Abstract
Free oxygen radicals and insufficient antioxidant enzymes have been implicated in the pathogenesis of hypercholesterolemia (HC). Trace elements function as cofactors in antioxidant enzymes. Antioxidant system and trace elements were investigated in many different studies including HC, but these subjects have not been investigated as a whole in these patients. The aim of the present study was to investigate the antioxidative system and trace elements in hypercholesterolemic patients given fluvastatin therapy.
We examined malondialdehyde (MDA), copper zinc-superoxide dismutase (CuZn-SOD), and glutathione peroxidase (GSH-Px) activities together with copper (Cu), iron (Fe), and zinc (Zn) levels in erythrocytes of 35 patients with HC and 27 healthy control subjects. It was found that in patients with HC, erythrocyte MDA was significantly higher than those of controls and erythrocyte CuZn-SOD and GSH-Px activities were significantly lower in patients with HC. Erythrocyte iron levels were significantly higher than those of controls, and erythrocyte copper and zinc levels were significantly lower in patients with HC. Plasma lipid levels and the oxidative state were analyzed in statin-treatment groups given fluvastatin therapy before and after a 3-mo treatment period.
In conclusion, we found that fluvastatin has significant antioxidant properties and these effects might be very important in managing dyslipidemia by improving endothelial function.
Similar content being viewed by others
References
W. Palinski and S. Tsimikas, Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis, J. Am. Soc. Nephrol. 13(6), 1673–1681 (2002).
S. Wolfrum, K. S. Jensen, and J. K. Liao, Endothelium-dependent effects of statins, Arterioscler. Thromb. Vasc. Biol. 27, 729–736 (2003).
L. J. Ignarro, C. Napoli, and J. Loscalzo, Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview, Circ. Res. 90, 21–28 (2002).
A. M. Gotto, Jr, Statin therapy: where are we? where do we go next? Am. J. Cardiol. 87, 13B-18B (2001).
C. Guijarro, L. M. Blanco-Colio, M. Ortego, et al., 3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture, Circ. Res. 83, 490–500 (1998).
L. Liu, P. Moesner, N. L. Kovach, et al., Integrin-dependent leukocyte adhesion involves geranylgeranylated protein(s), J. Biol. Chem. 274, 33,334–33,340 (1999).
F. M. Sacks, M. A. Pfeffer, L. A. Moye, et al., The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators, N. Engl. J. Med. 335, 1001–1009 (1996).
M. Essig, G. Nguyen, D. Prie, et al., 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells: role of geranylgeranylation and Rho proteins, Circ. Res. 37, 683–690 (1998).
U. Laufs, K. Gertz, P. Huang, et al., Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice, Stroke 31, 2442–2449 (2000).
S. Wassmann, U. Laufs, A. T. Baumer, et al., HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species, Hypertension 37, 1450–7145 (2001).
S. I. McFarlane, R. Muniyappa, R. Francisco, et al., Clinical review 145. Pleiotropic effects of statins: lipid reduction and beyond, J. Clin. Endocrinol. Metab. 87(4), 1451–1458 (2002).
F. Galli, F. Canestrari, and G. Bellomo, Pathophysiology of the oxidative stress and its implication in uremia and dialysis, in Vitamin E-Bonded Membrane. A Further Step in Dialysis Optimization, C. Ronco and G. La Greca (eds.), Contributions in Nephrology, Vol. 27, Karger, Basel, pp. 1–31 (1999).
J. Hopkins and G. R. Tudhope, Glutathione peroxidase in human red cells in health and disease, Br. J. Haematol. 25, 563–575 (1973).
J. Nève, Methods in determination of selenium states, J. Trace Elements Electrolytes Health Dis. 5, 1–17 (1991).
N. W. Alcock, Trace elements, in Clinical Chemistry, 3rd ed., L. A. Kaplan and A. J. Pesce (eds.), Mosby-Year Book, St. Louis, MO, p. 746 (1996).
J. Aaseth and T. Norsth, Copper, in Handbook on the Toxicology of Metals, L. Friberg, G. F. Nordberg, and V. B. Vouk (eds.), Elsevier, New York, Vol. II, pp. 233–249 (1986).
