Increased expression and catalytic activity of prostacyclin synthase after simvastatin application to human umbilical vein endothelial cells

Authors

  • Sun-Ah Cho Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan
  • Su-Jun Lee Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University, Busan https://orcid.org/0000-0002-3570-0598

DOI:

https://doi.org/10.2298/ABS201028050C

Keywords:

prostacyclin, prostacyclin synthase, CYP8A1, simvastatin, CAR, cardiovascular disease

Abstract

Paper description:

  • This study investigates whether prostacyclin synthase (PGIS) is induced by statins in human umbilical vein endothelial cells (HUVEC).
  • The cells were exposed to five structurally different statins (atorvastatin, simvastatin, pravastatin, lovastatin and rosuvastatin), and the expression and catalytic activity of PGIS was investigated.
  • Simvastatin induced PGIS expression at both transcriptional and translational levels, with increased prostacyclin metabolite synthesis.
  • This finding provides a novel basis for understanding inter-individual variations of prostacyclin levels in humans.

Abstract: In addition to lowering blood cholesterol levels, statins are known to exert antiplatelet effects. One of the key factors contributing to the antiplatelet effects of statins includes the upregulation of prostacyclin (PGI2) level. The present study was undertaken to determine the effects of statins on prostacyclin synthase (PGIS, CYP8A1) and PGI2 synthesis at the molecular level. Human umbilical vein endothelial cells (HUVEC) were exposed to five structurally different statins (atorvastatin, simvastatin, pravastatin, lovastatin, and rosuvastatin) and changes in CYP8A1 expression levels and the metabolic activities of CYP8A1 were investigated. Among the tested statins, simvastatin induced significant PGIS expression at both transcriptional (2.9-fold, P<0.05) and translational (1.8-fold, P<0.05) levels. Treatment with a constitutive androstane receptor (CAR) agonist, phenobarbital, significantly increased CYP8A1 mRNA expression (3-fold, P<0.01). A metabolite of prostacyclin, 6-keto prostaglandin F1α, was significantly increased by treatment with simvastatin (P<0.01) and markedly repressed by the CYP8A1 inhibitor tranylcypromine (P<0.01) and the CAR antagonist clotrimazole (P<0.01) in HUVEC. The results of this study improve our understanding of the inter-individual variations in PGI2 levels. Clinical studies in humans are necessary to confirm the present in vitro results.

Downloads

Download data is not yet available.

References

Alghamdi J, Alqadi A, Alharf A, Almuzzaini B, Mahmud A, Barhoumi T, Badreldin HA, Alaamery M, Sandosh Padmanabhan S. Blood pressure-lowering activity of statins: a systematic literature review and meta-analysis of placebo-randomized controlled trials. Eur J Clin Pharmacol. 2020;76:174-54.

Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010;121(2):306-14.

Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;2013(1):Cd004816.

Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf. 2011;10(3):373-87.

Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med. 2008;359(8):789-99.

Pleiner J, Schaller G, Mittermayer F, Zorn S, Marsik C, Polterauer S, Kapiotis S, Wolzt M. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation. 2004;110(21):3349-54.

Notarbartolo A, Davì G, Averna M, Barbagallo CM, Ganci A, Giammarresi C, Placa La FP, Patrono C. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15(2):247-51.

Levine L. Statins stimulate arachidonic acid release and prostaglandin I2 production in rat liver cells. Lipids Health Dis. 2003;2:1.

Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97(12):1129-35.

Santos MT, Fuset MP, Ruano M, Moscardó A, Valles J. Effect of atorvastatin on platelet thromboxane A(2) synthesis in aspirin-treated patients with acute myocardial infarction. Am J Cardiol. 2009;104(12):1618-23.

Vane JR, Botting RM. Pharmacodynamic profile of prostacyclin. Am J Cardiol. 1995;75(3):3a-10a.

FitzGerald GA, Smith B, Pedersen AK, Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med. 1984;310(17):1065-8.

Kobayashi K, Yamanaka Y, Iwazaki N, Nakajo I, Hosokawa M, Negishi M, Chiba K. Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor. Drug Metab Dispos. 2005;33(7):924-9.

Oates JA, FitzGerald GA, Branch RA, Jackson EK, Knapp HR, Roberts LJ, 2nd. Clinical implications of prostaglandin and thromboxane A2 formation (2). N Engl J Med. 1988;319(12):761-7.

Nakayama T, Soma M, Rehemudula D, Takahashi Y, Tobe H, Satoh M, Uwabo J, Kunimoto M, Kanmatsuse K. Association of 5' upstream promoter region of prostacyclin synthase gene variant with cerebral infarction. Am J Hypertens. 2000;13(12):1263-7.

Iwai N, Katsuya T, Ishikawa K, Mannami T, Ogata J, Higaki J, Ogihara T, Tanabe T, Baba S. Human prostacyclin synthase gene and hypertension : the Suita Study. Circulation. 1999;100(22):2231-6.

Nakayama T, Soma M, Rahmutula D, Izumi Y, Kanmatsuse K. Nonsense mutation of prostacyclin synthase gene in a family. Lancet. 1997;349(9069):1887-8.

Nakayama T, Soma M, Saito S, Honye J, Yajima J, Rahmutula D, Kaneko Y, Sato M, Uwabo J, Aoi N, Kosuge K, Kunimoto M, Kanmatsuse K, Kokubun S. Association of a novel single nucleotide polymorphism of the prostacyclin synthase gene with myocardial infarction. Am Heart J. 2002;143(5):797-801.

Xie X, Ma YT, Fu ZY, Yang YN, Ma X, Chen BD, Wang YH, Liu F. Association of polymorphisms of PTGS2 and CYP8A1 with myocardial infarction. Clin Chem Lab Med. 2009;47(3):347-52.

