Skip to main content
SpringerLink
Log in

Necrotic cell death in atherosclerosis

  • Review
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Necrosis is a type of cell death characterized by a gain in cell volume, swelling of organelles, rupture of the plasma membrane and subsequent loss of intracellular contents. For a long time, the process has been considered as a merely accidental and uncontrolled form of cell death, but accumulating evidence suggests that it can also occur in a regulated fashion. Morphological studies using transmission electron microscopy indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Various stimuli in the plaque including high levels of oxidative stress, depletion of cellular ATP, impaired clearance of apoptotic cells and increased intracellular calcium may cause necrotic death. Although the role of necrosis in atherosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis through induction of inflammation and enlargement of the necrotic core. In addition, necrosis contributes to plaque instability by releasing tissue factor, matrix degrading proteases and pro-angiogenic compounds. Therapeutic agents against necrosis are limited, but efforts have recently been made to inhibit the necrotic pathway or its pro-inflammatory effects.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ait-Oufella H, Kinugawa K, Zoll J, Simon T, Boddaert J, Heeneman S, Blanc-Brude O, Barateau V, Potteaux S, Merval R, Esposito B, Teissier E, Daemen MJ, Leseche G, Boulanger C, Tedgui A, Mallat Z (2007) Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation 115:2168–2177. doi:10.1161/CIRCULATIONAHA.106.662080

    PubMed  CAS  Google Scholar 

  2. Ait-Oufella H, Pouresmail V, Simon T, Blanc-Brude O, Kinugawa K, Merval R, Offenstadt G, Leseche G, Cohen PL, Tedgui A, Mallat Z (2008) Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler Thromb Vasc Biol 28:1429–1431. doi:10.1161/ATVBAHA.108.169078

    PubMed  CAS  Google Scholar 

  3. Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192:565–570. doi:10.1084/jem.192.4.565

    PubMed  CAS  Google Scholar 

  4. Bao L, Li Y, Deng SX, Landry D, Tabas I (2006) Sitosterol-containing lipoproteins trigger free sterol-induced caspase-independent death in ACAT-competent macrophages. J Biol Chem 281:33635–33649. doi:10.1074/jbc.M606339200

    PubMed  CAS  Google Scholar 

  5. Benko R, Pacher P, Vaslin A, Kollai M, Szabo C (2004) Restoration of the endothelial function in the aortic rings of apolipoprotein E deficient mice by pharmacological inhibition of the nuclear enzyme poly(ADP-ribose) polymerase. Life Sci 75:1255–1261. doi:10.1016/j.lfs.2004.04.007

    PubMed  CAS  Google Scholar 

  6. Beohar N, Flaherty JD, Davidson CJ, Maynard RC, Robbins JD, Shah AP, Choi JW, MacDonald LA, Jorgensen JP, Pinto JV, Chandra S, Klaus HM, Wang NC, Harris KR, Decker R, Bonow RO (2004) Antirestenotic effects of a locally delivered caspase inhibitor in a balloon injury model. Circulation 109:108–113. doi:10.1161/01.CIR.0000105724.30980.CD

    PubMed  CAS  Google Scholar 

  7. Boisvert WA, Rose DM, Boullier A, Quehenberger O, Sydlaske A, Johnson KA, Curtiss LK, Terkeltaub R (2006) Leukocyte transglutaminase 2 expression limits atherosclerotic lesion size. Arterioscler Thromb Vasc Biol 26:563–569. doi:10.1161/01.ATV.0000203503.82693.c1

    PubMed  CAS  Google Scholar 

  8. Boyle JJ, Wilson B, Bicknell R, Harrower S, Weissberg PL, Fan TP (2000) Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis. J Pathol 192:234–242. doi:10.1002/1096-9896(2000)9999:9999<:AID-PATH699>3.0.CO;2-9

