Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Upregulation of Beta 1 and Arachidonic Acid Metabolizing Enzymes in the Mouse Hearts and Kidneys after Sub Chronic Administration of Rofecoxib

Author(s): Noor Askar, Yazun Jarrar*, Munir Gharaibeh and Mohammad Alqudah

Volume 16, Issue 3, 2023

Published on: 10 August, 2022

Article ID: e130422203477 Pages: 12

DOI: 10.2174/1874467215666220413085316

Price: $65

Abstract

Background: An imbalance in the levels of arachidonic acid (ARA) metabolites in cardiovascular disorders and drug-induced cardiotoxicity have been previously described.

Aims: This study aimed to investigate the influence of cyclooxygenase-2 (COX-2) selective inhibitors on the gene expression of ARA-metabolizing genes and beta1 gene in the hearts and kidneys of experimental mice.

Methods: Thirty-five balb/c mice were divided into five groups with seven mice per group. The groups were then given two distinct types of COX-2 selective inhibitors, rofecoxib and celecoxib, in two different doses equivalent to those used in human treatment for 30 days. The mRNA expression of beta1, ace2, and ARA-metabolizing genes, coxs, lipoxygenases (aloxs), and cytochrome p450 (cyp450s) in mice heart and kidneys were assessed. Genes were analyzed using real-time polymerase chain reaction analysis. In addition, rofecoxib-induced histological alterations were examined.

Results: It was found that only the high dose of rofecoxib (5 mg/kg) caused toxicological alterations, a finding that was indicated by a significant increase (P < 0.05) in the relative weight of the mouse hearts and increase in the ventricle wall thickness as observed through pathohistological examination. This increase was associated with a significant increase in the mRNA expression level of the beta1 receptor in both the heart and kidneys of the mice (53- and 12-fold, respectively). The expression of both cox1 and 2 genes was increased 4-fold in the kidneys. In addition, the expression of the alox12 gene increased significantly (by 67-fold in the heart and by 21-fold in the kidney), while alox15 gene expression was upregulated in the heart by 8-fold and 5-fold in the kidney. The genes responsible for synthesizing 20- Hydroxyeicosatetraenoic acid (cyp4a12 and cyp1a1) were significantly upregulated (P < 0.05) in the hearts of high-dose rofecoxib-treated mice by 7- and 17 -fold, respectively. In addition, the expression of epoxyeicosatrienoic acid-synthesizing genes, cyp2c29 and cyp2j5, was increased significantly (P < 0.05) in the hearts of high-dose rofecoxib-treated mice by 4- and 16-fold, respectively.

Conclusion: Rofecoxib caused upregulation of the mRNA expression of the beta 1 gene in association with increased expression of ARA-metabolizing genes in mouse hearts and kidneys. These findings may help us understand the molecular cardiotoxic mechanism of rofecoxib.

Keywords: Arachidonic acid, beta1, cardiotoxicity, gene expression, NSAIDs, rofecoxib.

