Top

Published in:

01-06-2018

The Role of Soluble Epoxide Hydrolase Enzyme on Daunorubicin-Mediated Cardiotoxicity

Authors: Zaid H. Maayah, Ghada Abdelhamid, Osama H. Elshenawy, Ahmed A. El-Sherbeni, Hassan N. Althurwi, Erica McGinn, Doaa Dawood, Ahmad H. Alammari, Ayman O. S. El-Kadi

Published in: Cardiovascular Toxicology | Issue 3/2018

Abstract

Several studies have demonstrated the role of cytochrome P450 (CYP) and its associated arachidonic acid (AA) metabolites in the anthracyclines-induced cardiac toxicity. However, the ability of daunorubicin (DNR) to induce cardiotoxicity through the modulation of CYP and its associated AA metabolites has not been investigated yet. Therefore, we hypothesized that DNR-induced cardiotoxicity is mediated through the induction of cardiotoxic hydroxyeicosatetraenoic acids and/or the inhibition of cardioprotctive epoxyeicosatrienoic acids (EETs). To test our hypothesis, Sprague–Dawley rats were treated with DNR (5 mg/kg i.p.) for 24 h, whereas human ventricular cardiomyocytes RL-14 cells were exposed to DNR in the presence and absence of 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB), a soluble epoxide hydrolase (sEH) inhibitor. Thereafter, real-time PCR, Western blot analysis and liquid chromatography-electron spray ionization mass spectroscopy were used to determine the level of gene expression, protein expression and AA metabolites, respectively. Our results showed that DNR-induced cardiotoxicity in vivo and in vitro as evidenced by the induction of hypertrophic and fibrotic markers. Moreover, the DNR-induced cardiotoxicity was associated with a dramatic increase in the formation of cardiac DHET/EET metabolites both in vivo and in RL-14 cells suggesting a sEH enzyme dependent mechanism. Interestingly, inhibition of sEH using tAUCB, a selective sEH inhibitor, significantly protects against DNR-induced cardiotoxicity. Mechanistically, the protective effect tAUCB was mediated through the induction of P50 nuclear factor-κB and the inhibition of phosphorylated p38. In conclusion, our study provides the first evidence that DNR induces cardiotoxicity through a sEH-mediated EETs degradation-dependent mechanism.

Minotti, G., Menna, P., Salvatorelli, E., Cairo, G., & Gianni, L. (2004). Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Reviews, 56, 185–229.CrossRefPubMed

Cernecka, H., Doka, G., Srankova, J., Pivackova, L., Malikova, E., Galkova, K., et al. (2016). Ramipril restores PPARbeta/delta and PPARgamma expressions and reduces cardiac NADPH oxidase but fails to restore cardiac function and accompanied myosin heavy chain ratio shift in severe anthracycline-induced cardiomyopathy in rat. European Journal of Pharmacology, 791, 244–253.CrossRefPubMed

Takemura, G., & Fujiwara, H. (2007). Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Progress in Cardiovascular Diseases, 49, 330–352.CrossRefPubMed

Deng, S., Yan, T., Jendrny, C., Nemecek, A., Vincetic, M., Godtel-Armbrust, U., et al. (2014). Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both topoisomerase II isoforms. BMC Cancer, 14, 842.CrossRefPubMedPubMedCentral

Roman, R. J. (2002). P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiological Reviews, 82, 131–185.CrossRefPubMed

Capdevila, J., Chacos, N., Werringloer, J., Prough, R. A., & Estabrook, R. W. (1981). Liver microsomal cytochrome P-450 and the oxidative metabolism of arachidonic acid. Proceedings of the National Academy of Sciences of the United States of America, 78, 5362–5366.CrossRefPubMedPubMedCentral

Maayah, Z. H., & El-Kadi, A. O. (2016). The role of mid-chain hydroxyeicosatetraenoic acids in the pathogenesis of hypertension and cardiac hypertrophy. Archives of Toxicology, 90, 119–136.CrossRefPubMed

Elshenawy, O. H., Anwar-Mohamed, A., & El-Kadi, A. O. (2013). 20-Hydroxyeicosatetraenoic acid is a potential therapeutic target in cardiovascular diseases. Current Drug Metabolism, 14, 706–719.CrossRefPubMed

Tacconelli, S., & Patrignani, P. (2014). Inside epoxyeicosatrienoic acids and cardiovascular disease. Frontiers in Pharmacology, 5, 239.CrossRefPubMedPubMedCentral

10.