J. H. Kramer, T. Mak, and W. B. Weblicki, Differential sensitivity of canine cardiac sarcolemmal and microsomal enzymes to inhibition by free radical induced lipid peroxidation, Circ. Res. 55, 120–124 (1984).
S. U. Rajguru, G. S. Yeargans, and N. W. Seidler, Exercise causes oxidative damage to rat skeletal muscle microsomes while increasing cellular sulphydryls, Life Sci. 54, 149–157 (1993).
V. Nair, G. A. Turner, and R. J. Offerman, Novel adducts from the modification of nucleic acid bases by malondialdehyde, J. Am. Chem. Soc. 106, 3370–3371 (1984).
A. Aydin, H. Orhan, A. Sayal, et al., Oxidative stress and nitric oxide related parameters in type II diabetes mellitus: effects of glycemic control, Clin. Biochem. 34, 65–70 (2001).
S. K. Jain, Hyperglycemia can cause membrane lipid peroxidation and osmotic fragility in human red blood cells, J. Biol. Chem. 264, 21,340–21,345 (1989).
S. Taddel, A. Virdis, L. Ghiadoni, et al., Effects of hypertensive drugs on endothelial dysfunction: clinical implications, Drugs 62(2), 265–284 (2002).
H. Sies, Oxidative stress: introductory remarks, in Oxidative Stress, H. Sies (ed.), Academic, Orlando, FL, p. 1 (1985).
M. N. Diaz, B. Frei, J. A. Vita, et al., Antioxidants and atherosclerotic heart disease, N. Engl. J. Med. 337, 408 (1997).
M. L. Kennedy, M. L. Failla, and J. C. Smith, Jr., Influence of genetic obesity on tissue concentrations of zinc, copper, manganese, and iron in mice, J. Nutr. 116, 1432–1441 (1986).
S. Delbosc, M. Morena, F. Djouad, et al., 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes, J. Cardiovasc. Pharmacol. 40(4), 611–617 (2002).
R. De Caterina, F. Cipollone, F. P. Filardo, et al., Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in hypercholesterolemic subjects: no further effect of vitamin E, Circulation 106(20), 2543–2549 (2002).
J. Beltowski, G. Wojcicka, M. Mydlarczyk, et al., Cerivastatin modulates plasma paraoxonase/arylesterase activity and oxidant-antioxidant balance in the rat, Pol. J. Pharmacol. 54(2), 143–150 (2002).
R. E. Wildman and S. Mao, Tissue-specific alterations in lipoprotein lipase activity in copper-deficient rats, Biol. Trace Element Res. 80(3), 221–229 (2001).
M. Fields and C. G. Lewis, Level of dietary iron, not type of dietary fat, is hyperlipidemic in copper-deficient rats, Am. Coll. Nutr. 18(4), 353–357 (1999).
D. J. Lamb, G. L. Reeves, A. Taylor, et al., Dietary copper supplementation reduces atherosclerosis in the cholesterol-fed rabbit, Atherosclerosis 146(1), 33–43 (1999).
A. E. Say, M. Gursurer, M. V. Yazicioglu, et al., Impact of body iron status on myocardial perfusion, left ventricular function, and angiographic morphologic features in patients with hypercholesterolemia, Am. Heart J. 143(2), 257–264 (2002).
R. G. Weginwar, S. Enomoto, R. Hirunuma, et al., Correlation between serum cholesterols and trace element uptake in liver, kidney, and blood of hypercholesterolemic mice, Biol. Trace Element Res. 86(3), 249–268 (2002).
J. Delattre, S. Lepage, M. C. Jaudon, et al., The plasma antioxidant status and trace elements in patients with familial hypercholesterolemia treated with LDL-apheresis, Ann. Pharm. Fr. 56(1), 18–25 (1998).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yilmaz, M.I., Baykal, Y., Kilic, M. et al. Effects of statins on oxidative stress. Biol Trace Elem Res 98, 119–127 (2004). https://doi.org/10.1385/BTER:98:2:119
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/BTER:98:2:119