    PubMed  CAS  Google Scholar 

  9. Christofferson DE, Yuan J (2010) Cyclophilin A release as a biomarker of necrotic cell death. Cell Death Differ 17:1942–1943. doi:10.1038/cdd.2010.123

    PubMed  CAS  Google Scholar 

  10. Crisby M, Kallin B, Thyberg J, Zhivotovsky B, Orrenius S, Kostulas V, Nilsson J (1997) Cell death in human atherosclerotic plaques involves both oncosis and apoptosis. Atherosclerosis 130:17–27. doi:10.1016/S0021-9150(96)06037-6

    PubMed  CAS  Google Scholar 

  11. Cuchacovich R, Espinoza LR (2009) Does TNF-alpha blockade play any role in cardiovascular risk among rheumatoid arthritis (RA) patients? Clin Rheumatol 28:1217–1220. doi:10.1007/s10067-009-1208-x

    PubMed  Google Scholar 

  12. de Almeida CJ, Linden R (2005) Phagocytosis of apoptotic cells: a matter of balance. Cell Mol Life Sci 62:1532–1546. doi:10.1007/s00018-005-4511-y

    PubMed  Google Scholar 

  13. Declercq W, Vanden Berghe T, Vandenabeele P (2009) RIP kinases at the crossroads of cell death and survival. Cell 138:229–232. doi:10.1016/j.cell.2009.07.006

    PubMed  CAS  Google Scholar 

  14. Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, Sanvito F, Arrigoni G, Bianchi ME (2001) The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol 152:1197–1206. doi:10.1083/jcb.152.6.1197

    PubMed  CAS  Google Scholar 

  15. Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313–321. doi:10.1038/nchembio.83

    PubMed  CAS  Google Scholar 

  16. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119. doi:10.1038/nchembio711

    PubMed  CAS  Google Scholar 

  17. Di Micco P, Ferrazzi P, Libre L, Mendolicchio L, Quaglia I, De Marco M, Colombo A, Bacci M, Rota LL, Lodigiani C (2009) Intima-media thickness evolution after treatment with infliximab in patients with rheumatoid arthritis. Int J Gen Med 2:141–144. doi:10.2147/IJGM.S5178

    PubMed  CAS  Google Scholar 

  18. Doran JP, Howie AJ, Townend JN, Bonser RS (1996) Detection of myocardial infarction by immunohistological staining for C9 on formalin fixed, paraffin wax embedded sections. J Clin Pathol 49:34–37. doi:10.1136/jcp.49.1.34

    PubMed  CAS  Google Scholar 

  19. Erbel C, Dengler TJ, Wangler S, Lasitschka F, Bea F, Wambsganss N, Hakimi M, Bockler D, Katus HA, Gleissner CA (2011) Expression of IL-17A in human atherosclerotic lesions is associated with increased inflammation and plaque vulnerability. Basic Res Cardiol 106:125–134. doi:10.1007/s00395-010-0135-y

    PubMed  CAS  Google Scholar 

  20. Erdmann E, Charbonnel B, Wilcox R (2009) Thiazolidinediones and cardiovascular risk—a question of balance. Curr Cardiol Rev 5:155–165. doi:10.2174/157340309788970333

    PubMed  CAS  Google Scholar 

  21. Fernandez-Ortiz A, Badimon JJ, Falk E, Fuster V, Meyer B, Mailhac A, Weng D, Shah PK, Badimon L (1994) Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol 23:1562–1569. doi:10.1016/0735-1097(94)90657-2

    PubMed  CAS  Google Scholar 

  22. Festjens N, Vanden Berghe T, Cornelis S, Vandenabeele P (2007) RIP1, a kinase on the crossroads of a cell’s decision to live or die. Cell Death Differ 14:400–410

    PubMed  CAS  Google Scholar 

  23. Festjens N, Vanden Berghe T, Vandenabeele P (2006) Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 1757:1371–1387. doi:10.1016/j.bbabio.2006.06.014

