Oxidative Stress and Abdominal Aortic Aneurysms

Reference work entry


The role of inflammation in the pathogenesis of abdominal aortic aneurysm (AAA) is well established. Reactive oxygen species (ROS) as products of localized inflammation process can cause a gradual degradation of the extracellular matrix through an upregulation of matrix metalloproteinases and apoptosis of smooth muscle cells (SMC) of the vascular wall, which is associated with localized structural deterioration and progressive aortic dilatation.

Oxidative stress not only has a key role in pathogenesis of AAA but also during AAA repair. It is likely to result as a response to an ischemia/reperfusion injury (IRI) to the lower limbs and gastrointestinal tract. Modulation of ROS production or activity and restriction of the oxidative stress degree may suppress AAA formation and improve AAA repair results.


Abdominal aortic aneurysm Oxidative stress ROS 


  1. Aivatidi C, Vourliotakis G, Georgopoulos S, Sigala F, Bastounis E, Papalambros E (2011) Oxidative stress during abdominal aortic aneurysm repair–biomarkers and antioxidant’s protective effect: a review. Eur Rev Med Pharmacol Sci 15(3):245–252PubMedGoogle Scholar
  2. Alsac JM, Journe C, Louedec L, Dai J, Julia P, Fabiani JN, Michel JB (2011) Downregulation of remodelling enzymatic activity induced by an angiotensin-converting enzyme inhibitor (perindopril) reduces the degeneration of experimental abdominal aortic aneurysms in a rat model. Eur J Vasc Endovasc Surg 41(4):474–480PubMedCrossRefGoogle Scholar
  3. Bown MJ, Sutton AJ, Bell PR, Sayers RD (2002) A meta-analysis of 50 years of ruptured abdominal aortic aneurysm repair. Br J Surg 89:714–730PubMedCrossRefGoogle Scholar
  4. Brandes RP, Kreuzer J (2005) Vascular NADPH oxidases: molecular mechanisms of activation. Cardiovasc Res 65:16–27PubMedCrossRefGoogle Scholar
  5. Chello M, Mastroroberto P, Romano R, Castaldo P, Bevacqua E, Marchese AR (1996) Protection by coenzyme Q10 of tissue reperfusion injury during abdominal aortic cross-clamping. J Cardiovasc Surg (Torino) 37(3):229–35Google Scholar
  6. Collard CD, Gelman S (2001) Pathophysiology, clinical manifestations, and prevention of ischemia-reperfusion injury. Anesthesiology 94:1133–1138PubMedCrossRefGoogle Scholar
  7. Daugherty A, Cassis LA (2004) Mouse models of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 24:429–434PubMedCrossRefGoogle Scholar
  8. De Keulenaer GW, Chappell DC, Ishizaka N, Nerem RM, Alexander RW, Griendling KK (1998) Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide producing NADH oxidase. Circ Res 82:1094–1101PubMedCrossRefGoogle Scholar
  9. Del Rio D, Stewart AJ, Pellegrini N (2005) A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis 15(4):316–328PubMedCrossRefGoogle Scholar
  10. Ejiri J, Inoue N, Tsukube T, Munezane T, Hino Y, Kobayashi S, Hirata K, Kawashima S, Imajoh-Ohmi S, Hayashi Y, Yokozaki H, Okita Y, Yokoyama M (2003) Oxidative stress in the pathogenesis of thoracic aortic aneurysm. Protective role of statin and angiotensin II type 1 receptor blocker. Cardiovasc Res 59:988–996PubMedCrossRefGoogle Scholar
  11. Formigli L, Lombardo LD, Adembri C, Brunelleschi S, Ferrari E, Novelli GP (1992) Neutrophils as mediators of human skeletal muscle ischemia-reperfusion syndrome. Hum Pathol 23(6):627–634PubMedCrossRefGoogle Scholar
  12. Formigli L, Manneschi LI, Adembri C, Orlandini SZ, Pratesi C, Novelli GP (1995) Expression of E-selectin in ischemic and reperfused human skeletal muscle. Ultrastruct Pathol 19(3):193–200PubMedCrossRefGoogle Scholar
