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Permanent link (DOI): https://doi.org/10.7939/R3ZW75

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Mechanisms of epoxyeicosatrienoic acid-induced cardioprotection Open Access

Descriptions

Other title
Subject/Keyword
Cytochrome P450
Aging
Cardioprotection
Ischemia reperfusion injury
Epoxyeicosatrienoic acids
soluble epoxide hydrolase
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Chaudhary, Ketul R
Supervisor and department
Seubert, John M (Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Jurasz, Paul (Pharmacy and Pharmaceutical Sciences)
Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
Seubert, John (Pharmacy and Pharmaceutical Sciences)
Dyck, Jason (Pediatric)
Lee, Craig (Eshelman School of Pharmacy, University of North Carolina)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
Pharmaceutical Sciences
Date accepted
2012-05-11T15:11:29Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Ischemic heart disease remains a major cause of illness, disability and death worldwide, as such there remains a need for novel pharmacological agents that protect against myocardial ischemia reperfusion (I/R) injury. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase metabolites of arachidonic acid, which have demonstrated protective properties against cardiac I/R injury. However, the exact mechanism(s) of cardioprotection remains unknown. The work presented in this thesis investigated potential mechanisms underlying EET-induced cardioprotection in young and aged animal models. I/R injury was examine in the Langendorff isolated perfused heart model. Key results demonstrate that preventing EET-removal by inhibiting soluble epoxide hydolase (sEH), with sEH inhibitor (sEHi) or targeted deletion (sEH null), improves left ventricular functional (LVDP) recovery and reduce injury following I/R. The improved postischemic recovery was blocked by phosphoinositide 3-kinase (PI3K) inhibitors. Data demonstrated that increased B-type natriuretic peptide (BNP) mRNA and protein expression in sEH null and EET-perfused wild type (WT) hearts. Moreover, perfusion with BNP receptor antagonist attenuated the improved postischemic LVDP recovery. Increased expression of activated PKCε and Akt were found in WT hearts perfused with either 11,12-EET or BNP. In addition, treatment with the PI3K inhibitor (wortmannin) abolished improved postishcemic functional recovery in 11,12-EET treated hearts but not of BNP treated hearts. In the final study, data demonstrates that EET-induced cardioprotection remains effective in aged mice. Importantly, aging is a major risk factor for development of IHD and increases susceptibility to I/R injury. Furthermore, many cardioprotective strategies become ineffective in aged animals. Interesting data from aged mice demonstrated that the cardiomyocyte specific over-expression of CYP2J2 (CYP2J2 Tr) reduces the cardioprotective response. The loss of cardioprotection in aged CYP2J2 Tr was attributed to increased linoleic metabolite (DiHOME), oxidative stress and decreased protein phosphatase 2a activation. Moreover, all these effects and loss of cardioprotection in aged CYP2J2 Tr mice can be prevented by sEHi. In summary, results from this thesis clearly demonstrate EETs protect the heart against I/R injury and the protective effects are mediated through BNP and PI3K pathway. In addition, we demonstrate the effectiveness of EETs and sEHi in protecting the heart against I/R injury in aged animals.
Language
English
DOI
doi:10.7939/R3ZW75
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. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. 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.
Citation for previous publication
Chaudhary KR, Batchu SN, Das D, Suresh MR, Falck JR, Graves JP, Zeldin DC, Seubert JM. Role of B-type natriuretic peptide in epoxyeicosatrienoic acid-mediated improved post-ischaemic recovery of heart contractile function. Cardiovasc Res. 2009 Jul 15;83(2):362-70.Chaudhary KR, Batchu SN, Seubert JM. Cytochrome P450 enzymes and the heart. IUBMB Life. 2009 Oct;61(10):954-60.Chaudhary KR, Abukhashim M, Hwang SH, Hammock BD, Seubert JM. Inhibition of soluble epoxide hydrolase by trans-4- [4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid is protective against ischemia-reperfusion injury. J Cardiovasc Pharmacol. 2010 Jan;55(1):67-73

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