Maayah, Z. H., & El-Kadi, A. O. (2016). 5-, 12- and 15-Hydroxyeicosatetraenoic acids induce cellular hypertrophy in the human ventricular cardiomyocyte, RL-14 cell line, through MAPK- and NF-kappaB-dependent mechanism. Archives of Toxicology, 90, 359–373.CrossRefPubMed

11.

Maayah, Z. H., Abdelhamid, G., & El-Kadi, A. O. (2015). Development of cellular hypertrophy by 8-hydroxyeicosatetraenoic acid in the human ventricular cardiomyocyte, RL-14 cell line, is implicated by MAPK and NF-kappaB. Cell Biology and Toxicology, 31, 241–259.CrossRefPubMed

12.

Elshenawy, O. H., Anwar-Mohamed, A., Abdelhamid, G., & El-Kadi, A. O. (2013). Murine atrial HL-1 cell line is a reliable model to study drug metabolizing enzymes in the heart. Vascular Pharmacology, 58, 326–333.CrossRefPubMed

13.

Maayah, Z. H., Althurwi, H. N., El-Sherbeni, A. A., Abdelhamid, G., Siraki, A. G., & El-Kadi, A. O. (2017). The role of cytochrome P450 1B1 and its associated mid-chain hydroxyeicosatetraenoic acid metabolites in the development of cardiac hypertrophy induced by isoproterenol. Molecular and Cellular Biochemistry, 429, 151–165.CrossRefPubMed

14.

Althurwi, H. N., Elshenawy, O. H., & El-Kadi, A. O. (2014). Fenofibrate modulates cytochrome P450 and arachidonic acid metabolism in the heart and protects against isoproterenol-induced cardiac hypertrophy. Journal of Cardiovascular Pharmacology, 63, 167–177.CrossRefPubMed

15.

Imig, J. D., Zhao, X., Capdevila, J. H., Morisseau, C., & Hammock, B. D. (2002). Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Hypertension, 39, 690–694.CrossRefPubMed

16.

Althurwi, H. N., Tse, M. M., Abdelhamid, G., Zordoky, B. N., Hammock, B. D., & El-Kadi, A. O. (2013). Soluble epoxide hydrolase inhibitor, TUPS, protects against isoprenaline-induced cardiac hypertrophy. British Journal of Pharmacology, 168, 1794–1807.CrossRefPubMedPubMedCentral

17.

Althurwi, H. N., Maayah, Z. H., Elshenawy, O. H., & El-Kadi, A. O. (2015). Early changes in cytochrome P450 s and their associated arachidonic acid metabolites play a crucial role in the initiation of cardiac hypertrophy induced by isoproterenol. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 43, 1254–1266.CrossRef

18.

Maayah, Z. H., Althurwi, H. N., Abdelhamid, G., Lesyk, G., Jurasz, P., & El-Kadi, A. O. (2016). CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a mid-chain HETEs-dependent mechanism. Pharmacological Research, 105, 28–43.CrossRefPubMed

19.

Alsaad, A. M., Zordoky, B. N., El-Sherbeni, A. A., & El-Kadi, A. O. (2012). Chronic doxorubicin cardiotoxicity modulates cardiac cytochrome P450-mediated arachidonic acid metabolism in rats. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 40, 2126–2135.CrossRef

20.

Zordoky, B. N., Anwar-Mohamed, A., Aboutabl, M. E., & El-Kadi, A. O. (2010). Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats. Toxicology and Applied Pharmacology, 242, 38–46.CrossRefPubMed

21.

Zordoky, B. N., Aboutabl, M. E., & El-Kadi, A. O. (2008). Modulation of cytochrome P450 gene expression and arachidonic acid metabolism during isoproterenol-induced cardiac hypertrophy in rats. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 36, 2277–2286.CrossRef

22.

Maayah, Z. H., Ansari, M. A., El Gendy, M. A., Al-Arifi, M. N., & Korashy, H. M. (2014). Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway. Archives of Toxicology, 88, 725–738.PubMed

23.

Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25, 402–408.CrossRefPubMed

24.

