Multi-target Approach for Oxidative Stress Modulation by Aspirin, Salicylates and Other NSAIDs: Clinical Implications in Atherosclerosis

  • Eugenia YiannakopoulouEmail author


Atherosclerosis is a multifactorial process with oxidative stress being implicated in its pathophysiology. Aspirin and salicylates have pleiotropic effects. Among these pleiotropic effects, modulation of stress response by salicylates is quite interesting. Salicylates modulate stress response in prokaryotic organisms as well as in eukaryotic cells. Modulation of stress response by salicylates is due to the effect of salicylates on cell signalling pathways as well as to the pro-oxidant–antioxidant effects of salicylates. Aspirin and salicylates target oxidative stress in atherosclerosis through multiple antiplatelet-independent mechanisms of action, including scavenging of reactive oxygen species, enhancement of nitrous oxide release, inhibition of superoxide anion release, induction of GSH-dependent antioxidant mechanisms and epigenetic regulation of antioxidant enzymes. Thus, aspirin and salicylates are promising multi-target agents against oxidative stress implicated in atherosclerosis. Based on this evidence, the role of aspirin in the primary prevention of atherosclerosis should be revisited.


Atherosclerosis Oxidative stress Aspirin Salicylates Pharmacological modulation 


  1. 1.
    Cervadoro A, Palomba R, Vergaro G et al (2018) Targeting inflammation with nanosized drug delivery platforms in cardiovascular diseases: immune cell modulation in atherosclerosis. Front Bioeng Biotechnol 6:177. eCollection 2018CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Uchiyama S (2017) Aspirin for primary stroke prevention in elderly patients with vascular risk factors. J Gen Fam Med 18:331–335PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Lee SK, Khambhati J, Varghese T et al (2017) Comprehensive primary prevention of cardiovascular disease in women. Clin Cardiol 40:832–838PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Saito Y, Okada S, Ogawa H et al (2017) Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus: 10-year follow-up of a randomized controlled trial. Circulation 135:659–670PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Ogawa H, Nakayama M, Morimoto T et al (2008) Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 300:2134–2141PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Wolff T1, Miller T, Ko S (2009) Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. preventive services task force. Ann Intern Med Mar 150:405–410CrossRefGoogle Scholar
  7. 7.
    Yiannakopoulou E (2011) Hemoptysis under diclofenac and antiplatelet doses of aspirin. Pharmacology 87:1–4PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Yiannakopoulou E (2005) Cellular mechanisms of adaptation in oxidative stress and in heat shock in Saccharomyces cerevisiae: the effect of antioxidants. Msc thesis for the Msc Medical Biology Medical School and Department of Biology, University of AthensGoogle Scholar
  9. 9.
    Yiannakopoulou E (2007) Investigation of the role of salicylates in preconditioning. Final report for postdoctoral research (IKY Scholarship 15109/07.10.2005)Google Scholar
  10. 10.
    Yiannakopoulou ΕC, Delitheos A, Tiligada E (2005) Dose-dependent effect of non-steroidal anti-inflammatory agents on the cellular stress response. Epitheor Klin Farmacol Farmakokinet 23:39–41Google Scholar
  11. 11.
    Yiannakopoulou ΕC, Tiligada E (2007) Pharmacological preconditioning in the oxidative stress response of eukaryotic cells: in process method validation. Epitheor Klin Farmacol Farmakokinet 25:30–32Google Scholar
  12. 12.
    Yiannakopoulou E (2009) Oxidative stress-antioxidant mechanisms-clinical implications. Arch Greek Med 26:23–35Google Scholar
  13. 13.
    Yiannakopoulou E (2014) Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents--implications for cancer treatment and chemoprevention. Cell Oncol (Dordr) 37:167–178CrossRefGoogle Scholar
  14. 14.
    Yiannakopoulou E (2012) Modulation of lymphangiogenesis: a new target for aspirin and other nonsteroidal anti-inflammatory agents? A systematic review. J Clin Pharmacol 52:1749–1754PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Yin MJ, Yamamoto Y, Gaynor RB (1999) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396:77–80CrossRefGoogle Scholar
  16. 16.
    Yiannakopoulou E (2003) Quality of diagnosis and treatment of arterial hypertension in Greece. PhD thesis, Medical School University of Athens, GreeceGoogle Scholar