Graphical Abstract
[1]
Sinha, M.; Gautam, L.; Shukla, P.K.; Kaur, P.; Sharma, S.; Singh, T.P. Current perspectives in NSAID-induced gastropathy. Mediators Inflamm., 2013, 2013, 258209.
[http://dx.doi.org/10.1155/2013/258209] [PMID: 23576851]
[2]
Crofford, L.J. Use of NSAIDs in treating patients with arthritis. Arthritis Res. Ther., 2013, 15(Suppl. 3), S2.
[http://dx.doi.org/10.1186/ar4174] [PMID: 24267197]
[3]
Gunter, B.R.; Butler, K.A.; Wallace, R.L.; Smith, S.M.; Harirforoosh, S. Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis. J. Clin. Pharm. Ther., 2017, 42(1), 27-38.
[http://dx.doi.org/10.1111/jcpt.12484] [PMID: 28019014]
[4]
Bacchi, S.; Palumbo, P.; Sponta, A.; Coppolino, M.F. Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. Antiinflamm. Antiallergy Agents Med. Chem., 2012, 11(1), 52-64.
[http://dx.doi.org/10.2174/187152312803476255] [PMID: 22934743]
[5]
Antman, E.M.; Bennett, J.S.; Daugherty, A.; Furberg, C.; Roberts, H.; Taubert, K.A. Use of nonsteroidal antiinflammatory drugs: An update for clinicians: a scientific statement from the American Heart Association. Circulation, 2007, 115(12), 1634-1642.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.181424] [PMID: 17325246]
[6]
Ghosh, R.; Alajbegovic, A.; Gomes, A.V. NSAIDs and cardiovascular diseases: Role of reactive oxygen species. Oxid. Med. Cell. Longev., 2015, 2015, 536962.
[http://dx.doi.org/10.1155/2015/536962]
[7]
Chou, R; Helfand, M; Peterson, K; Dana, T; Roberts, C. Drug Class review on cyclo-oxygenase (COX)-2 inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs). Final Report Update 2006, 3
[8]
Davies, N.M.; Jamali, F. COX-2 selective inhibitors cardiac toxicity: getting to the heart of the matter. J. Pharm. Pharm. Sci., 2004, 7(3), 332-336.
[PMID: 15576013]
[9]
Liu, J-Y.; Li, N.; Yang, J.; Li, N.; Qiu, H.; Ai, D.; Chiamvimonvat, N.; Zhu, Y.; Hammock, B.D. Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events. Proc. Natl. Acad. Sci. USA, 2010, 107(39), 17017-17022.
[http://dx.doi.org/10.1073/pnas.1011278107] [PMID: 20837537]
[10]
Jarrar, Y.B.; Jarrar, Q.; Abed, A.; Abu-Shalhoob, M. Effects of nonsteroidal anti-inflammatory drugs on the expression of arachidonic acid-metabolizing Cyp450 genes in mouse hearts, kidneys and livers. Prostaglandins Other Lipid Mediat., 2019, 141, 14-21.
[http://dx.doi.org/10.1016/j.prostaglandins.2019.02.003] [PMID: 30763676]
[11]
Waldman, M.; Peterson, S.J.; Arad, M.; Hochhauser, E. The role of 20-HETE in cardiovascular diseases and its risk factors. Prostaglandins Other Lipid Mediat., 2016, 125, 108-117.
[http://dx.doi.org/10.1016/j.prostaglandins.2016.05.007] [PMID: 27287720]
[12]
Drolet, B.; Pilote, S.; Gélinas, C.; Kamaliza, A-D.; Blais-Boilard, A.; Virgili, J.; Patoine, D.; Simard, C. altered protein expression of cardiac CYP2J and Hepatic CYP2C, CYP4A, and CYP4F in a mouse model of type II diabetes-a link in the onset and development of cardiovascular disease? Pharmaceutics, 2017, 9(4), 44.
[http://dx.doi.org/10.3390/pharmaceutics9040044] [PMID: 29023376]
[13]
Rocic, P.; Schwartzman, M.L. 20-HETE in the regulation of vascular and cardiac function. Pharmacol. Ther., 2018, 192, 74-87.