    PubMed  CAS  Google Scholar 

  24. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, Suffredini AF (2003) Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101:2652–2660. doi:10.1182/blood-2002-05-1300

    PubMed  CAS  Google Scholar 

  25. Freudenberger T, Oppermann M, Heim HK, Mayer P, Kojda G, Schror K, Fischer JW (2010) Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice. Basic Res Cardiol 105:479–486. doi:10.1007/s00395-010-0091-6

    PubMed  CAS  Google Scholar 

  26. Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR (2000) Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol 164:1663–1667

    PubMed  CAS  Google Scholar 

  27. Gossl M, Herrmann J, Tang H, Versari D, Galili O, Mannheim D, Rajkumar SV, Lerman LO, Lerman A (2009) Prevention of vasa vasorum neovascularization attenuates early neointima formation in experimental hypercholesterolemia. Basic Res Cardiol 104:695–706. doi:10.1007/s00395-009-0036-0

    PubMed  Google Scholar 

  28. Guyton JR, Klemp KF (1996) Development of the lipid-rich core in human atherosclerosis. Arterioscler Thromb Vasc Biol 16:4–11

    PubMed  CAS  Google Scholar 

  29. Hans CP, Feng Y, Naura AS, Zerfaoui M, Rezk BM, Xia H, Kaye AD, Matrougui K, Lazartigues E, Boulares AH (2009) Protective effects of PARP-1 knockout on dyslipidemia-induced autonomic and vascular dysfunction in ApoE mice: effects on eNOS and oxidative stress. PLoS One 4:e7430. doi:10.1371/journal.pone.0007430

    PubMed  Google Scholar 

  30. Hans CP, Zerfaoui M, Naura AS, Catling A, Boulares AH (2008) Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability. Cardiovasc Res 78:429–439. doi:10.1093/cvr/cvn018

    PubMed  CAS  Google Scholar 

  31. Hodge S, Hodge G, Brozyna S, Jersmann H, Holmes M, Reynolds PN (2006) Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages. Eur Respir J 28:486–495. doi:10.1183/09031936.06.00001506

    PubMed  CAS  Google Scholar 

  32. Inoue K, Kawahara K, Biswas KK, Ando K, Mitsudo K, Nobuyoshi M, Maruyama I (2007) HMGB1 expression by activated vascular smooth muscle cells in advanced human atherosclerosis plaques. Cardiovasc Pathol 16:136–143. doi:10.1016/j.carpath.2006.11.006

    PubMed  CAS  Google Scholar 

  33. Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, Geborek P (2005) Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol 32:1213–1218

    PubMed  CAS  Google Scholar 

  34. Jialal I, Devaraj S (2003) Antioxidants and atherosclerosis: don’t throw out the baby with the bath water. Circulation 107:926–928. doi:10.1161/01.CIR.0000048966.26216.4C

    PubMed  CAS  Google Scholar 

  35. Jin ZG, Lungu AO, Xie L, Wang M, Wong C, Berk BC (2004) Cyclophilin A is a proinflammatory cytokine that activates endothelial cells. Arterioscler Thromb Vasc Biol 24:1186–1191. doi:10.1161/01.ATV.0000130664.51010.28

    PubMed  CAS  Google Scholar 

  36. Kalinina N, Agrotis A, Antropova Y, DiVitto G, Kanellakis P, Kostolias G, Ilyinskaya O, Tararak E, Bobik A (2004) Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol 24:2320–2325. doi:10.1161/01.ATV.0000145573.36113.8a

    PubMed  CAS  Google Scholar 

  37. Kanellakis P, Agrotis A, Kyaw TS, Koulis C, Ahrens I, Mori S, Takahashi HK, Liu K, Peter K, Nishibori M, Bobik A (2011) High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 31:313–319. doi:10.1161/ATVBAHA.110.218669