  13. Formigli L, Ibba Manneschi L, Tani A, Gandini E, Adembri C, Pratesi C, Novelli GP, Zecchi Orlandini S (1997) Vitamin E prevents neutrophil accumulation and attenuates tissue damage in ischemic-reperfused human skeletal muscle. Histol Histopathol 12(3):663–669PubMedGoogle Scholar
  14. Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT (1995) Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 15:1145–1151PubMedCrossRefGoogle Scholar
  15. Gavrila D, Li W-G, Daugherty A, Cassis LA, Miller FJ Jr, Oberley LW, Dellsperger KC, Weintraub NL (2005) Vitamin E inhibits abdominal aortic aneurysm formation in angiotensin II-infused, apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 25:1671–1677PubMedCentralPubMedCrossRefGoogle Scholar
  16. Hackam DG, Thiruchelvam D, Redelmeier DA (2006) Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case–control study. Lancet 368:659–665PubMedCrossRefGoogle Scholar
  17. Hoornweg LL, Storm-Versloot MN, Ubbink DT, Koelemay MJ, Legemate DA, Balm R (2008) Meta analysis on mortality of ruptured abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 35(5):558–570PubMedCrossRefGoogle Scholar
  18. Inoue N, Muramatsu M, Jin D, Takai S, Hayashi T, Katayama H, Kitaura Y, Tamai H, Miyazaki M (2009a) Involvement of vascular angiotensin II-forming enzymes in the progression of aortic abdominal aneurysms in angiotensin II- infused ApoE-deficient mice. J Atheroscler Thromb 16(3):164–171PubMedCrossRefGoogle Scholar
  19. Inoue N, Muramatsu M, Jin D, Takai S, Hayashi T, Katayama H, Kitaura Y, Tamai H, Miyazaki M (2009b) Effects of chymase inhibitor on angiotensin II-induced abdominal aortic aneurysm development in apolipoprotein E-deficient mice. Atherosclerosis 204(2):359–364PubMedCrossRefGoogle Scholar
  20. Khaira HS, Maxwell SR, Thomason H, Thorpe GH, Green MA, Shearman CP (1996) Antioxidant depletion during aortic aneurysm repair. Br J Surg 83(3):401–403PubMedCrossRefGoogle Scholar
  21. King VL, Trivedi DB, Gitlin JM, Loftin CD (2006) Selective cyclooxygenase-2 inhibition with celecoxib decreases angiotensin II-induced abdominal aortic aneurysm formation in mice. Arterioscler Thromb Vasc Biol 26:1137–1143PubMedCrossRefGoogle Scholar
  22. Lassegue B, Clempus RE (2003) Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 285:R277–R297PubMedGoogle Scholar
  23. Leurs LJ, Visser P, Laheij RJ, Buth J, Harris PL, Blankensteijn JD (2006) Statin use is associated with reduced all-cause mortality after endovascular abdominal aortic aneurysm repair. Vascular 14:1–8PubMedCrossRefGoogle Scholar
  24. Li WG, Miller FJ Jr, Zhang HJ, Spitz DR, Oberley LW, Weintraub NL (2001) H(2)O(2)-induced O(2) production by a non-phagocytic NAD(P)H oxidase causes oxidant injury. J Biol Chem 276:29251–29256PubMedCentralPubMedCrossRefGoogle Scholar
  25. Li WG, Stoll LL, Rice JB, Xu SP, Miller FJ, Chatterjee P, Hu L, Oberley LW, Spector AA, Weintraub NL (2003) Activation of NAD(P)H oxidase by lipid hydroperoxides: mechanism of oxidant-mediated smooth muscle cytotoxicity. Free Radic Biol Med 34:937–946PubMedCrossRefGoogle Scholar
  26. Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW et al (2005) The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem 280:4617–4626PubMedCrossRefGoogle Scholar
  27. Lindsay TF, Memari N, Ghanekar A, Walker P, Romaschin A (1997) Rupture of an abdominal aortic aneurysm causes priming of phagocytic oxidative burst. J Vasc Surg 25(4):599–610PubMedCrossRefGoogle Scholar
  28. Lindsay TF, Luo XP, Lehotay DC, Rubin BB, Anderson M, Walker PM, Romaschin AD (1999) Ruptured abdominal aortic aneurysm, a “two-hit” ischemia/reperfusion injury: evidence from an analysis of oxidative products. J Vasc Surg 30(2):219–228PubMedCrossRefGoogle Scholar