[http://dx.doi.org/10.1016/j.pharmthera.2018.07.004] [PMID: 30048707]
[14]
Bellien, J.; Joannides, R. Epoxyeicosatrienoic acid pathway in human health and diseases. J. Cardiovasc. Pharmacol., 2013, 61(3), 188-196.
[http://dx.doi.org/10.1097/FJC.0b013e318273b007] [PMID: 23011468]
[15]
Tacconelli, S.; Patrignani, P. Inside epoxyeicosatrienoic acids and cardiovascular disease. Front. Pharmacol., 2014, 5, 239.
[http://dx.doi.org/10.3389/fphar.2014.00239] [PMID: 25426071]
[16]
Seubert, J.M.; Zeldin, D.C.; Nithipatikom, K.; Gross, G.J. Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury. Prostaglandins Other Lipid Mediat., 2007, 82(1-4), 50-59.
[http://dx.doi.org/10.1016/j.prostaglandins.2006.05.017] [PMID: 17164132]
[17]
Theken, K.N.; Deng, Y.; Kannon, M.A.; Miller, T.M.; Poloyac, S.M.; Lee, C.R. Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism. Drug Metab. Dispos., 2011, 39(1), 22-29.
[http://dx.doi.org/10.1124/dmd.110.035287] [PMID: 20947618]
[18]
Alsaad, A.M.; Zordoky, B.N.; El-Sherbeni, A.A.; El-Kadi, A.O. Chronic doxorubicin cardiotoxicity modulates cardiac cytochrome P450-mediated arachidonic acid metabolism in rats. Drug Metab. Dispos., 2012, 40(11), 2126-2135.
[http://dx.doi.org/10.1124/dmd.112.046631] [PMID: 22867862]
[19]
Aghazadeh-Habashi, A.; Asghar, W.; Jamali, F. Drug-disease interaction: effect of inflammation and nonsteroidal anti-inflammatory drugs on cytochrome P450 metabolites of arachidonic acid. J. Pharm. Sci., 2018, 107(2), 756-763.
[http://dx.doi.org/10.1016/j.xphs.2017.09.020] [PMID: 28989019]
[20]
Bernstein, D.; Fajardo, G.; Zhao, M.; Urashima, T.; Powers, J.; Berry, G.; Kobilka, B.K. Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes. Am. J. Physiol. Heart Circ. Physiol., 2005, 289(6), H2441-H2449.
[http://dx.doi.org/10.1152/ajpheart.00005.2005] [PMID: 16040722]
[21]
Fajardo, G.; Zhao, M.; Urashima, T.; Farahani, S.; Hu, D-Q.; Reddy, S.; Bernstein, D. Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice. J. Mol. Cell. Cardiol., 2013, 63, 155-164.
[http://dx.doi.org/10.1016/j.yjmcc.2013.07.016] [PMID: 23920331]
[22]
Vasić M.; Lončar-Turukalo, T.; Tasić T.; Matić M.; Glumac, S.; Bajić D.; Popović B.; Japundžić-Žigon, N. Cardiovascular variability and β-ARs gene expression at two stages of doxorubicin - Induced cardiomyopathy. Toxicol. Appl. Pharmacol., 2019, 362, 43-51.
[http://dx.doi.org/10.1016/j.taap.2018.10.015] [PMID: 30342983]
[23]
Olfert, ED; Cross, BM; McWilliam, AA Guide to the care and use of experimental animals: Canadian Council on Animal Care Ottawa. 1993.
[24]
Reagan-Shaw, S.; Nihal, M.; Ahmad, N. Dose translation from animal to human studies revisited. FASEB J., 2008, 22(3), 659-661.
[http://dx.doi.org/10.1096/fj.07-9574LSF] [PMID: 17942826]
[25]
Hou, F.; Li, S.; Wang, J.; Kang, X.; Weng, Y.; Xing, G. Identification and validation of reference genes for quantitative real-time PCR studies in long yellow daylily, Hemerocallis citrina Borani. PLoS One, 2017, 12(3), e0174933.
[http://dx.doi.org/10.1371/journal.pone.0174933] [PMID: 28362875]
[26]
