Pharmacogenetic Implications of Statin Therapy on Oxidative Stress in Coronary Artery Disease

  • Nivas Shyamala
  • Surekha Rani Hanumanth


Coronary artery disease (CAD) remains the leading global public health burden in cardiovascular diseases. Atherosclerosis is a primary mechanism to cause CAD with the contribution of epidemiological, traditional, genetic, and epigenetic risk factors. Statins, prescribed drugs for lowering of cholesterol levels, also have pleiotropic effect on oxidative stress, inflammation, apoptosis, etc. Reactive oxygen species (ROS)-induced oxidative stress associates with risk factors and participates in initiation and progression of disease. ROS molecules generated as superoxides (O2ˉ), singlet/triplet oxygen, peroxides (H2O2, ONOO), and hydroxyl radicals (HO) via reactions catalyzed by endothelial nitric oxide synthase, myeloperoxidase, NADPH oxidase, and xanthine oxidase enzyme are encoded by eNOS, MPO, NOX, and XO genes, respectively. Polymorphisms in eNOS, MPO, NOX, and XO genes influence the expression and attributes to interindividual variation in response to statin drugs. Differential response to statin drug insights into emerging of pharmacogenetic studies to understand the genetic makeup and treat the patient with suitable drug and dose. In clinical practice, pharmacogenetic approach toward oxidative stress is a future emerging trend in personalized medicine development.


Coronary artery disease Oxidative stress Reactive oxygen species Statins Pharmacogenetics 



This work was supported by UGC, New Delhi, India: MRP-2013 (F.No.42-52/2013[SR]), BSR-Fellowship, CPEPA, and OU-DST-PURSE-II Programme (C-DST-PURSE- II/23/2017), ICMR-SRF (ID No. 2019-4183).