    PubMed  CAS  Google Scholar 

  38. Katsuda S, Kaji T (2003) Atherosclerosis and extracellular matrix. J Atheroscler Thromb 10:267–274

    PubMed  CAS  Google Scholar 

  39. Kim SH, Lessner SM, Sakurai Y, Galis ZS (2004) Cyclophilin A as a novel biphasic mediator of endothelial activation and dysfunction. Am J Pathol 164:1567–1574. doi:10.1016/S0002-9440(10)63715-7

    PubMed  CAS  Google Scholar 

  40. Kleinbongard P, Heusch G, Schulz R (2010) TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 127:295–314. doi:10.1016/j.pharmthera.2010.05.002

    PubMed  CAS  Google Scholar 

  41. Kockx M, Jessup W, Kritharides L (2010) Cyclosporin A and atherosclerosis—cellular pathways in atherogenesis. Pharmacol Ther 128:106–118. doi:10.1016/j.pharmthera.2010.06.001

    PubMed  CAS  Google Scholar 

  42. Kockx MM, Herman AG (2000) Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res 45:736–746. doi:10.1016/S0008-6363(99)00235-7

    PubMed  CAS  Google Scholar 

  43. Konstandin MH, Aksoy H, Wabnitz GH, Volz C, Erbel C, Kirchgessner H, Giannitsis E, Katus HA, Samstag Y, Dengler TJ (2009) Beta2-integrin activation on T cell subsets is an independent prognostic factor in unstable angina pectoris. Basic Res Cardiol 104:341–351. doi:10.1007/s00395-008-0770-8

    PubMed  CAS  Google Scholar 

  44. Krysko DV, Denecker G, Festjens N, Gabriels S, Parthoens E, D’Herde K, Vandenabeele P (2006) Macrophages use different internalization mechanisms to clear apoptotic and necrotic cells. Cell Death Differ 13:2011–2022. doi:10.1038/sj.cdd.4401900

    PubMed  CAS  Google Scholar 

  45. Kunishima A, Takemura G, Takatsu H, Hayakawa Y, Kanoh M, Qiu X, Fujiwara T, Fujiwara H (1999) Mode and role of cell death during progression of atherosclerotic lesions in hypercholesterolemic rabbits. Heart Vessels 14:295–306

    PubMed  CAS  Google Scholar 

  46. Li S, Sun Y, Liang CP, Thorp EB, Han S, Jehle AW, Saraswathi V, Pridgen B, Kanter JE, Li R, Welch CL, Hasty AH, Bornfeldt KE, Breslow JL, Tabas I, Tall AR (2009) Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet. Circ Res 105:1072–1082. doi:10.1161/CIRCRESAHA.109.199570

    PubMed  CAS  Google Scholar 

  47. Li W, Hellsten A, Jacobsson LS, Blomqvist HM, Olsson AG, Yuan XM (2004) Alpha-tocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits. J Mol Cell Cardiol 37:969–978. doi:10.1016/j.yjmcc.2004.07.009

    PubMed  CAS  Google Scholar 

  48. Lundberg B (1985) Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis 56:93–110. doi:10.1016/0021-9150(85)90087-5

    PubMed  CAS  Google Scholar 

  49. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241. doi:10.1038/35025203

    PubMed  CAS  Google Scholar 

  50. Madamanchi NR, Vendrov A, Runge MS (2005) Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 25:29–38. doi:10.1161/01.ATV.0000150649.39934.13

    PubMed  CAS  Google Scholar 

  51. Maderna P, Godson C (2003) Phagocytosis of apoptotic cells and the resolution of inflammation. Biochim Biophys Acta 1639:141–151. doi:10.1016/j.bbadis.2003.09.004

    PubMed  CAS  Google Scholar 

  52. Malesevic M, Kuhling J, Erdmann F, Balsley MA, Bukrinsky MI, Constant SL, Fischer G (2010) A cyclosporin derivative discriminates between extracellular and intracellular cyclophilins. Angew Chem Int Ed Engl 49:213–215. doi:10.1002/anie.200904529