Skogastierna C, Björkhem-Bergman L, Bergman P, Eliasson E, Rane A, Ekström L. Influence of simvastatin on the thromboxane and prostacyclin pathways, in vitro and in vivo. J Cardiovasc Pharmacol. 2013;61(1):1-7.

Bertrand-Thiebault C, Masson C, Siest G, Batt AM, Visvikis-Siest S. Effect of HMGCoA reductase inhibitors on cytochrome P450 expression in endothelial cell line. J Cardiovasc Pharmacol. 2007;49(5):306-15.

Nakayama T, Soma M, Izumi Y, Kanmatsuse K. Organization of the human prostacyclin synthase gene. Biochem Biophys Res Commun. 1996;221(3):803-6.

Breuer HW. Hypertriglyceridemia: a review of clinical relevance and treatment options: focus on cerivastatin. Curr Med Res Opin. 2001;17(1):60-73.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-8.

Wada M, Yokoyama C, Hatae T, Shimonishi M, Nakamura M, Imai Y, Ullrich V, Tanabe T. Purification and characterization of recombinant human prostacyclin synthase. J Biochem. 2004;135(4):455-63.

Cho SA, Rohn-Glowacki KJ, Jarrar YB, Yi M, Kim WY, Shin JG, Lee SJ. Analysis of genetic polymorphism and biochemical characterization of a functionally decreased variant in prostacyclin synthase gene (CYP8A1) in humans. Arch Biochem Biophys. 2015;569:10-8.

Matys V, Kel-Margoulis OV, Fricke E, Liebich I, Land S, Barre-Dirrie A, Reuter I, Chekmenev D, Krull M, Hornischer K, Voss N, Stegmaier P, Lewicki-Potapov B, Saxel H, Kel AE, Wingender E. TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 2006;34(Database issue):D108-10.

Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. Jama. 2001;286(1):64-70.

Pirro M, Simental-Mendía LE, Bianconi V, Watts GF, Banach M, Sahebkar A. Effect of Statin Therapy on Arterial Wall Inflammation Based on 18F-FDG PET/CT: A Systematic Review and Meta-Analysis of Interventional Studies. J Clin Med. 2019;8(1):118.

Chruściel P, Sahebkar A, Rembek-Wieliczko M, Serban MC, Ursoniu S, Mikhailidis DP, Jones SR, Mosteoru S, Blaha MJ, Martin SS, Rysz J, Toth PP, Lip GYH, Pencina MJ, Ray KK, Banach M, Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Impact of statin therapy on plasma adiponectin concentrations: A systematic review and meta-analysis of 43 randomized controlled trial arms. Atherosclerosis. 2016;253:194-208.

Wassmann S, Wassmann K, Nickenig G. Modulation of oxidant and antioxidant enzyme expression and function in vascular cells. Hypertension. 2004;44(4):381-6.

Ortego M, Bustos C, Hernández-Presa MA, Tuñón J, Díaz C, Hernández G, Egido J. Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis. 1999;147(2):253-61.

Komukai M, Wajima YS, Tashiro J, Shinomiya M, Saito Y, Morisaki N. Carvastatin suppresses intimal thickening of rabbit carotid artery after balloon catheter injury probably through the inhibition of vascular smooth muscle cell proliferation and migration. Scand J Clin Lab Invest. 1999;59(3):159-66.

Huang HC, Wang SS, Lee JY, Chen YC, Lee FY, Lin HC, Chang CC, Lee SD. Simvastatin effects on portal-systemic collaterals of portal hypertensive rats. J Gastroenterol Hepatol. 2010;25(8):1401-9.

Kobayashi K, Hashimoto M, Honkakoski P, Negishi M. Regulation of gene expression by CAR: an update. Arch Toxicol. 2015;89(7):1045-55.

Chen Y, Goldstein JA. The transcriptional regulation of the human CYP2C genes. Curr Drug Metab. 2009;10(6):567-78.

Ozen G, Norel X. Prostanoids in the pathophysiology of human coronary artery. Prostaglandins Other Lipid Mediat. 2017;133:20-8.

Fisslthaler B, Michaelis UR, Randriamboavonjy V, Busse R, Fleming I. Cytochrome P450 epoxygenases and vascular tone: novel role for HMG-CoA reductase inhibitors in the regulation of CYP 2C expression. Biochim Biophys Acta. 2003;1619(3):332-9.

Dauchy S, Miller F, Couraud PO, Weaver RJ, Weksler B, Romero IA, Scherrmann JM, Waziers ID, Decleves X. Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells. Biochem Pharmacol. 2009;77(5):897-909.

Swales KE, Moore R, Truss NJ, Tucker A, Warner TD, Negishi M, Bishop-Bailey D. Pregnane X receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress. Cardiovasc Res. 2012;93(4):674-81.

Moore LB, Parks DJ, Jones SA, Bledsoe RK, Consler TG, Stimmel JB, Goodwin B, Liddle C, Blanchard SG, Willson TM, Collins JL, Kliewer SA. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J Biol Chem. 2000;275(20):15122-7.

Fetalvero KM, Martin KA, Hwa J. Cardioprotective prostacyclin signaling in vascular smooth muscle. Prostaglandins Other Lipid Mediat. 2007;82(1-4):109-18.

Nakayama T. Genetic polymorphisms of prostacyclin synthase gene and cardiovascular disease. Int Angiol. 2010;29(2 Suppl):33-42.

Downloads

Published

2020-12-25

How to Cite

1.
Cho S-A, Lee S-J. Increased expression and catalytic activity of prostacyclin synthase after simvastatin application to human umbilical vein endothelial cells. Arch Biol Sci [Internet]. 2020Dec.25 [cited 2022Aug.7];72(4):567-74. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/6039

Issue

Section

Articles