  29. Lizarbe TR, Tarín C, Gómez M, Lavin B, Aracil E, Orte LM, Zaragoza C (2009) Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN. Am J Pathol 175(4):1421–1430PubMedCentralPubMedCrossRefGoogle Scholar
  30. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT (2002) Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 110:625–632PubMedCentralPubMedCrossRefGoogle Scholar
  31. MacMillan-Crow LA, Thompson JA (1999) Tyrosine modifications and inactivation of active site manganese superoxide dismutase mutant (Y34F) by peroxynitrite. Arch Biochem Biophys 366:82–88PubMedCrossRefGoogle Scholar
  32. McCormick ML, Gavrila D, Weintraub NL (2007) Role of oxidative stress in the pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 27(3):461–469PubMedCrossRefGoogle Scholar
  33. Meli DN, Christen S, Leib SL (2003) Matrix metalloproteinase-9 in pneumococcal meningitis: activation via an oxidative pathway. J Infect Dis 187:1411–1415PubMedCrossRefGoogle Scholar
  34. Miller FJ Jr, Sharp WJ, Fang X, Oberley LW, Oberley TD, Weintraub NL (2002) Oxidative stress in human abdominal aortic aneurysms: a potential mediator of aneurysmal remodeling. Arterioscler Thromb Vasc Biol 22:560–565PubMedCrossRefGoogle Scholar
  35. Miyake T, Morishita R (2009) Pharmacological treatment of abdominal aortic aneurysm. Cardiovasc Res 83(3):436–443PubMedCrossRefGoogle Scholar
  36. Morita T, Imai T, Yamaguchi T, Sugiyama T, Katayama S, Yoshino G (2003) Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: role of bilirubin and carbon monoxide generated by the enzyme. Antioxid Redox Signal 5:439–447PubMedCrossRefGoogle Scholar
  37. Novelli GP, Adembri C, Gandini E, Orlandini SZ, Papucci L, Formigli L, Manneschi LI, Quattrone A, Pratesi C, Capaccioli S (1997) Vitamin E protects human skeletal muscle from damage during surgical ischemia-reperfusion. Am J Surg 173(3):206–209PubMedCrossRefGoogle Scholar
  38. Paik DC, Ramey WG, Dillon J, Tilson MD (1997) The nitrite/elastin reaction: implications for in vivo degenerative effects. Connect Tissue Res 36:241–251PubMedCrossRefGoogle Scholar
  39. Papalambros E, Sigala F, Georgopoulos S, Paraskevas KI, Andreadou I, Menenakos X, Sigalas P, Papalambros AL, Vourliotakis G, Giannopoulos A, Bakoyiannis C, Bastounis E (2007) Malondialdehyde as an indicator of oxidative stress during abdominal aortic aneurysm repair. Angiology 58(4):477–482PubMedCrossRefGoogle Scholar
  40. Paraskevas KI, Liapis CD, Hamilton G, Mikhailidis DP (2006) Can statins reduce perioperative morbidity and mortality in patients undergoing non-cardiac vascular surgery? Eur J Vasc Endovasc Surg 32:286–293PubMedCrossRefGoogle Scholar
  41. Põder P, Pulge A, Kals J, Aavik A, Zilmer K, Kullisaar T, Kairane C, Zilmer M (2003) Is elective abdominal aortic aneurysm repair accompanied by high grade oxidative stress? Scand J Surg 92(3):206–209PubMedGoogle Scholar
  42. Pyo R, Lee JK, Shipley JM, Curci JA, Mao D, Ziporin SJ, Ennis TL, Shapiro SD, Senior RM, Thompson RW (2000) Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest 105:1641–1649PubMedCentralPubMedCrossRefGoogle Scholar
  43. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS (1996) Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 98:2572–2579PubMedCentralPubMedCrossRefGoogle Scholar
  44. Rowlands TE, Homer-Vanniasinkam S (2001) Pro- and anti-inflammatory cytokine release in open versus endovascular repair of abdominal aortic aneurysm. Br J Surg 88(10):1335–1340PubMedCrossRefGoogle Scholar
  45. Saratzis A, Kitas GD, Saratzis N, Melas N (2010) Can statins suppress the development of abdominal aortic aneurysms? A review of the current evidence. Angiology 61(2):137–144PubMedCrossRefGoogle Scholar