  1. 1.
    World Health Organization (2016) Technical package for cardiovascular disease management in primary health care. Hearts 76Google Scholar
  2. 2.
    MoHFW (2017) India: health of the nation’s states. Government report, pp 70–75Google Scholar
  3. 3.
    Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Hansson GK, Libby P, Tabas I (2015) Inflammation and plaque vulnerability. J Intern Med 278:483–493PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Mack M, Gopal A (2016) Epidemiology, traditional and novel risk factors in coronary artery disease. Heart Fail Clin 12:1–10PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Teng N, Maghzal GJ, Talib J, Rashid I, Lau AK, Stocker R (2017) The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture. Redox Rep 22:51–73PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Libby P, Rocha VZ (2018) All roads lead to IL-6: a central hub of cardiometabolic signaling. Int J Cardiol 259:213–215PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Forrester SJ, Kikuchi DS, Hernandes MS, Xu Q, Griendling KK (2018) Reactive oxygen species in metabolic and inflammatory signaling. Circ Res 122:877–902PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Vichova T, Motovska Z (2013) Oxidative stress: predictive marker for coronary artery disease. Exp Clin Cardiol 18:88–91Google Scholar
  10. 10.
    Cai H, Harrison DG (2000) The role of oxidant stress. Circ Res 87:840–844PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Reiner, De Backer G, Fras Z, Kotseva K, Tokgözoglu L, Wood D, De Bacquer D (2016) Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries – findings from the EUROASPIRE IV survey. Atherosclerosis 246:243–250PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Catapano AL, Graham I, De Backer G et al (2016) 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 37:2999–3058lPubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Oesterle A, Laufs U, Liao JK (2017) Pleiotropic effects of statins on the cardiovascular system. Circ Res 120:229–243PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kitzmiller JP, Binkley PF, Pandey SR, Suhy AM, Baldassarre D, Hartmann K (2013) Statin pharmacogenomics: pursuing biomarkers for predicting clinical outcomes. Discov Med 16:45–51PubMedPubMedCentralGoogle Scholar
  15. 15.
    Mangravite LM, Thorn CF, Krauss RM (2006) Clinical implications of pharmacogenomics of statin treatment. Pharm J 6:360–374Google Scholar
  16. 16.
    Phaniendra A, Jestadi DB, Periyasamy L (2015) Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem 30:11–26PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Panth N, Paudel KR, Parajuli K (2016) Reactive oxygen species: a key hallmark of cardiovascular disease. Adv Med 2016:1–12CrossRefGoogle Scholar
  18. 18.
    Madamanchi NR, Vendrov A, Runge MS (2005) Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 25:29–38PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Ushio-fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK (1996) p22 phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II- induced hypertrophy in vascular smooth muscle cells ∗. J Biol Chem 271:23317–23321PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Sorescu D, Weiss D, Lassègue B et al (2002) Superoxide production and expression of Nox family proteins in human atherosclerosis. Circulation 105:1429–1435PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Chistiakov DA, Melnichenko AA, Myasoedova VA, Grechko AV, Orekhov AN (2017) Mechanisms of foam cell formation in atherosclerosis. J Mol Med 95:1153–1165PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Yu XH, Fu YC, Zhang DW, Yin K, Tang CK (2013) Foam cells in atherosclerosis. Clin Chim Acta 424:245–252PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Mishra TK, Mishra C, Das B (2013) An approach to the classification, diagnosis and management of vulnerable plaque. J Indian Coll Cardiol 3:57–66CrossRefGoogle Scholar
  25. 25.
    Stone NJ, Robinson JG, Lichtenstein AH et al (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American college of cardiology/American heart association task force on practice guidelines. J Am Coll Cardiol 63:2889–2934PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Endo A (2010) A historical perspective on the discovery of statins. Proc Jpn Acad Ser B 86:484–493CrossRefGoogle Scholar
  27. 27.
    Singh P, Saxena R, Srinivas G, Pande G, Chattopadhyay A (2013) Cholesterol biosynthesis and homeostasis in regulation of the cell cycle. PLoS One 8(3):e58833. Scholar
  28. 28.
    Liao JK, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89–118PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Oliveira-Paula GH, Lacchini R, Tanus-Santos JE (2017) Clinical and pharmacogenetic impact of endothelial nitric oxide synthase polymorphisms on cardiovascular diseases. Nitric Oxide Biol Chem 63:39–51CrossRefGoogle Scholar
  30. 30.
    Laufs U, Kilter H, Konkol C, Wassmann S, Bohm M, Nickenig G (2002) Impact of HMG CoA reductase inhibition on small GTPases in the heart. Cardiovasc Res 53:911–920PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Abe K, Nakayama M, Yoshimura M et al (2005) Increase in the transcriptional activity of the endothelial nitric oxide synthase gene with fluvastatin: a relation with the -786T>C polymorphism. Pharmacogenet Genomics 15:329–336PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Nagassaki S, Sertório JTC, Metzger IF, Bem AF, Rocha JBT, Tanus-Santos JE (2006) eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite. Free Radic Biol Med 41:1044–1049PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Gimbrone MA, García-Cardeña G (2016) Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 118:620–636PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Verhaar MC (2004) Free radical production by dysfunctional eNOS. Heart 90:494–495PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Sullivan JC, Pollock JS (2006) Coupled and uncoupled NOS: separate but equal? Uncoupled NOS in endothelial cells is a critical pathway for intracellular signaling. Circ Res 98:717–719PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Matsubara K, Higaki T, Matsubara Y, Nawa A (2015) Nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. Int J Mol Sci 16:4600–4614PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kumar GR, Spurthi KM, Kumar GK et al (2016) Genetic polymorphisms of eNOS (-786T/C, Intron 4b/4a & 894G/T) and its association with asymptomatic first degree relatives of coronary heart disease patients. Nitric Oxide Biol Chem 60:40–49CrossRefGoogle Scholar
  38. 38.
    Laufs U, Liao JK (1998) Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 273:24266–24271PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Laufs U, La Fata V, Plutzky J, Liao JK (1998) Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97:1129–1135PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Ruan F, Zheng Q, Wang J (2012) Mechanisms of bone anabolism regulated by statins. Biosci Rep 32:511–519PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Wolfrum S, Dendorfer A, Rikitake Y, Stalker TJ, Scalia R, Dominiak P, Liao JK (2009) Inhibition of rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 24:1842–1847. NIH Public AccessCrossRefGoogle Scholar