  17. 17.
    Yiannakopoulou E, Papadopulos IS, Cokkinos DV et al (2005) Adherence to antihypertensive treatment: a critical factor for blood pressure control. Eur J Cardiovasc Prev Rehabil 2005(12):243–249CrossRefGoogle Scholar
  18. 18.
    Lu L, Qin Y, Chen C et al (2018) Beneficial effects exerted by paeonol in the management of atherosclerosis. Oxidative Med Cell Longev 2018:1098617Google Scholar
  19. 19.
    Υiannakopoulou E, Νikiteas N, Perrea D et al (2012) Pharmacological preconditioning of oxidative stress response: systematic review. Surg Laparosc Endosc Percutan Tech 22:200–204CrossRefGoogle Scholar
  20. 20.
    Yiannakopoulou E, Tiligada E (2009) Preconditioning effect of salicylates against oxidative stress in yeast. J Appl Microbiol 106:903–908PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Yiannakopoulou EC, Tiligada E (2006) Acetaminophen modulates the oxidative stress response in eucaryotic cells. Rev Clin Pharmacol Pharmacokinet 20:125–127Google Scholar
  22. 22.
    Radimer K, Bindewald B, Hughes J et al Dietary supplement use by US adults: data from the national health and nutrition examination survey, 1999–2000. Am J Epidemiol 160:339–349PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Kim HJ, Giovannucci E, Rosner B et al (2014) Longitudinal and secular trends in dietary supplement use: nurses’ health study and health professionals follow-up study, 1986–2006. J Acad Nutr Diet 114:436–443PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Joshipura KJ, Hu FB, Manson JE et al (2001) The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med 134:1106–1114PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Miedema MD, Petrone A, Shikany JM et al (2015) Association of fruit and vegetable consumption during early adulthood with the prevalence of coronary artery calcium after 20 years of follow-up: the coronary artery risk development in young adults (CARDIA) study. Circulation 132:1990–1998PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Christen WG, Gaziano JM, Hennekens CH (2000) Design of physicians’ health study II—a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol 10:125–134PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Yiannakopoulou E (2012) Does pharmacodynamic interaction of non enzymatic antioxidants modify response to anti-oxidant therapy in the process of atherosclerosis? J Cardiovasc Pharmacol 17:366–372CrossRefGoogle Scholar
  28. 28.
    Mohanakumar KP, Muralikrishnan D, Thomas B (2000) Neuroprotection by sodium salicylate against 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced neurotoxicity. Brain Res 864:281–290PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Bektaşoğlu B, Ozyürek M, Güçlü K et al (2008) Hydroxyl radical detection with a salicylate probe using modified CUPRAC spectrophotometry and HPLC. Talanta 77:90–97PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Rivas-Estilla AM, Bryan-Marrugo OL, Trujillo-Murillo K et al (2012) Cu/Zn superoxide dismutase (SOD1) induction is implicated in the antioxidative and antiviral activity of acetylsalicylic acid in HCV-expressing cells. Am J Physiol Gastrointest Liver Physiol 302:G1264–G7327PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Wróbel M, Góralska J, Jurkowska H et al (2017) Similar effect of sodium nitroprusside and acetylsalicylic acid on antioxidant system improvement in mouse liver but not in the brain. Biochimie 135:181–185PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Gondor OK, Pál M, Darkó É et al (2016) Salicylic acid and sodium salicylate alleviate cadmium toxicity to different extents in maize (Zea mays L.). PLoS One 11:e0160157PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Oliveira VC, Constante SAR, Polloni L et al (2018) Protective effect of aspirin against mitomycin C-induced carcinogenicity, assessed by the test for detection of epithelial tumor clones (warts) in Drosophila melanogaster. Drug Chem Toxicol 41:330–33733PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Jian Z, Tang L, Yi X et al (2016) Aspirin induces Nrf2-mediated transcriptional activation of haem oxygenase-1 in protection of human melanocytes from H2 O2 -induced oxidative stress. J Cell Mol Med 20:1307–1318PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Bonaterra GA, Heinrich E, Kelber O et al (2010a) Anti-inflammatory effects of the willow bark extract STW 33-I (Proaktiv®) in LPS-activated human monocytes and differentiated macrophages. Phytomedicine 17:1106–1113PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Enayat S, Banerjee S (2009) Comparative antioxidant activity of extracts from leaves, bark and catkins of Salix aegyptiaca sp. Food Chem 116:23–28CrossRefGoogle Scholar
