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Metabolic Modulation in Heart Disease Open Access


Other title
ischemic heart disease
pulmonary arterial hypertension
fatty acid oxidation
glucose oxidation
myocardial energy metabolism
Type of item
Degree grantor
University of Alberta
Author or creator
Sidhu, Vaninder K.
Supervisor and department
Lopaschuk, Gary (Pharmacology)
Examining committee member and department
Lehner, Richard (Pediatrics)
Dyck, Jason (Pharmacology)
Plane, Frances (Pharmacology)
Department of Pharmacology

Date accepted
Graduation date
Master of Science
Degree level
Ischemic heart disease and pulmonary arterial hypertension are often accompanied by a drastic change in myocardial energy metabolism that favors fatty acid oxidation and glycolysis, respectively, over glucose oxidation. This form of energy production is both inefficient and detrimental to the myocardium. However, both the glucose and fatty acid oxidative pathways can be targeted to improve cardiac function. Specifically, decreasing fatty acid oxidation and/or increasing glucose metabolism can improve cardiac efficiency in these disease states. This thesis examines the metabolic changes in pulmonary hypertension and demonstrates the therapeutic advantages of metabolic modulation with dichloroacetate through restoring oxidative metabolism. We also investigate the effect of altered fatty acid metabolism on cardiac recovery following an ischemic episode using the acetyl CoA carboxylase-2 knockout mouse. Increased rates of fatty acid oxidation impair cardiac efficiency, but following ischemia these hearts sustain little injury owing to an adaptation in the 5’-AMPK–ACC–malonyl CoA pathway.
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
Piao L, Sidhu VK, Fang Y, Ryan JJ, Parikh KS, Hong Z, Toth PT, Morrow E, Kutty S, Lopaschuk GD, Archer SL. FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: Therapeutic benefits of dichloroacetate. Journal of Molecular Medicine. 2012 Dec 18. [Epub ahead of print]

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