Abstract
Rosuvastatin is a cholesterol-lowering drug that also attenuates the inflammatory process and oxidative stress via the reduction of superoxide anion production. Superoxide anions are metabolized by manganese-dependent superoxide dismutase (MnSOD or SOD2) in the mitochondria. In humans, there is a gene polymorphism where a change of alanine (Ala) to valine (Val) occurs at the 16th amino acid (Ala16Val-SOD2). The VV genotype has been associated with the risk of developing several metabolic diseases, such as hypercholesterolemia. Thus, to further explore this phenomenon, this study investigated the influence of the Val16Ala-SOD2 polymorphism on the lipid profile and inflammatory and fibrinolytic biomarkers of 122 hypercholesterolemic patients undergoing the first pharmacological cholesterol-lowering therapy who were treated with 20 mg rosuvastatin for 120 days. The findings indicate that the VV patients who present a low-efficiency SOD2 enzyme exhibit an attenuated response to rosuvastatin compared with the A-allele patients. The effect of rosuvastatin on inflammatory and fibrinolytic biomarkers was also less intense in the VV patients. These results suggest some pharmacogenetic effects of Val16Ala-SOD2 in hypercholesterolemia treatment.
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References
Mahalwar R, Khanna D . Pleiotropic antioxidant potential of rosuvastatin in preventing cardiovascular disorders. Eur J Pharmacol 2013; 711: 57–62.
McTaggart F . Comparative pharmacology of rosuvastatin. Atherosclerosis 2003; 4: 9–14.
Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ . Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol 2010; 105: 69–76.
Haas MJ, Horani MH, Parseghian SA, Mooradian AD . Statins prevent dextrose-induced endothelial barrier dysfunction, possibly through inhibition of superoxide formation. Diabetes 2006; 55: 474–479.
Schupp N, Schmid U, Heidland A, Stopper H . Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis. Atherosclerosis 2008; 199: 278–287.
Laufs U, Gertz K, Dirnagl U, Böhm M, Nickenig G, Endres M . Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res 2002; 942: 23–30.
Huang J, Lin SC, Nadershahi A, Watts SW, Sarkar R . Role of redox signaling and poly (adenosine diphosphate-ribose) polymerase activation in vascular smooth muscle cell growth inhibition by nitric oxide and peroxynitrite. J Vasc Surg 2008; 47: 599–607.
Muller G, Morawietz H . Nitric oxide, NAD(P)H oxidase and atherosclerosis. Antioxid Redox Signal 2009; 11: 1711–1731.
Shimoda-Matsubayashi S, Matsumine H, Kobayashi T, Nakagawa-Hattori Y, Shimizu Y, Mizuno Y . Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. Biochem Biophys Res Commun 1996; 226: 561–565.
Bresciani G, Cruz IB, de Paz JA, Cuevas MJ, González-Gallego J . The MnSOD Ala16Val SNP: relevance to human diseases and interaction with environmental factors. Free Radic Res 2013; 47: 781–792.
Duarte MM, Moresco RN, Duarte T, Santi A, Bagatini MD, Da Cruz IB et al. Oxidative stress in hypercholesterolemia and its association with Ala16Val superoxide dismutase gene polymorphism. Clin Biochem 2010; 43: 1118–1123.
Montano MA, Barrio Lera JP, Gottlieb MG, Krewer Cda C, da Rocha MI, Mânica-Cattani MF et al. Association between manganese superoxide dismutase (MnSOD) gene polymorphism and elderly obesity. Mol Cell Biochem 2009; 32: 33–40.
Gottlieb MG, Schwanke CH, Santos AF, Jobim PF, Müssel DP, da Cruz IB . Association among oxidized LDL levels, MnSOD, apolipoprotein E polymorphisms, and cardiovascular risk factors in a south Brazilian region population. Genet Mol Res 2005; 4: 691–703.
Fujimoto H, Kobayashi H, Ohno M . Age-induced reduction in mitochondrial manganese superoxide dismutase activity and tolerance of macrophages against apoptosis induced by oxidized low density lipoprotein. Circ J 2010; 74: 353–360.
Montano MA, da Cruz IB, Duarte MM, Krewer Cda C, da Rocha MI, Mânica-Cattani MF et al. Inflammatory cytokines in vitro production are associated with Ala16Val superoxide dismutase gene polymorphism of peripheral blood mononuclear cells. Cytokine 2012; 60: 30–33.
Kakko S, Päivänsalo M, Koistinen P, Kesäniemi YA, Kinnula VL, Savolainen MJ . The signal sequence polymorphism of the MnSOD gene is associated with the degree of carotid atherosclerosis. Atherosclerosis 2003; 168: 147–152.
Nakanishi S, Yamane K, Ohishi W, Nakashima R, Yoneda M, Nojima H et al. Manganese superoxide dismutase Ala16Val polymorphism is associated with the development of type 2 diabetes in Japanese-Americans. Diabetes Res Clin Pract 2008; 81: 381–385.