Fanelli, A.; Ghisi, D.; Aprile, P.L.; Lapi, F. Cardiovascular and cerebrovascular risk with nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 inhibitors: latest evidence and clinical implications. Ther. Adv. Drug Saf., 2017, 8(6), 173-182.
[http://dx.doi.org/10.1177/2042098617690485] [PMID: 28607667]
[27]
Varga, Z. rafay ali Sabzwari S, Vargova V. Cardiovascular risk of nonsteroidal anti-inflammatory drugs: an under-recognized public health issue. Cureus, 2017, 9(4), e1144.
[28]
Tacconelli, S.; Bruno, A.; Grande, R.; Ballerini, P.; Patrignani, P. Nonsteroidal anti-inflammatory drugs and cardiovascular safety - translating pharmacological data into clinical readouts. Expert Opin. Drug Saf., 2017, 16(7), 791-807.
[http://dx.doi.org/10.1080/14740338.2017.1338272] [PMID: 28569569]
[29]
Park, K.; Bavry, A.A. Risk of stroke associated with nonsteroidal anti-inflammatory drugs. Vasc. Health Risk Manag., 2014, 10, 25-32.
[PMID: 24421643]
[30]
Gudbjornsson, B.; Thorsteinsson, S.B.; Sigvaldason, H.; Einarsdottir, R.; Johannsson, M.; Zoega, H.; Halldorsson, M.; Thorgeirsson, G. Rofecoxib, but not celecoxib, increases the risk of thromboembolic cardiovascular events in young adults-a nationwide registry-based study. Eur. J. Clin. Pharmacol., 2010, 66(6), 619-625.
[http://dx.doi.org/10.1007/s00228-010-0789-2] [PMID: 20157701]
[31]
Arber, N.; Eagle, C.J.; Spicak, J.; Rácz, I.; Dite, P.; Hajer, J.; Zavoral, M.; Lechuga, M.J.; Gerletti, P.; Tang, J.; Rosenstein, R.B.; Macdonald, K.; Bhadra, P.; Fowler, R.; Wittes, J.; Zauber, A.G.; Solomon, S.D.; Levin, B. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med., 2006, 355(9), 885-895.
[http://dx.doi.org/10.1056/NEJMoa061652] [PMID: 16943401]
[32]
Subih, M.; Al-Kalaldeh, M.; Salami, I.; Al-Hadid, L.; Abu-Sharour, L. Predictors of uncertainty among postdischarge coronary artery bypass graft patients in Jordan. J. Vasc. Nurs., 2018, 36(2), 85-90.
[http://dx.doi.org/10.1016/j.jvn.2017.11.001] [PMID: 29747788]
[33]
Mason, R.P.; Walter, M.F.; McNulty, H.P.; Lockwood, S.F.; Byun, J.; Day, C.A.; Jacob, R.F. Rofecoxib increases susceptibility of human LDL and membrane lipids to oxidative damage: a mechanism of cardiotoxicity. J. Cardiovasc. Pharmacol., 2006, 47(Suppl. 1), S7-S14.
[http://dx.doi.org/10.1097/00005344-200605001-00003] [PMID: 16785833]
[34]
Wang, B.; Wu, L.; Chen, J.; Dong, L.; Chen, C.; Wen, Z.; Hu, J.; Fleming, I.; Wang, D.W. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct. Target. Ther., 2021, 6(1), 94.
[http://dx.doi.org/10.1038/s41392-020-00443-w] [PMID: 33637672]
[35]
Pavoine, C.; Magne, S.; Sauvadet, A.; Pecker, F. Evidence for a beta2-adrenergic/arachidonic acid pathway in ventricular cardiomyocytes. Regulation by the beta1-adrenergic/camp pathway. J. Biol. Chem., 1999, 274(2), 628-637.
[http://dx.doi.org/10.1074/jbc.274.2.628] [PMID: 9872996]
[36]
FitzGerald, G.A.; Patrono, C. The coxibs, selective inhibitors of cyclooxygenase-2. N. Engl. J. Med., 2001, 345(6), 433-442.
[http://dx.doi.org/10.1056/NEJM200108093450607] [PMID: 11496855]
[37]
Arora, M.; Choudhary, S.; Singh, P.K.; Sapra, B.; Silakari, O. Structural investigation on the selective COX-2 inhibitors mediated cardiotoxicity: A review. Life Sci., 2020, 251, 117631.