Chun, Y. J., Kim, S., Kim, D., Lee, S. K., & Guengerich, F. P. (2001). A new selective and potent inhibitor of human cytochrome P450 1B1 and its application to antimutagenesis. Cancer Research, 61, 8164–8170.PubMed

25.

El-Sherbeni, A. A., & El-Kadi, A. O. (2014). Characterization of arachidonic acid metabolism by rat cytochrome P450 enzymes: The involvement of CYP1As. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 42, 1498–1507.CrossRef

26.

Liu, Y., Peterson, D. A., Kimura, H., & Schubert, D. (1997). Mechanism of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Journal of Neurochemistry, 69, 581–593.CrossRefPubMed

27.

Sambrook, J., Fritsch, E. F., & Maniatatis, T. (1989). In N. Ford (Ed.), Molecular cloning. A laboratory manual. Plainview, NY: Cold Spring Harbour Laboratory Press.

28.

Andrews, N. C., & Faller, D. V. (1991). A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Research, 19, 2499.CrossRefPubMedPubMedCentral

29.

Bhattacharya, N., Sarno, A., Idler, I. S., Fuhrer, M., Zenz, T., Dohner, H., et al. (2010). High-throughput detection of nuclear factor-kappaB activity using a sensitive oligo-based chemiluminescent enzyme-linked immunosorbent assay. International Journal of Cancer, 127, 404–411.PubMed

30.

Horenstein, M. S., Vander Heide, R. S., & L’Ecuyer, T. J. (2000). Molecular basis of anthracycline-induced cardiotoxicity and its prevention. Molecular Genetics and Metabolism, 71, 436–444.CrossRefPubMed

31.

Cusack, B. J., Young, S. P., & Olson, R. D. (1995). Daunorubicin and daunorubicinol pharmacokinetics in plasma and tissues in the rat. Cancer Chemotherapy and Pharmacology, 35, 213–218.CrossRefPubMed

32.

Freireich, E. J., Gehan, E. A., Rall, D. P., Schmidt, L. H., & Skipper, H. E. (1966). Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemotherapy Reports, 50, 219–244.PubMed

33.

Urbanova, D., Bubanska, E., Hrebik, M., & Mladosievicova, B. (2010). Heart transplant in a childhood leukemia survivor: A case report. Experimental and Clinical Transplantation: Official Journal of the Middle East Society for Organ Transplantation, 8, 79–81.

34.

Urbanova, D., Urban, L., Danova, K., & Simkova, I. (2008). Natriuretic peptides: Biochemical markers of anthracycline cardiac toxicity? Oncology Research, 17, 51–58.CrossRefPubMed

35.

Shan, K., Lincoff, A. M., & Young, J. B. (1996). Anthracycline-induced cardiotoxicity. Annals of Internal Medicine, 125, 47–58.CrossRefPubMed

36.

Bryant, J., Picot, J., Levitt, G., Sullivan, I., Baxter, L., & Clegg, A. (2007). Cardioprotection against the toxic effects of anthracyclines given to children with cancer: A systematic review. Health Technology Assessment, 11, 1–84.CrossRef

37.

Chen, C., Heusch, A., Donner, B., Janssen, G., Gobel, U., & Schmidt, K. G. (2009). Present risk of anthracycline or radiation-induced cardiac sequelae following therapy of malignancies in children and adolescents. Klinische Padiatrie, 221, 162–166.CrossRefPubMed

38.

Lencova-Popelova, O., Jansova, H., Jirkovsky, E., Bures, J., Jirkovska-Vavrova, A., Mazurova, Y., et al. (2016). Are cardioprotective effects of NO-releasing drug molsidomine translatable to chronic anthracycline cardiotoxicity settings? Toxicology, 372, 52–63.CrossRefPubMed

39.

Fatkin, D., McConnell, B. K., Mudd, J. O., Semsarian, C., Moskowitz, I. G., Schoen, F. J., et al. (2000). An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. The Journal of Clinical Investigation, 106, 1351–1359.CrossRefPubMedPubMedCentral

40.

Kiriazis, H., & Kranias, E. G. (2000). Genetically engineered models with alterations in cardiac membrane calcium-handling proteins. Annual Review of Physiology, 62, 321–351.CrossRefPubMed

41.