    PubMed  CAS  Google Scholar 

  53. Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A (1999) Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99:348–353

    PubMed  CAS  Google Scholar 

  54. Martinet W, Knaapen MWM, De Meyer GRY, Herman AG, Kockx MM (2002) Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation 106:927–932. doi:10.1161/01.CIR.0000026393.47805.21

    PubMed  CAS  Google Scholar 

  55. Meilhac O, Escargueil-Blanc I, Thiers JC, Salvayre R, Negre-Salvayre A (1999) Bcl-2 alters the balance between apoptosis and necrosis, but does not prevent cell death induced by oxidized low density lipoproteins. FASEB J 13:485–494

    PubMed  CAS  Google Scholar 

  56. Morimoto K, Janssen WJ, Fessler MB, McPhillips KA, Borges VM, Bowler RP, Xiao YQ, Kench JA, Henson PM, Vandivier RW (2006) Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J Immunol 176:7657–7665

    PubMed  CAS  Google Scholar 

  57. Murdaca G, Colombo BM, Puppo F (2009) Anti-TNF-alpha inhibitors: a new therapeutic approach for inflammatory immune-mediated diseases: an update upon efficacy and adverse events. Int J Immunopathol Pharmacol 22:557–565

    PubMed  CAS  Google Scholar 

  58. Nagy N, Melchior-Becker A, Fischer JW (2010) Long-term treatment with the AT1-receptor antagonist telmisartan inhibits biglycan accumulation in murine atherosclerosis. Basic Res Cardiol 105:29–38. doi:10.1007/s00395-009-0051-1

    PubMed  CAS  Google Scholar 

  59. Nazzal D, Cantero AV, Therville N, Segui B, Negre-Salvayre A, Thomsen M, Benoist H (2006) Chlamydia pneumoniae alters mildly oxidized low-density lipoprotein-induced cell death in human endothelial cells, leading to necrosis rather than apoptosis. J Infect Dis 193:136–145. doi:10.1086/498617

    PubMed  CAS  Google Scholar 

  60. Nigro P, Satoh K, O’Dell MR, Soe NN, Cui Z, Mohan A, Abe J, Alexis JD, Sparks JD, Berk BC (2011) Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 208:53–66. doi:10.1084/jem.20101174

    PubMed  CAS  Google Scholar 

  61. Oumouna-Benachour K, Hans CP, Suzuki Y, Naura A, Datta R, Belmadani S, Fallon K, Woods C, Boulares AH (2007) Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation 115:2442–2450. doi:10.1161/CIRCULATIONAHA.106.668756

    PubMed  CAS  Google Scholar 

  62. Pacher P, Szabo C (2007) Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev 25:235–260. doi:10.1111/j.1527-3466.2007.00018.x

    PubMed  CAS  Google Scholar 

  63. Peng TI, Jou MJ (2010) Oxidative stress caused by mitochondrial calcium overload. Ann N Y Acad Sci 1201:183–188. doi:10.1111/j.1749-6632.2010.05634.x

    PubMed  CAS  Google Scholar 

  64. Phair RD (1988) Cellular calcium and atherosclerosis: a brief review. Cell Calcium 9:275–284. doi:10.1016/0143-4160(88)90008-5

    PubMed  CAS  Google Scholar 

  65. Popa C, van Tits LJ, Barrera P, Lemmers HL, van den Hoogen FH, van Riel PL, Radstake TR, Netea MG, Roest M, Stalenhoef AF (2009) Anti-inflammatory therapy with tumour necrosis factor alpha inhibitors improves high-density lipoprotein cholesterol antioxidative capacity in rheumatoid arthritis patients. Ann Rheum Dis 68:868–872. doi:10.1136/ard.2008.092171

    PubMed  CAS  Google Scholar 

  66. Porto A, Palumbo R, Pieroni M, Aprigliano G, Chiesa R, Sanvito F, Maseri A, Bianchi ME (2006) Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein. FASEB J 20:2565–2566. doi:10.1096/fj.06-5867fje