  37. 37.
    Ishikado A, Sono Y, Matsumoto M et al (2013) Willow bark extract increases antioxidant enzymes and reduces oxidative stress through activation of Nrf2 in vascular endothelial cells and Caenorhabditis elegans. Free Radic Biol Med 65:1506–1515PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Maniqlia FP, Costa JA (2016) Effects of acetylsalicylic acid usage on inflammatory and oxidative stress markers in hemodialysis patients. Inflammation 9:243–24734CrossRefGoogle Scholar
  39. 39.
    Berg K, Langaas M, Ericsson M et al (2013) Acetylsalicylic acid treatment until surgery reduces oxidative stress and inflammation in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg 43:1154–1163PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Berg K, Haaverstad R, Astudillo R et al (2006) Oxidative stress during coronary artery bypass operations: importance of surgical trauma and drug treatment. Scand Cardiovasc J 40:291–297PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Grosser N, Abate A, Oberle S et al (2003) Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun 308:956–960PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Grosser N, Schroder H (2003) Aspirin protects endothelial cells from oxidant damage via the nitric oxide-cGMP pathway. Arterioscler Thromb Vasc Biol 23:1345–1351PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    He B, Zhao S, Zhang W et al (2010) Salicylate prevents hepatic oxidative stress activation caused by short-term elevation of free fatty acids in vivo. Diabetes Res Clin Pract 89:150–156PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    He B1, Zhao S, Zhang W et al (2010) Effect of sodium salicylate on oxidative stress and insulin resistance induced by free fatty acids. Hepatobiliary Pancreat Dis Int 9:49–53PubMedPubMedCentralGoogle Scholar
  45. 45.
    Wu R, Lamontagne D, de Champlain J (2002) Antioxidative properties of acetylsalicylic acid on vascular tissues from normotensive and spontaneously hypertensive rats. Circulation 105:387–9235PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    El MA, Wu R, de Champlain J (2002) Prevention of hypertension, hyperglycemia and vascular oxidative stress by aspirin treatment in chronically glucose-fed rats. J Hypertens 20:1407–1412CrossRefGoogle Scholar
  47. 47.
    Wu R, Laplante MA, De Champlain J (2004) Prevention of angiotensin II-induced hypertension, cardiovascular hypertrophy and oxidative stress by acetylsalicylic acid in rats. J Hypertens 22:793–801PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Tauseef M, Sharma KK, Fahim M (2007) Aspirin restores normal baroreflex function in hypercholesterolemic rats by its antioxidative action. Eur J Pharmacol 556:136–143PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Mei L, Daud MK, Ullah N et al (2015) Pretreatment with salicylic acid and ascorbic acid significantly mitigate oxidative stress induced by copper in cotton genotypes. Environ Sci Pollut Res Int 22:9922–9931PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Tauseef M, Shahid M, Sharma KK et al (2008) Antioxidative action of aspirin on endothelial function in hypercholesterolaemic rats. Basic Clin Pharmacol Toxicol 103:314–321PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Podhaisky H-P, Abate A, Polte T et al (1997) Aspirin protects endothelial cells from oxidative stress–possible synergism with vitamin E. FEBS Lett 417:349–351PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Korkmaz-Icöz S, Atmanli A, Radovits T, Li S et al (2016) Administration of zinc complex of acetylsalicylic acid after the onset of myocardial injury protects the heart by upregulation of antioxidant enzymes. J Physiol Sci 66:113–125PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Korkmaz S, Atmanli A, Li S, Radovits T et al (2015) Superiority of zinc complex of acetylsalicylic acid to acetylsalicylic acid in preventing postischemic myocardial dysfunction. Exp Biol Med (Maywood) 240:1247–1255CrossRefGoogle Scholar
  54. 54.
    Amel Zabihi N, Mahmoudabady M, Soukhtanloo M et al (2018) Salix alba attenuated oxidative stress in the heart and kidney of hypercholesterolemic rabbits. Avicenna J Phytomed 8:63–72PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Biomedical Sciences, Faculty of Health SciencesUniversity of West AtticaAthensGreece

Personalised recommendations