  42. 42.
    Gundapaneni KK, Galimudi RK, Kondapalli MS, Gantala SR, Mudigonda S, Padala C, Shyamala N, Sahu SK, Hanumanth SR (2017) Oxidative stress markers in coronary artery disease patients with diabetes mellitus. Int J Diab Dev Ctries 37:190–194CrossRefGoogle Scholar
  43. 43.
    Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, David J, Sessa WC, Walsh K (2010) The HMGCoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6:1004–1010. NIH Public AccessCrossRefGoogle Scholar
  44. 44.
    Shimokawa H, Takeshita A (2005) Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 25:1767–1775PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Silva PS, Lacchini R, Gomes Vde A, Tanus-Santos JE (2011) Pharmacogenetic implications of the eNOS polymorphisms for cardiovascular action drugs. Arq Bras Cardiol 96:e27–e34PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Grishkovskaya XI, Paumann-Page M, Tscheliessnig R et al (2017) Structure of human promyeloperoxidase (proMPO) and the role of the propeptide in processing and maturation. J Biol Chem 292:8244–8261PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kumar AP, Reynolds WF (2005) Statins downregulate myeloperoxidase gene expression in macrophages. Biochem Biophys Res Commun 331:442–451PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Zhang R, Brennan ML, Shen Z, MacPherson JC, Schmitt D, Molenda CE, Hazen SL (2002) Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem 277:46116–46122PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Wang Y, Chen X-Y, Wang K, Li S, Zhang X-Y (2017) Myeloperoxidase polymorphism and coronary artery disease risk: a meta-analysis. Medicine (Baltimore) 96:e7280CrossRefGoogle Scholar
  50. 50.
    Ndrepepa G, Braun S, Schömig A, Kastrati A (2011) Impact of therapy with statins, beta-blockers and angiotensin-converting enzyme inhibitors on plasma myeloperoxidase in patients with coronary artery disease. Clin Res Cardiol 100:327–333PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Sygitowicz G, Maciejak A, Piniewska-Juraszek J, Pawlak M, Gora M, Burzynska B, Dluzniewski M, Opolski G, Sitkiewicz D (2015) Interindividual variability of atorvastatin treatment influence on the MPO gene expression in patients after acute myocardial infarction. Acta Biochim Pol 63(1):89–95. Scholar
  52. 52.
    Touyz RM, Briones AM, Sedeek M, Burger D, Montezano AC (2011) NOX isoforms and reactive oxygen species in vascular health. Mol Interv 11:27–35PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Kwok JMF, Ma CCH, Ma S (2013) Recent development in the effects of statins on cardiovascular disease through Rac1 and NADPH oxidase. Vasc Pharmacol 58:21–30CrossRefGoogle Scholar
  54. 54.
    Maack C, Kartes T, Kilter H, Schäfers HJ, Nickenig G, Böhm M, Laufs U (2003) Oxygen free radical, release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment. Circulation 108:1567–1574PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Antonopoulos AS, Margaritis M, Shirodaria C, Antoniades C (2012) Translating the effects of statins: from redox regulation to suppression of vascular wall inflammation. Thromb Haemost 108:840–848PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Guzik TJ, West NEJ, Black E, McDonald D, Ratnatunga C, Pillai R, Channon KM (2000) Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res 86:e85–e90PubMedPubMedCentralGoogle Scholar
  57. 57.
    Zhang J, Wang M, Li Z, Bi X, Song J, Weng S, Fu G (2016) NADPH oxidase activation played a critical role in the oxidative stress process in stable coronary artery disease. Am J Transl Res 8:5199–5210PubMedPubMedCentralGoogle Scholar
  58. 58.
    Cahilly C, Ballantyne CM, Lim DS, Gotto A, Marian AJ (2000) A variant of p22(phox), involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis. Circ Res 86:391–395PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Ito D, Murata M, Watanabe K, Yoshida T (2000) C242T polymorphism of NADPH oxidase p22 PHOX gene and ischemic cerebrovascular disease in the Japanese population. Stroke 31(4):936–940PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Xu Q, Yuan F, Shen X, Wen H, Li W, Cheng B, Wu J (2014) Polymorphisms of C242T and A640G in CYBA gene and the risk of coronary artery disease: a meta-analysis. PLoS One 9(1):e84251. Scholar
  61. 61.
    Gardemann A, Mages P, Katz N, Tillmanns H, Haberbosch W (1999) The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals. Atherosclerosis 145:315–323PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Hamilton PK, Hughes SMT, Plumb RD, Devine A, Leahey W, Lyons KS, Johnston D, McVeigh GE (2010) Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia. Clin Sci 118:359–366PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Antoniades C, Bakogiannis C, Tousoulis D et al (2010) Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. Circulation 122(11 Suppl):S66–S73. Scholar
  64. 64.
    Inoue I, Goto S, Mizotani K, Awata T, Mastunaga T, Kawai S, Nakajima T, Hokari S, Komoda T, Katayama S (2000) Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary e. Life Sci 67:863–876PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Kudo M, Moteki T, Sasaki T, Konno Y, Ujiie S, Onose A, Mizugaki M, Ishikawa M, Hiratsuka M (2008) Functional characterization of human xanthine oxidase allelic variants. Pharmacogenet Genomics 18:243–251PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Chung HY, Baek BS, Song SH, Kim MS, Huh JI, Shim KH, Kim KW, Lee KH (1997) Oxidation xanthine oxidase I [(reversible XOD ) Proteolys ~ Xant ~ ine]. Age (Omaha) 20:127–140CrossRefGoogle Scholar
  67. 67.
    Zdrenghea M, Sitar-Tǎut A, Cismaru G, Zdrenghea D, Pop D (2017) Xanthine oxidase inhibitors in ischaemic heart disease. Cardiovasc J Afr 28:201–204PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Landmesser U, Spiekermann S, Preuss C, Sorrentino S, Fischer D, Manes C, Mueller M, Drexler H (2007) Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease. Arterioscler Thromb Vasc Biol 27:943–948PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Wu B, Hao Y, Shi J et al (2015) Association between xanthine dehydrogenase tag single nucleotide polymorphisms and essential hypertension. Mol Med Rep 12:5685–5690PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Greig D, Alcaino H, Castro PF et al (2011) Xanthine-oxidase inhibitors and statins in chronic heart failure: effects on vascular and functional parameters. J Heart Lung Transplant 30:408–413PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Delbosc S, Cristol JP, Descomps B, Mimran A, Jover B (2002) Simvastatin prevents angiotensin II-induced cardiac alteration and oxidative stress. Hypertension 40:142–147PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Nivas Shyamala
    • 1
  • Surekha Rani Hanumanth
    • 1
  1. 1.Department of Genetics & BiotechnologyOsmania UniversityHyderabadIndia

Personalised recommendations