    PubMed  CAS  Google Scholar 

  67. Postlethwaite AE, Kang AH (1976) Collagen-and collagen peptide-induced chemotaxis of human blood monocytes. J Exp Med 143:1299–1307

    PubMed  CAS  Google Scholar 

  68. Rock KL, Kono H (2008) The inflammatory response to cell death. Annu Rev Pathol 3:99–126. doi:10.1146/annurev.pathmechdis.3.121806.151456

    PubMed  CAS  Google Scholar 

  69. Rouhiainen A, Tumova S, Valmu L, Kalkkinen N, Rauvala H (2007) Pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J Leukoc Biol 81:49–58. doi:10.1189/jlb.0306200

    PubMed  CAS  Google Scholar 

  70. Saelens X, Festjens N, Parthoens E, Vanoverberghe I, Kalai M, van Kuppeveld F, Vandenabeele P (2005) Protein synthesis persists during necrotic cell death. J Cell Biol 168:545–551. doi:10.1083/jcb.200407162

    PubMed  CAS  Google Scholar 

  71. Sarai M, Hartung D, Petrov A, Zhou J, Narula N, Hofstra L, Kolodgie F, Isobe S, Fujimoto S, Vanderheyden JL, Virmani R, Reutelingsperger C, Wong ND, Gupta S, Narula J (2007) Broad and specific caspase inhibitor-induced acute repression of apoptosis in atherosclerotic lesions evaluated by radiolabeled annexin A5 imaging. J Am Coll Cardiol 50:2305–2312. doi:10.1016/j.jacc.2007.08.044

    PubMed  CAS  Google Scholar 

  72. Satoh K, Matoba T, Suzuki J, O’Dell MR, Nigro P, Cui Z, Mohan A, Pan S, Li L, Jin ZG, Yan C, Abe J, Berk BC (2008) Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation. Circulation 117:3088–3098. doi:10.1161/CIRCULATIONAHA.107.756106

    PubMed  CAS  Google Scholar 

  73. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195. doi:10.1038/nature00858

    PubMed  CAS  Google Scholar 

  74. Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR (2006) Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 177:1272–1281

    PubMed  CAS  Google Scholar 

  75. Schrijvers DM, De Meyer GRY, Kockx MM, Herman AG, Martinet W (2005) Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol 25:1256–1261. doi:10.1161/01.ATV.0000166517.18801.a7

    PubMed  CAS  Google Scholar 

  76. Seeger FH, Sedding D, Langheinrich AC, Haendeler J, Zeiher AM, Dimmeler S (2010) Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression. Basic Res Cardiol 105:389–397. doi:10.1007/s00395-009-0072-9

    PubMed  CAS  Google Scholar 

  77. Seimon TA, Wang Y, Han S, Senokuchi T, Schrijvers DM, Kuriakose G, Tall AR, Tabas IA (2009) Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice. J Clin Invest 119:886–898. doi:10.1172/JCI37262

    PubMed  CAS  Google Scholar 

  78. Senior RM, Griffin GL, Mecham RP (1980) Chemotactic activity of elastin-derived peptides. J Clin Invest 66:859–862. doi:10.1172/JCI109926

    PubMed  CAS  Google Scholar 

  79. Senior RM, Griffin GL, Mecham RP, Wrenn DS, Prasad KU, Urry DW (1984) Val-Gly-Val-Ala-Pro-Gly, a repeating peptide in elastin, is chemotactic for fibroblasts and monocytes. J Cell Biol 99:870–874. doi:10.1083/jcb.99.3.870

    PubMed  CAS  Google Scholar 

  80. Sherry B, Yarlett N, Strupp A, Cerami A (1992) Identification of cyclophilin as a proinflammatory secretory product of lipopolysaccharide-activated macrophages. Proc Natl Acad Sci USA 89:3511–3515. doi:10.1073/pnas.89.8.3511

