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Permanent link (DOI): https://doi.org/10.7939/R3X923

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Cardioprotection by Drug-Induced Changes in Glucose and Glycogen Metabolism Open Access

Descriptions

Other title
Subject/Keyword
isolated perfused working rat heart
myocardial glycolysis
phosphofructokinase
protein phosphatases
Myocardial glycogen metabolism
glycogen synthase kinase-3
p38 mitogen-activated protein kinase
myocardial glucose uptake
5'AMP-activated protein kinase
Myocardial energy substrate metabolism
Myocardial Ischemia/reperfusion injury
adenosine
Myocardial glucose metabolism
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Omar, Mohamed Abdalla
Supervisor and department
Clanachan, AS (Pharmacology)
Examining committee member and department
Dyck, JRB (Pediatrics)
Light, PE (Pharmacology)
Seubert, J (Pharmacy)
Mcneill, J (Faculty of Pharmaceutical Sciences, University of British Columbia)
Department
Department of Pharmacology
Specialization

Date accepted
2011-11-01T22:14:57Z
Graduation date
2012-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Myocardial energy substrate metabolism is subjected to significant changes during ischemia and reperfusion (I/R), which can greatly influence post-ischemic recovery of left-ventricular (LV) mechanical function. One of the main mechanisms that contribute to I/R injury is the accumulation of protons and resultant Ca2+ overload, which occurs mainly as a result of uncoupling of glycolysis and glucose oxidation. Pharmacological interventions that improve the coupling between glycolysis and glucose oxidation are of particular interest. In this thesis, we focus on the role of partitioning of glucose between different metabolic pathways on post-ischemic recovery of LV mechanical function. We examine different approaches to limit excessive glycolysis during reperfusion and identify various targets in the glycolytic pathway that can be modulated to protect against myocardial I/R injury. Utilizing the isolated perfused working rat heart model, we demonstrate that pre-ischemic glycogen content is an important determinant factor controlling ischemia-induced changes in glucose metabolism. Our results challenge current dogma by demonstrating that ischemia-induced activation of 5’AMP-activated protein kinase (AMPK) results in accelerated glucose uptake only under conditions where pre-ischemic glycogen is depleted while in hearts with replenished pre-ischemic glycogen, ischemia-induced activation of glycogenolysis supplies sufficient substrate for glycolysis without the need to stimulate glucose uptake. Furthermore, we show that inhibition of glycogen synthase kinase-3 (GSK-3) repartitions glucose-6-phosphate away from glycolysis as a result of stimulation of glycogen synthesis. This limits proton production from glucose metabolism and subsequently reduces intracellular Ca2+ overload, which limits LV mechanical dysfunction in early reperfusion. These results provide a novel mechanism to explain cardioprotection mediated by GSK-3 inhibition. In the final study in this thesis, we demonstrate that adenosine-induced cardioprotection is mediated by activation of Ser/Thr protein phosphatase activity that reduces the phosphorylation of AMPK, which subsequently inhibits phosphofructokinase-2 and slows glycolysis and proton production during reperfusion. Our results challenge the current paradigm by demonstrating the benefits of limiting excessive AMPK activation during reperfusion. Overall, this thesis highlights the importance of glucose and glycogen metabolism in the pathogenesis of I/R injury and presents a number of approaches to manipulate the balance between glycolysis and glucose oxidation and thereby limit myocardial I/R injury.
Language
English
DOI
doi:10.7939/R3X923
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.
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File title: Thesis-final-4
File author: Mohamed Omar
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