Locher, M. R., Razumova, M. V., Stelzer, J. E., Norman, H. S., & Moss, R. L. (2011). Effects of low-level α-myosin heavy chain expression on contractile kinetics in porcine myocardium. American Journal of Physiology. Heart and Circulatory Physiology, 300, H869–H878.CrossRefPubMedPubMedCentral

42.

Neckar, J., Kopkan, L., Huskova, Z., Kolar, F., Papousek, F., Kramer, H. J., et al. (2012). Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension. Clinical Science, 122, 513–525.CrossRefPubMedPubMedCentral

43.

Zhang, Y., El-Sikhry, H., Chaudhary, K. R., Batchu, S. N., Shayeganpour, A., Jukar, T. O., et al. (2009). Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity. American Journal of Physiology: Heart and Circulatory Physiology, 297, H37–H46.PubMedPubMedCentral

44.

Yang, S., Lin, L., Chen, J. X., Lee, C. R., Seubert, J. M., Wang, Y., et al. (2007). Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-alpha via MAPK and PI3K/Akt signaling pathways. American Journal of Physiology: Heart and Circulatory Physiology, 293, H142–H151.CrossRefPubMedPubMedCentral

45.

Zordoky, B. N., Anwar-Mohamed, A., Aboutabl, M. E., & El-Kadi, A. O. (2011). Acute doxorubicin toxicity differentially alters cytochrome P450 expression and arachidonic acid metabolism in rat kidney and liver. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 39, 1440–1450.CrossRef

46.

Liu, L., Chen, C., Gong, W., Li, Y., Edin, M. L., Zeldin, D. C., et al. (2011). Epoxyeicosatrienoic acids attenuate reactive oxygen species level, mitochondrial dysfunction, caspase activation, and apoptosis in carcinoma cells treated with arsenic trioxide. The Journal of Pharmacology and Experimental Therapeutics, 339, 451–463.CrossRefPubMedPubMedCentral

47.

Kroetz, D. L., & Zeldin, D. C. (2002). Cytochrome P450 pathways of arachidonic acid metabolism. Current Opinion in Lipidology, 13, 273–283.CrossRefPubMed

48.

Spector, A. A. (2009). Arachidonic acid cytochrome P450 epoxygenase pathway. Journal of Lipid Research, 50(Suppl), S52–S56.CrossRefPubMedPubMedCentral

49.

Zhao, X., Pollock, D. M., Inscho, E. W., Zeldin, D. C., & Imig, J. D. (2003). Decreased renal cytochrome P450 2C enzymes and impaired vasodilation are associated with angiotensin salt-sensitive hypertension. Hypertension, 41, 709–714.CrossRefPubMed

50.

Luo, G., Zeldin, D. C., Blaisdell, J. A., Hodgson, E., & Goldstein, J. A. (1998). Cloning and expression of murine CYP2Cs and their ability to metabolize arachidonic acid. Archives of Biochemistry and Biophysics, 357, 45–57.CrossRefPubMed

51.

Yu, Z., Xu, F., Huse, L. M., Morisseau, C., Draper, A. J., Newman, J. W., et al. (2000). Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circulation Research, 87, 992–998.CrossRefPubMed

52.

Morisseau, C., & Hammock, B. D. (2005). Epoxide hydrolases: Mechanisms, inhibitor designs, and biological roles. Annual Review of Pharmacology and Toxicology, 45, 311–333.CrossRefPubMed

53.

Xu, D., Li, N., He, Y., Timofeyev, V., Lu, L., Tsai, H. J., et al. (2006). Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors. Proceedings of the National Academy of Sciences of the United States of America, 103, 18733–18738.CrossRefPubMedPubMedCentral

54.

Imig, J. D., & Hammock, B. D. (2009). Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nature Reviews Drug Discovery, 8, 794–805.CrossRefPubMedPubMedCentral

55.

Pearson, G., Robinson, F., Beers Gibson, T., Xu, B. E., Karandikar, M., Berman, K., et al. (2001). Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions. Endocrine Reviews, 22, 153–183.PubMed

56.

Li, S. E. M., Mingyan, E., & Yu, B. (2008). Adriamycin induces myocardium apoptosis through activation of nuclear factor kappaB in rat. Molecular Biology Reports, 35, 489–494.CrossRefPubMed

57.