    PubMed  CAS  Google Scholar 

  81. Sun C, Liang C, Ren Y, Zhen Y, He Z, Wang H, Tan H, Pan X, Wu Z (2009) Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Res Cardiol 104:42–49. doi:10.1007/s00395-008-0738-8

    PubMed  CAS  Google Scholar 

  82. Suzuki J, Jin ZG, Meoli DF, Matoba T, Berk BC (2006) Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells. Circ Res 98:811–817. doi:10.1161/01.RES.0000216405.85080.a6

    PubMed  CAS  Google Scholar 

  83. Szondy Z, Sarang Z, Molnar P, Nemeth T, Piacentini M, Mastroberardino PG, Falasca L, Aeschlimann D, Kovacs J, Kiss I, Szegezdi E, Lakos G, Rajnavolgyi E, Birckbichler PJ, Melino G, Fesus L (2003) Transglutaminase 2−/− mice reveal a phagocytosis-associated crosstalk between macrophages and apoptotic cells. Proc Natl Acad Sci USA 100:7812–7817. doi:10.1073/pnas.0832466100

    PubMed  CAS  Google Scholar 

  84. Tabas I (2005) Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol 25:2255–2264. doi:10.1161/01.ATV.0000184783.04864.9f

    PubMed  CAS  Google Scholar 

  85. Tabas I (2007) Apoptosis and efferocytosis in mouse models of atherosclerosis. Curr Drug Targets 8:1288–1296. doi:10.2174/138945007783220623

    PubMed  CAS  Google Scholar 

  86. Taylor KR, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, Gallo RL (2004) Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J Biol Chem 279:17079–17084. doi:10.1074/jbc.M310859200

    PubMed  CAS  Google Scholar 

  87. Thorp E, Cui D, Schrijvers DM, Kuriakose G, Tabas I (2008) Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe−/− mice. Arterioscler Thromb Vasc Biol 28:1421–1428. doi:10.1161/ATVBAHA.108.167197

    PubMed  CAS  Google Scholar 

  88. Thorp E, Kuriakose G, Shah YM, Gonzalez FJ, Tabas I (2007) Pioglitazone increases macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions of nondiabetic low-density lipoprotein receptor-null mice. Circulation 116:2182–2190. doi:10.1161/CIRCULATIONAHA.107.698852

    PubMed  CAS  Google Scholar 

  89. Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I (2009) Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe−/− and Ldlr−/− mice lacking CHOP. Cell Metab 9:474–481. doi:10.1016/j.cmet.2009.03.003

    PubMed  CAS  Google Scholar 

  90. Thorp E, Li Y, Bao L, Yao PM, Kuriakose G, Rong J, Fisher EA, Tabas I (2009) Brief report: increased apoptosis in advanced atherosclerotic lesions of Apoe−/− mice lacking macrophage Bcl-2. Arterioscler Thromb Vasc Biol 29:169–172. doi:10.1161/ATVBAHA.108.176495

    PubMed  CAS  Google Scholar 

  91. Tiyerili V, Zimmer S, Jung S, Wassmann K, Naehle CP, Lutjohann D, Zimmer A, Nickenig G, Wassmann S (2010) CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res Cardiol 105:465–477. doi:10.1007/s00395-010-0090-7

    PubMed  CAS  Google Scholar 

  92. Tyurina YY, Serinkan FB, Tyurin VA, Kini V, Yalowich JC, Schroit AJ, Fadeel B, Kagan VE (2004) Lipid antioxidant, etoposide, inhibits phosphatidylserine externalization and macrophage clearance of apoptotic cells by preventing phosphatidylserine oxidation. J Biol Chem 279:6056–6064. doi:10.1074/jbc.M309929200

    PubMed  CAS  Google Scholar 

  93. Ulloa L, Messmer D (2006) High-mobility group box 1 (HMGB1) protein: friend and foe. Cytokine Growth Factor Rev 17:189–201. doi:10.1016/j.cytogfr.2006.01.003