[http://dx.doi.org/10.1016/j.lfs.2020.117631] [PMID: 32251635]
[38]
Mason, P.J.; Jacobs, A.K.; Freedman, J.E. Aspirin resistance and atherothrombotic disease. J. Am. Coll. Cardiol., 2005, 46(6), 986-993.
[http://dx.doi.org/10.1016/j.jacc.2004.08.070] [PMID: 16168280]
[39]
Niederberger, E.; Tegeder, I.; Schäfer, C.; Seegel, M.; Grösch, S.; Geisslinger, G. Opposite effects of rofecoxib on nuclear factor-kappaB and activating protein-1 activation. J. Pharmacol. Exp. Ther., 2003, 304(3), 1153-1160.
[http://dx.doi.org/10.1124/jpet.102.044016] [PMID: 12604692]
[40]
Catani, M.V.; Savini, I.; Duranti, G.; Caporossi, D.; Ceci, R.; Sabatini, S.; Avigliano, L. Nuclear factor kappaB and activating protein 1 are involved in differentiation-related resistance to oxidative stress in skeletal muscle cells. Free Radic. Biol. Med., 2004, 37(7), 1024-1036.
[http://dx.doi.org/10.1016/j.freeradbiomed.2004.06.021] [PMID: 15336319]
[41]
Ikei, K.N.; Yeung, J.; Apopa, P.L.; Ceja, J.; Vesci, J.; Holman, T.R.; Holinstat, M. Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation. J. Lipid Res., 2012, 53(12), 2546-2559.
[http://dx.doi.org/10.1194/jlr.M026385] [PMID: 22984144]
[42]
Zheng, Z.; Li, Y.; Jin, G.; Huang, T.; Zou, M.; Duan, S. The biological role of arachidonic acid 12-lipoxygenase (ALOX12) in various human diseases. Biomed. Pharmacother., 2020, 129, 110354.
[http://dx.doi.org/10.1016/j.biopha.2020.110354] [PMID: 32540644]
[43]
Harats, D.; Shaish, A.; George, J.; Mulkins, M.; Kurihara, H.; Levkovitz, H.; Sigal, E. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol., 2000, 20(9), 2100-2105.
[http://dx.doi.org/10.1161/01.ATV.20.9.2100] [PMID: 10978255]
[44]
Roman, R.J. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev., 2002, 82(1), 131-185.
[http://dx.doi.org/10.1152/physrev.00021.2001] [PMID: 11773611]
[45]
Zordoky, B.N.; El-Kadi, A.O. Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases. Pharmacol. Ther., 2010, 125(3), 446-463.
[http://dx.doi.org/10.1016/j.pharmthera.2009.12.002] [PMID: 20093140]
[46]
Deng, Y.; Theken, K.N.; Lee, C.R. Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation. J. Mol. Cell. Cardiol., 2010, 48(2), 331-341.
[http://dx.doi.org/10.1016/j.yjmcc.2009.10.022] [PMID: 19891972]
[47]
Jarrar, Y.B.; Cho, S-A.; Oh, K-S.; Kim, D-H.; Shin, J-G.; Lee, S-J. Identification of cytochrome P450s involved in the metabolism of arachidonic acid in human platelets. Prostaglandins Leukot. Essent. Fatty Acids, 2013, 89(4), 227-234.
[http://dx.doi.org/10.1016/j.plefa.2013.06.008] [PMID: 23932368]
[48]
Inoue, K.; Sodhi, K.; Puri, N.; Gotlinger, K.H.; Cao, J.; Rezzani, R.; Falck, J.R.; Abraham, N.G.; Laniado-Schwartzman, M. Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE. Am. J. Physiol. Renal Physiol., 2009, 297(4), F875-F884.
[http://dx.doi.org/10.1152/ajprenal.00364.2009] [PMID: 19675180]
[49]
Singh, H.; Cheng, J.; Deng, H.; Kemp, R.; Ishizuka, T.; Nasjletti, A.; Schwartzman, M.L. Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension. Hypertension, 2007, 50(1), 123-129.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.089599] [PMID: 17548721]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy