Cardioprotection by Drug-Induced Changes in Glucose and Glycogen Metabolism

  • Author / Creator
    Omar, Mohamed Abdalla
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Pharmacology
  • Supervisor / co-supervisor and their department(s)
    • Clanachan, AS (Pharmacology)
  • Examining committee members and their departments
    • Dyck, JRB (Pediatrics)
    • Seubert, J (Pharmacy)
    • Mcneill, J (Faculty of Pharmaceutical Sciences, University of British Columbia)
    • Light, PE (Pharmacology)