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

Cardiovasc Toxicol. 2018 Jun;18(3):268-283. doi: 10.1007/s12012-017-9437-8.

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.

Keywords: Cytochrome P450; DNR; EETs; NF-κB; RL-14 cells; Rats; Soluble epoxide hydrolase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic*
  • Cardiomegaly / chemically induced*
  • Cardiomegaly / enzymology*
  • Cardiomegaly / pathology
  • Cardiomegaly / prevention & control
  • Cardiotoxicity
  • Cells, Cultured
  • Cytochrome P-450 Enzyme System / metabolism
  • Daunorubicin*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Epoxide Hydrolases / antagonists & inhibitors
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / metabolism*
  • Fibrosis
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Male
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • NF-kappa B p50 Subunit / metabolism
  • Phosphorylation
  • Rats, Sprague-Dawley
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • NF-kappa B p50 Subunit
  • Cytochrome P-450 Enzyme System
  • p38 Mitogen-Activated Protein Kinases
  • Epoxide Hydrolases
  • EPHX2 protein, human
  • EPHX2 protein, rat
  • Daunorubicin

Grant support