  46. Satoh K, Nigro P, Matoba T, O’Dell MR, Cui Z, Shi X, Mohan A, Yan C, Abe J, Illig KA, Berk BC (2009) Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat Med 15(6):649–656PubMedCentralPubMedCrossRefGoogle Scholar
  47. Schweitzer M, Mitmaker B, Obrand D, Sheiner N, Abraham C, Dostanic S, Meilleur M, Sugahara T, Chalifour LE (2010) Atorvastatin modulates matrix metalloproteinase expression, activity, and signaling in abdominal aortic aneurysms. Vasc Endovascular Surg 44(2):116–122PubMedCrossRefGoogle Scholar
  48. Shah PK (1997) Inflammation, metalloproteinases, and increased proteolysis: an emerging pathophysiological paradigm in aortic aneurysm. Circulation 96:2115–2117PubMedCrossRefGoogle Scholar
  49. Stocker R, Keaney JF Jr (2004) Role of oxidative modifications in atherosclerosis. Physiol Rev 84:1381–1478PubMedCrossRefGoogle Scholar
  50. Thomas M, Gavrila D, McCormick ML, Miller FJ Jr, Daugherty A, Cassis LA, Dellsperger KC, Weintraub NL (2006) Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation 114:404–413PubMedCentralPubMedCrossRefGoogle Scholar
  51. Thompson MM, Nasim A, Sayers RD, Thompson J, Smith G, Lunec J, Bell PR (1996) Oxygen free radical and cytokine generation during endovascular and conventional aneurysm repair. Eur J Vasc Endovasc Surg 12:70–75PubMedCrossRefGoogle Scholar
  52. Tsiara S, Elisaf M, Mikhailidis DP (2003) Early vascular benefits of statins. Curr Med Res Opin 19:540–546PubMedCrossRefGoogle Scholar
  53. Vendrov AE, Madamanchi NR, Hakim ZS, Rojas M, Runge MS (2006) Thrombin and NAD(P)H oxidase-Mediated regulation of CD44 and BMP4-Id pathway in VSMC, restenosis, and atherosclerosis. Circ Res 98(10):1254–1263PubMedCrossRefGoogle Scholar
  54. Westman B, Johansson G, Luo JL, Söderlund K, Wernerman J, Hammarqvist F (2006) Effects on skeletal muscle glutathione status of ischemia and reperfusion following abdominal aortic aneurysm surgery. Ann Vasc Surg 20(1):99–105PubMedCrossRefGoogle Scholar
  55. Wijnen MHWA, Roumen RMH, Vader HL, Goris RJA (2002) A multiantioxidant supplementation reduces damage from ischemia reperfusion in patients after lower torso ischemia. A randomized trial. Eur J Vasc Endovasc Surg 23:486–490PubMedCrossRefGoogle Scholar
  56. Wong PS, Eiserich JP, Reddy S, Lopez CL, Cross CE, van der Vliet A (2001) Inactivation of glutathione S-transferases by nitric oxide-derived oxidants: exploring a role for tyrosine nitration. Arch Biochem Biophys 394:216–228PubMedCrossRefGoogle Scholar
  57. Xiong W, MacTaggart J, Knispel R, Worth J, Persidsky Y, Baxter BT (2009a) Blocking TNF-alpha attenuates aneurysm formation in a murine model. J Immunol 183(4):2741–2746PubMedCentralPubMedCrossRefGoogle Scholar
  58. Xiong W, Mactaggart J, Knispel R, Worth J, Zhu Z, Li Y, Sun Y, Baxter BT, Johanning J (2009b) Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model. Atherosclerosis 202(1):128–134PubMedCentralPubMedCrossRefGoogle Scholar
  59. Yajima N, Masuda M, Miyazaki M, Nakajima N, Chien S, Shyy JY (2002) Oxidative stress is involved in the development of experimental abdominal aortic aneurysm: a study of the transcription profile with complementary DNA microarray. J Vasc Surg 36:379–385PubMedCrossRefGoogle Scholar
  60. Zhao L, Moos MP, Grabner R, Pedrono F, Fan J, Kaiser B, John N, Schmidt S, Spanbroek R, Lotzer K, Huang L, Cui J, Rader DJ, Evans JF, Habenicht AJ, Funk CD (2004) The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med 10:966–973PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Surgery, Division of Vascular Surgery401 General Military Hospital of AthensAthensGreece

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