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Mechanisms Underlying The Cardioprotective Effect of Inhibiting Soluble Epoxide Hydrolase

  • Author / Creator
    Akhnokh, Maria Kodsy
  • Ischemic heart Disease (IHD) remains a major cause of illness and death worldwide. Therefore, therapeutic agents to protect against myocardial ischemia are needed. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP) epoxygenase into the biologically active epoxyeicosatrienoic acids (EETs). EETs are further metabolized by soluble epoxide hydrolase (sEH) into the less active dihydroxyeicosatrienoic acid (DHET). Literature shows that sEH suppression and/or EETs maintain a cardioprotective effect by enhancing cell survivability and inhibiting cell death. However, the exact mechanism is still unknown. In this thesis, we investigated the potential mechanisms underlying the cardioprotective effect mediated by sEH inhibition in young mice. The main focus was to investigate if sEH suppression maintains mitochondrial efficiency after myocardial ischemia. sEH suppression was induced either pharmacologically by using sEH inhibitor or genetically by targeted deletion. Left anterior descending coronary artery (LAD) ligation was used to induce myocardial ischemia. Our results demonstrated that both pharmacological and genetic suppression of sEH mediate cardioprotective events through maintenance of mitochondrial efficiency. We showed that sEH inhibition prevents systolic dysfunction following ischemic injury by preserving the mitochondrial pool in the non-infarct region of the heart. Furthermore, inhibiting sEH preserved insulin sensitivity in post-MI hearts reflecting enhanced cardiac metabolism thereby suggesting there was activation of physiological recovery from ischemic insult.

  • Subjects / Keywords
  • Graduation date
    2015-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3MS3K664
  • 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
    Master's
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Seubert, John M (Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
    • Kassiri, Zamaneh (Physiology)
    • Ussher, John (Pharmacy and Pharmaceutical Sciences)