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Permanent link (DOI): https://doi.org/10.7939/R3MS3K664

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Mechanisms Underlying The Cardioprotective Effect of Inhibiting Soluble Epoxide Hydrolase Open Access

Descriptions

Other title
Subject/Keyword
Cardiac metabolism
sEH inhibition
Mitochondria
Myocardial ischemia
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Akhnokh, Maria Kodsy
Supervisor and department
Seubert, John M (Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
Ussher, John (Pharmacy and Pharmaceutical Sciences)
Kassiri, Zamaneh (Physiology)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2015-09-30T09:25:33Z
Graduation date
2015-11
Degree
Master of Science
Degree level
Master's
Abstract
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.
Language
English
DOI
doi:10.7939/R3MS3K664
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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