA, Pasini AF (2015) The atherosclerotic plaque vulnerability: focus on the roles of oxidative and endoplasmic reticulum stress in orchestrating macrophage apoptosis and the formation of the necrotic core. Curr Med Chem 22(13):1565–1572CrossRefPubMedGoogle Scholar
  79. 79.
    Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104:503–516CrossRefPubMedGoogle Scholar
  80. 80.
    Tabas I, Williams KJ, Boren J (2007) Sub-endothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116:1832–1844CrossRefPubMedGoogle Scholar
  81. 81.
    Kockx MM, Herman AG (2000) Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res 45:736–746CrossRefPubMedGoogle Scholar
  82. 82.
    Tabas I (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10:36–46CrossRefPubMedGoogle Scholar
  83. 83.
    Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480CrossRefPubMedGoogle Scholar
  84. 84.
    Van Vrè E, Ait-Oufella H, Tedgui A, Mallat Z (2012) Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol 32:887–893CrossRefPubMedGoogle Scholar
  85. 85.
    Tabas I (2010) The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ Res 7:839–850CrossRefGoogle Scholar
  86. 86.
    Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, Asada Y, Okada K, Ishibashi-Ueda H, Gabbiani G (2007) Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116:1226–1233CrossRefPubMedGoogle Scholar
  87. 87.
    Zhou J, Lhotak S, Hilditch BA, Austin RC (2005) Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation 111:1814–1821CrossRefPubMedGoogle Scholar
  88. 88.
    Cullinan SB, Diehl J (2004) A PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279:20108–20117CrossRefPubMedGoogle Scholar
  89. 89.
    Libby P, Lichtman AH, Hansson GK (2013) Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity 38:1092–1104CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17:1410–1422CrossRefPubMedGoogle Scholar
  91. 91.
    Drechsler M, Döring Y, Megens RT, Soehnlein O (2011) Neutrophilic granulocytes–promiscuous accelerators of atherosclerosis. Thromb Haemost 106:839–848CrossRefPubMedGoogle Scholar
  92. 92.
    Soehnlein O (2012) Multiple roles for neutrophils in atherosclerosis. Circ Res 110:875–888CrossRefPubMedGoogle Scholar
  93. 93.
    Doring Y, Drechsler M, Soehnlein O, Weber C (2015) Neutrophils in atherosclerosis: from mice to man. Arterioscler Thromb Vasc Biol 35:288–295CrossRefPubMedGoogle Scholar

Copyright information

© SIMI 2016

Authors and Affiliations

  • Chiara Mozzini
    • 1
    Email author
  • Ulisse Garbin
    • 1
  • Anna Maria Fratta Pasini
    • 1
  • Luciano Cominacini
    • 1
  1. 1.Section of Internal Medicine, Department of MedicineUniversity of VeronaVeronaItaly

Personalised recommendations