Ai, D., Pang, W., Li, N., Xu, M., Jones, P. D., Yang, J., et al. (2009). Soluble epoxide hydrolase plays an essential role in angiotensin II-induced cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 106, 564–569.CrossRefPubMedPubMedCentral

58.

Liu, Y., Dang, H., Li, D., Pang, W., Hammock, B. D., & Zhu, Y. (2012). Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice. PLoS ONE, 7, e39165.CrossRefPubMedPubMedCentral

59.

Frantz, S., Hu, K., Bayer, B., Gerondakis, S., Strotmann, J., Adamek, A., et al. (2006). Absence of NF-kappaB subunit p50 improves heart failure after myocardial infarction. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 20, 1918–1920.CrossRef

60.

Timmers, L., van Keulen, J. K., Hoefer, I. E., Meijs, M. F., van Middelaar, B., den Ouden, K., et al. (2009). Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction. Circulation Research, 104, 699–706.CrossRefPubMed

61.

Gaspar-Pereira, S., Fullard, N., Townsend, P. A., Banks, P. S., Ellis, E. L., Fox, C., et al. (2012). The NF-kappaB subunit c-Rel stimulates cardiac hypertrophy and fibrosis. The American Journal of Pathology, 180, 929–939.CrossRefPubMedPubMedCentral

62.

Liu, Y., Webb, H. K., Fukushima, H., Micheli, J., Markova, S., Olson, J. L., et al. (2012). Attenuation of cisplatin-induced renal injury by inhibition of soluble epoxide hydrolase involves nuclear factor kappaB signaling. The Journal of Pharmacology and Experimental Therapeutics, 341, 725–734.CrossRefPubMedPubMedCentral

63.

Wessells, J., Baer, M., Young, H. A., Claudio, E., Brown, K., Siebenlist, U., et al. (2004). BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. The Journal of Biological Chemistry, 279, 49995–50003.CrossRefPubMed

64.

Sawyer, D. B., Fukazawa, R., Arstall, M. A., & Kelly, R. A. (1999). Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Circulation Research, 84, 257–265.CrossRefPubMed

65.

Dragojew, S., Marczak, A., Maszewski, J., Ilnicki, K., & Jozwiak, Z. (2008). The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cellular & Molecular Biology Letters, 13, 182–194.CrossRef

66.

Masquelier, M., Zhou, Q. F., Gruber, A., & Vitols, S. (2004). Relationship between daunorubicin concentration and apoptosis induction in leukemic cells. Biochemical Pharmacology, 67, 1047–1056.CrossRefPubMed

Title: The Role of Soluble Epoxide Hydrolase Enzyme on Daunorubicin-Mediated Cardiotoxicity
Authors: Zaid H. Maayah
Ghada Abdelhamid
Osama H. Elshenawy
Ahmed A. El-Sherbeni
Hassan N. Althurwi
Erica McGinn
Doaa Dawood
Ahmad H. Alammari
Ayman O. S. El-Kadi
Publication date: 01-06-2018
Publisher: Springer US
Published in: Cardiovascular Toxicology / Issue 3/2018
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-017-9437-8

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

The Role of Soluble Epoxide Hydrolase Enzyme on Daunorubicin-Mediated Cardiotoxicity

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2018

Serum miR-30c Level Predicted Cardiotoxicity in Non-small Cell Lung Cancer Patients Treated with Bevacizumab

Inhibition of the Voltage-Dependent K+ Current by the Tricyclic Antidepressant Desipramine in Rabbit Coronary Arterial Smooth Muscle Cells

A Fatal Case of Amlodipine Toxicity Following Iatrogenic Hypercalcemia

Beneficial Role of Some Natural Products to Attenuate the Diabetic Cardiomyopathy Through Nrf2 Pathway in Cell Culture and Animal Models

In vivo Analysis of the Anti-atrial Fibrillatory, Proarrhythmic and Cardiodepressive Profiles of Dronedarone as a Guide for Safety Pharmacological Evaluation of Antiarrhythmic Drugs

Alleviation of Cardiac Damage by Dietary Fenugreek (Trigonella foenum-graecum) Seeds is Potentiated by Onion (Allium cepa) in Experimental Diabetic Rats via Blocking Renin–Angiotensin System

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page