The Effect Of Simvastatin On Nitric oxide Synthase Activity In Vascular Endothelial Cell Line (HUVEC)
Subject Areas :
Journal of Animal Biology
Seyede Fatemeh Hosseini
1
,
Tahereh Naji
2
,
Rahim Ahmadi
3
1 - Department of Pharmacy and Pharmaceutical Sciences, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
2 - Department of Pharmacy and Pharmaceutical Sciences, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
3 - Department of Physiology, Hamadan Branch, Islamic Azad University, Hamadan, Iran
Received: 2020-11-17
Accepted : 2021-05-05
Published : 2021-11-22
Keywords:
Simvastatin,
Nitric Oxide Synthase Enzyme,
HUVEC (Vascular Endothelial Cell,
Abstract :
Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A Reductase inhibitor widely used in lowering cholesterol levels.This study was aimed at assessing the effect of simvastatin on the activity of nitric oxide synthase in the vascular endothelial cell line HUVEC. MTT method was used to evaluate the effect of simvastatin on HUVEC vascular endothelial cell line. The effect of simvastatin on iNOS gene expression in HUVEC vascular endothelial cell line was investigated using real-time PCR technique. The effect of Simvastatin on the activity of endothelial nitric oxide synthase was investigated using grease colorimetry. With increasing Simvastatin concentration, the survival of HUVEC vascular endothelial cells decreased compared to the control group (P≤0.05). In addition, the expression of INOS enzyme gene in the group receiving 55 µl/ml of simvastatin was significantly different and increased compared to the control group (P≤0.05). Simvastatin at concentrations higher than 125 µl/ml simvastatin was not significantly different from the control group. However, at lower concentrations (62, 31, and 16 µl/ml), a significant difference was observed and increased compared to the control group (P≤0.05). Considering the decrease in the level of endothelial nitric oxide synthase and its effects on human diseases, especially cardiovascular diseases, the use of simvastatin can be helpful in patients exposed to disease due to endothelial nitric oxide dysfunction..
References:
Ahmed A.M. 2017. Inhibition of inducible nitric oxide synthase (iNOS) by simvastatin attenuates cardiac hypertrophy in rats. Folia Morphologica, 76(1): 15-27.
Albrecht E.W.J.A, Stegeman C.A, Heeringa P. 2003. Protective role of endothelial nitric oxide synthase. Journal of Pathology, 199: 8.
Amin-Hanjani S., Stagliano N.E., Yamada M. 2001. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke, 32: 980-986.
Arnal J.F., Dinh-Xuan A.T., Pueyo M. 1999. Endothelium-derived nitric oxide and vascular physiology and pathology. Cellular and Molecular Life Sciences, 55: 1078-1087.
Baspınar O., Bayram F., Korkmaz S., 2016. The effects of statin treatment on adrenal and sexual function and nitric oxide levels in hypercholesterolemic male patients treated with a statin. Journal of Clinical Lipidology, 10(6): 1452-1461.
Blauw G.J., Lagaay A.M., Smelt A. H, 1997. New strategies for prevention of ischemic stroke: The life study. Speringer, 28: 946-950.
Bocan T.M.A, Mazur M.J, Muller E.Q. 1994. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation. Atherosclerosis, 111: 127-142.
Conde K., Roy S., Freake H.C., 1999. Atorvastatin and simvastatin have distinct effects on hydroxy methylglutaryl-CoA reductase activity and mRNA abundance in the guinea pig. Lipids, 34(12): 1327-1332.
Endres M, Laufs U, Huang Z, et al. 1998. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proceedings of the National Academy of Sciences of USA, 95: 8880-8885.
Feron O., Dessy C., Moniotte S. 1999. Hypercholesterolemia decreases nitric oxide production bypromoting the interaction of caveolin and endothelial nitric oxide synthase. Clinical Investigation Journal, 103: 897-905.
Goldstein J.L, Brown M.S. 1990. Regulation of the mevalonate pathway. Nature, 343: 425-430.
Grünler J., Ericsson J., Dallner G. 1994. Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins. Biochimica et Biophysica Acta, 1212: 259-277.