    PubMed  CAS  Google Scholar 

  94. Van Herck JL, De Meyer GRY, Martinet W, Bult H, Vrints CJ, Herman AG (2010) Proteasome inhibitor bortezomib promotes a rupture-prone plaque phenotype in ApoE-deficient mice. Basic Res Cardiol 105:39–50. doi:10.1007/s00395-009-0054-y

    PubMed  CAS  Google Scholar 

  95. Van Herck JL, De Meyer GRY, Martinet W, Salgado RA, Shivalkar B, De Mondt R, Van De Ven H, Ludwig A, Van Der Veken P, Van Vaeck L, Bult H, Herman AG, Vrints CJ (2010) Multi-slice computed tomography with N1177 identifies ruptured atherosclerotic plaques in rabbits. Basic Res Cardiol 105:51–59. doi:10.1007/s00395-009-0052-0

    PubMed  Google Scholar 

  96. Vanden Berghe T, Kalai M, Denecker G, Meeus A, Saelens X, Vandenabeele P (2006) Necrosis is associated with IL-6 production but apoptosis is not. Cell Signal 18:328–335. doi:10.1016/j.cellsig.2005.05.003

    Google Scholar 

  97. Vejux A, Lizard G (2009) Cytotoxic effects of oxysterols associated with human diseases: induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol Aspects Med 30:153–170. doi:10.1016/j.mam.2009.02.006

    PubMed  CAS  Google Scholar 

  98. Victor VM, Apostolova N, Herance R, Hernandez-Mijares A, Rocha M (2009) Oxidative stress and mitochondrial dysfunction in atherosclerosis: mitochondria-targeted antioxidants as potential therapy. Curr Med Chem 16:4654–4667. doi:10.2174/092986709789878265

    PubMed  CAS  Google Scholar 

  99. Virmani R, Burke A, Willerson J, Farb A, Narula J, Kolodgie F (2007) The pathology of vulnerable plaque. In: Virmani R, Narula J, Leon M, Willerson J (eds) The vulnerable atherosclerotic plaque: strategies for diagnosis and management. Blackwell Futura, Malden, pp 21–36

    Google Scholar 

  100. Wei Y, Heng G, Ben H (2010) Pro-inflammatory activities induced by CyPA-EMMPRIN interaction in monocytes. Atherosclerosis 213:415–421. doi:10.1016/j.atherosclerosis.2010.09.033

    Google Scholar 

  101. Yang H, Tracey KJ (2010) Targeting HMGB1 in inflammation. Biochim Biophys Acta 1799:149–156. doi:10.1016/j.bbagrm.2009.11.019

    PubMed  CAS  Google Scholar 

  102. Yang H, Wang H, Czura CJ, Tracey KJ (2005) The cytokine activity of HMGB1. J Leukoc Biol 78:1–8. doi:10.1189/jlb.1104648

    PubMed  CAS  Google Scholar 

  103. Yang J, Huang C, Yang J, Jiang H, Ding J (2011) Statins attenuate high mobility group box-1 protein induced vascular endothelial activation : a key role for TLR4/NF-kappaB signaling pathway. Mol Cell Biochem 345:189–195. doi:10.1007/s11010-010-0572-9

    Google Scholar 

Download references

Acknowledgments

This work was supported by the Fund for Scientific Research-Flanders and the University of Antwerp.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Pharmacology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium

    Wim Martinet, Dorien M. Schrijvers & Guido R. Y. De Meyer

Authors
  1. Wim Martinet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dorien M. Schrijvers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guido R. Y. De Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wim Martinet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martinet, W., Schrijvers, D.M. & De Meyer, G.R.Y. Necrotic cell death in atherosclerosis. Basic Res Cardiol 106, 749–760 (2011). https://doi.org/10.1007/s00395-011-0192-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-011-0192-x

Keywords

Search

Navigation