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Mechanisms by Which Arachidonic acid Metabolite, Epoxyeicosatrienoic acid Elicit Cardioprotection Against Ischemic Reperfusion Injury Open Access


Other title
Plasma membrane ATP-sensitive potassium channels
Ischemia/Reperfusion injury
Epoxyeicosatrienoic acids
Phosphoinositide 3-kinase
Type of item
Degree grantor
University of Alberta
Author or creator
Supervisor and department
Dr. John Seubert (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Dr. Gavin Y. Oudit (Division of Cardiology, Faculty of Medicine and Dentistry)
Dr. Garrett J. Gross (Faculty Department of Pharmacology and Toxicology, Medical College of Wisconsin)
Dr. Peter Light (Department of Pharmacology, Faculty of Medicine and Dentistry)
Dr. Dion R. Brocks (Faculty of Pharmacy and Pharmaceutical Sciences)
Dr. Ayman El-Kadi (Faculty of Pharmacy and Pharmaceutical Sciences)
Faculty of Pharmacy and Pharmaceutical Sciences

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid that have cardioprotective properties but the exact mechanism(s) remains unknown. Evidence suggests phosphoinositide 3-kinase (PI3K) and plasma membraneATP-sensitive potassium channels (pmKATP) are important. However the role of the above two protective pathways and the corresponding intracellular cardioprotective mechanism involved is unknown. To investigate this, in the current study hearts from CYP2J2 transgenic mice or WT treated with either vehicle, EET, soluble epoxide hydrolase inhibitor or an EET analog (UA-8) were perfused in Langendorff mode for 40min of baseline and subjected to 20 or 30 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts with elevated EETs had improved ventricular functional recovery and reduced injury compared to WT hearts following ischemia/ reperfusion. Blocking of pmKATP channel activity abolished these EET mediated protective effects. Similarly inhibition of PI3K activity, either with the pan specific PI3K inhibitor wortmannin or class-I, PI3Kα specific inhibitor, PI-103, abolished the EET-mediated protective effect, but other PI3K isoform specific inhibitors failed to block the functional recovery. In addition to the improved post-ischemic functional recovery, increased expression of p-Akt an PI3K downstream target, decreased calcineurin activity, Ca2+ activated enzyme, and decreased translocation of proapoptotic protein BAD to mitochondria were noted in EET elevated hearts. All these protective actions of EETs were abolished when pmKATP channel activity was inhibited however, increased expression of p-Akt was still observed in these hearts, suggesting PI3K pathway is still active. Further in patch clamp experiments pre-treatment of myocytes with the PI3Kα inhibitor PI-103 significantly reduced the EET activation of pmKATP channels. Mechanistic studies using H9c2 cells demonstrate that EETs limit anoxia-reoxygenation triggered Ca2+ accumulation, decrease casapase-3 activity and maintain mitochondrial ΔΨm and decrease cell death compared to control. Both blocking of pmKATP channel and PI3Kα abolished EET mediated cytoprotection. Together our data suggest that EET-mediated cardioprotection involves activation of PI3Kα, upstream of pmKATP, which prevents Ca2+ overload and maintains mitochondrial function.
License granted by SRI NAGARJUN BATCHU ( on 2011-09-27T19:53:29Z (GMT): 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 the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein 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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