Hariyanto B., Kusnanto P., Purwanto B. 2019. The Effect of Simvastatin on Nitric Oxide and hs-CRP Levels in patients with Liver Cirrhosis at Dr. Moewardi Hospital, Surakarta. Indonesian Journal of Medicine, 4(1): 9-14.
Hebert P. R, Gaziano J. M, Chan K. S, et al. 1997. American. Medical Association, 27: 313-321.
Hernández-Perera O., Pérez-Sala D., Navarro-Antolin J. 1998. Effects of the 3-hydroxy-3-methylglutaryl-Co Areductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. Journal of Clinical Investigation, 101: 2711-2719.
Ho M.L, Chen Y.H., Liao H.J. 2009. Simvastatin increases osteoblasts and osteogenic proteins in ovariectomized rats. European Journal of Clinical Investigation, 39(4): 296-303.
Huang P.H, Chou R.H, Tsai H.Y. 2019. Biphasic effects of HMG-CoA reductase inhibitor, simvastatin, on angiogenesis through endothelial nitric-oxide synthase-dependent pathway. Strait Circulation Journal, 1(1): 7.
Ignarro L.J, Buga G.M, Wood K.S, 1987. Endothelium derived relaxing factor produced and released from artery and vein is nitric oxide, Proceedings of the National Academy of Sciences of USA, 84: 9265.
Ignarro L.J. 1990. Nitric oxide. A novel signal transduction mechanism for transcellular communication. Hypertension,16: 477-83.
Ignarro L.J. 1990. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochemical and Biophysical Research Communications, 170(2): 843-850.
Johnson‐Anuna L. N, Eckert G. P, Franke C 2007. Simvastatin protects neurons from cytotoxicity by up‐regulating Bcl‐2 mRNA and protein. Journal of Neurochemistry, 101(1): 77-86.
Mason R. P, Dawoud H, Jacob R. F, et al. 2018. Eicosapentaenoic acid improves endothelial function and nitric oxide bioavailability in a manner that is enhanced in combination with a statin. Biomedicine and Pharmacotherapy, 103: 1231-1237.
McGirt MJ, Lynch JR, Parra A, et al. 2002. Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke, 33: 2950-2956.
Meininger C.J., Marinos R.S., Hatakeyama K, et al. 2000. Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency, Biochemistry Journal, 349(1): 353-356.
Naoum J. J, Zhang S, Woodside K. J, et al. 2004. Aortic eNOS expression and phosphorylation in Apo-E knockout mice: differing effects of rapamycin and simvastatin. Surgery, 136(2): 323-328.
Packard C.J., Klein C.B. 1998. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation, 97: 1440-1445.
Palmer R.M.J, Ferrige A.G, Moncada S. 1987. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature, 327: 524-526.
Panza J.A. 1997. Endothelial dysfunction in essential hypertension. Clinical Cardiology, 20: 26-33.
Risé P., Ghezzi S., Carissimi R. 2007. Δ5 desaturase mRNA levels are increased by simvastatin via SREBP-1 at early stages, not via PPARα, in THP-1 cells. European Journal of Pharmacology, 571(2-3): 97-105.
Sacks F.M., Pfeffer M.A., Moye L.A., Rouleau J.L., Rutherford J.D. 1996. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. England Journal Medicine, 335(14): 1001-1009.
Scandinavian Simvastatin Survival Study Group. 1994. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Simvastatin Survival Study Group. Lancet, 344: 1389-1383.
Shepherd J., Cobbe S.M., Ford I., 1995. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. England Journal of Medicine, 333: 1301-1307.
Stockklauser-Farber K., Ballhausen T., Laufer A. 2000. Influence of diabetes on cardiac nitric oxide synthase expression and activity. Biochimica et Biophysica Acta, 1535(1): 10-20.
Witztum J.L. 1996. Drugs used in the treatment of hyper lipoproteinemias. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics. J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, and A.G. Gilman, editors. McGraw-Hill, New York, 875-897.
Yamaç A. H, Kılıç Ü. 2018. Effect of statins on sirtuin 1 and endothelial nitric oxide synthase expression in young patients with a history of premature myocardial infarction. Journal of Turkish Society Cardiology, 46(3): 205-215.
_||_