Chen H, Yu M, Li M, Zhao R, Zhu Q, Zhou W et al. Polymorphic variations in manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1), and catalase (CAT) contribute to elevated plasma triglyceride levels in Chinese patients with type 2 diabetes or diabetic cardiovascular disease. Mol Cell Biochem 2012; 363: 85–91.
Möllsten A, Jorsal A, Lajer M, Vionnet N, Tarnow L . The V16A polymorphism in SOD2 is associated with increased risk of diabetic nephropathy and cardiovascular disease in type 1 diabetes. Diabetologia 2009; 52: 2590–2593.
Hovnik T, Dolzan V, Bratina NU, Podkrajsek KT, Battelino T . Genetic polymorphisms in genes encoding antioxidant enzymes are associated with diabetic retinopathy in type 1 diabetes. Diabetes Care 2009; 322: 258–262.
Kangas-Kontio T, Vavuli S, Kakko SJ, Penna J, Savolainen ER, Savolainen MJ et al. Polymorphism of the manganese superoxide dismutase gene but not of vascular endothelial growth factor gene is a risk factor for diabetic retinopathy. Br J Ophthalmol 2009; 93: 1401–1406.
Möllsten A, Marklund SL, Wessman M, Svensson M, Forsblom C, Parkkonen M et al. A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy. Diabetes 2007; 56: 265–269.
Taufer M, Peres A, de Andrade VM, de Oliveira G, Sá G, do Canto ME et al. Is the Val16Ala manganese superoxide dismutase polymorphism associated with the aging process? J Gerontol A Biol Sci Med Sci 2005; 60: 432–438.
Austin MA, Hutter CM, Zimmern RL, Humphries SE . Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol 2004; 160: 421–429.
Barbisan F, Motta J, Trott A, Azzolin V, Dornelles EB, Marcon M et al. Blood mononuclear cells may be modulated by the Ala16Val-SOD2 gene polymorphism. PLoS One 2014; 9: e107299.
Ruiz-Sanz JI, Aurrekoetxea I, Matorras R, Ruiz-Larrea MB . Ala16Val SOD2 polymorphism is associated with higher pregnancy rates in in vitro fertilization cycles. Fertil Steril 2011; 95: 1601–1605.
Bachorik PS, Albers JJ . Precipitation methods for quantification of lipoproteins. Methods Enzymol 1986; 129: 78–100.
Jones P, Kafonek S, Laurora I, Hunninghake D . Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81: 582–587.
Becer E, Çırakoğlu A . Association of the Ala16Val MnSOD gene polymorphism with plasma leptin levels and oxidative stress biomarkers in obese patients. Gene 2015; 568: 35–39.
Stein EA, Davidson MH, Dobs AS, Schrott H, Dujovne CA, Bays H et al. Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin U.S. Study Group. Am J Cardiol 1998; 82: 311–316.
Ballantyne CM, Weiss R, Moccetti T, Cain VA, Palmer MK, Karlson BW et al. Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol 2007; 99: 673–680.
Sacks FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT et al. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation 1998; 97: 1446–1452.
Simon JA, Lin F, Hulley SB, Blanche PJ, Waters D, Shiboski S et al. Phenotypic predictors of response to simvastatin therapy among African–Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol 2006; 97: 843–850.
Burnett JR, Hooper AJ . Common and rare gene variants affecting plasma LDL cholesterol. Clin Biochem Rev 2008; 29: 11–26.
Thompson JF, Hyde CL, Wood LS, Paciga SA, Hinds DA, Cox DR et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating To New Targets (TNT) Cohort. Circ Cardiovasc Genet 2009; 2: 173–181.
Ihu M, Tomlinson B . Current perspectives on rosuvastatin. Integr Blood Press Control 2013; 6: 15–25.
Link A, Ayadhi T, Böhm M, Nickenig G . Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. Eur Heart J 2006; 27: 2945–2955.
Martin PD, Warwick MJ, Dane AL, Hill SJ, Giles PB, Phillips PJ et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther 2003; 25: 2822–2835.
Birmingham BK, Bujac SR, Elsby R, Azumaya CT, Wei C, Chen Y et al. Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States. Eur J Clin Pharmacol 2015; 71: 329–340.
Hua WJ, Hua WX, Fang HJ . The role of OATP1B1 and BCRP in pharmacokinetics and DDI of novel statins. Cardiovasc Ther 2012; 30: e234–e241.
Acknowledgements
We thank the Biogenomic Lab groups and all the volunteers who helped in the present investigation. The work was supported by grant and fellowships from the Brazilian governmental funds: CNPq, FAPERGS and CAPES.
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Duarte, T., da Cruz, I., Barbisan, F. et al. The effects of rosuvastatin on lipid-lowering, inflammatory, antioxidant and fibrinolytics blood biomarkers are influenced by Val16Ala superoxide dismutase manganese-dependent gene polymorphism. Pharmacogenomics J 16, 501–506 (2016). https://doi.org/10.1038/tpj.2015.91
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DOI: https://doi.org/10.1038/tpj.2015.91
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