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THE ROLE OF CYTOCHROME P450 AND THEIR ASSOCIATED ARACHIDONIC ACID METABOLITES IN THE INITIATION AND PROGRESSION OF CARDIAC HYPERTROPHY

  • Author / Creator
    Althurwi, Hassan N
  • Heart failure (HF) is the leading cause of mortality and disability in adults worldwide. Cardiac hypertrophy is an independent risk factor and one of the major hallmarks of HF. Research in cardiac hypertrophy is considered as a research into the early events in the development of HF. The expression of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) enzymes has been identified in the heart and their levels have been reported to be altered during cardiac hypertrophy and HF. The role of CYP enzymes in cardiac hypertrophy emerge from their ability to metabolize arachidonic acid to the cardioprotective epoxyeicosatrienoic acids (EETs) and the cardiotoxic 20-hydroxyeicosatetraenoic acid (20-HETE) metabolites. Therefore, the objective of the present work was to investigate the role of CYP enzymes, sEH, and CYP-derived arachidonic acid metabolites in the pathogenesis of cardiac hypertrophy. Our results show that cardiac hypertrophy was initiated after 72 hours and 6 hours of isoproterenol treatment in rat and human fetal ventricular cell line, RL-14, respectively. Studies performed at the prehypertrophy phase showed decreases in the expression of CYP epoxygenases and an induction of sEH activity. Consequently, lower EET and higher dihydroxyeicosatrienoic acid (DHETs) levels were observed prior to cardiac enlargement. On the other hand, isoproterenol caused an induction of CYP1A1, CYP1B1, CYP2B1, CYP2B2, CYP4A3 and CYP4F4 expression during the established phase of cardiac hypertrophy, which consequently led to lower levels of EETs and higher levels of 20-HETE. Interestingly, inhibition of sEH by 1-(1-methanesulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) attenuated the progression of cardiac hypertrophy and fibrosis induced by isoproterenol. Moreover, TUPS significantly inhibited the isoproterenol-mediated effects on CYP enzymes and their associated metabolites. Furthermore, we showed that fenofibrate significantly induced the cardiac expression of CYP epoxygenases such as CYP2B1, CYP2B2, CYP2C11, and CYP2C23, whereas it decreased the expression of the cardiac ω-hydroxylase CYP4A3. Consequently, fenofibrate significantly increased the formation of cardiac EETs whereas it decreased the cardiac level of 20-HETE. Interestingly, fenofibrate significantly decreased the hypertrophic markers and the increase in heart-to-body weight ratio induced by isoproterenol. Finally, we showed that increasing EET levels by induction of CYP epoxygenases, sEH inhibition, or exogenous administration of EET prevented the initiation of cardiac hypertrophy through a nuclear factor-kB-mediated mechanism. Taken together, these findings reveal a crucial role of CYP, sEH, and CYP-mediated arachidonic acid metabolism in the initiation and progression of cardiac hypertrophy, which may lead to discovery of novel targets for the prevention of HF at an early stage.

  • Subjects / Keywords
  • Graduation date
    2016-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3QB9VB21
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • PHARMACEUTICAL SCIENCES
  • Supervisor / co-supervisor and their department(s)
    • El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Anderson, Hope (Faculty of Pharmacy & Department of Pharmacology & Therapeutics, University of Manitoba)
    • Marsh, Sharon (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Jurasz, Paul (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Brocks, Dion (Faculty of Pharmacy and Pharmaceutical Sciences)
    • Baker, Glen (Department of Psychiatry)