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

• Published in: Cardiovascular toxicology Vol. 18; no. 3; pp. 268 - 283
• Main Authors: Maayah, Zaid H., Abdelhamid, Ghada, Elshenawy, Osama H., El-Sherbeni, Ahmed A., Althurwi, Hassan N., McGinn, Erica, Dawood, Doaa, Alammari, Ahmad H., El-Kadi, Ayman O. S.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2018; Springer; Springer Nature B.V
• Subjects: Acids; Animals; Anthracycline; Antibiotics, Antineoplastic; Arachidonic acid; Benzoic acid; Biocompatibility; Biomedical and Life Sciences; Biomedicine; Carbonyls; Cardiology; Cardiomegaly - chemically induced; Cardiomegaly - enzymology; Cardiomegaly - pathology; Cardiomegaly - prevention & control; Cardiomyocytes; Cardiotoxicity; Cells, Cultured; Cytochrome; Cytochrome P-450; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Daunorubicin; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Enzymes; Epoxide hydrolase; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - genetics; Epoxide Hydrolases - metabolism; Ethylenediaminetetraacetic acid; Eutrophication; Fibrosis; Gene expression; Heart; Heart diseases; Humans; Hydrolases; Hydroxyeicosatetraenoic Acids - metabolism; In vivo methods and tests; Inhibition; Inhibitors; Ionization; Liquid chromatography; Male; Mass spectrometry; Mass spectroscopy; Metabolites; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; NF-kappa B p50 Subunit - metabolism; Organic acids; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology/Toxicology; Phosphorylation; Rats; Rats, Sprague-Dawley; Rodents; Signal Transduction; Staphylococcal enterotoxin H; Toxicity; Ventricle; NF-κB; RL-14 cells; Cytochrome P450; Soluble epoxide hydrolase; Rats; DNR; EETs
• ISSN: 1530-7905; 1559-0259
• DOI: 10.1007/s12012-017-9437-8

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.