Dr Gary Lopaschuk
Adjunct Professor & AHFMR Scientist
PhD (Pharmacology and Toxicology), University of British Columbia, 1983
Post-Doctoral Fellowship, The Milton S. Hershey Medical Centre Department of Physiology, 1983-1985
Research: Understanding how energy metabolism is regulated in the heart under physiological and pathological conditions
Research Interests / Laboratory Techniques
The heart needs a constant and plentiful source of fuel to maintain normal pump function. The main source of fuel for the heart is normally a combination of carbohydrates and fatty acids. However, in many forms of heart disease, fatty acids dominate as a source of fuel. For example, in uncontrolled diabetes or following a heart attack, almost all the energy needed by the heart is obtained from fatty acids. This is detrimental to the heart and can compromise heart function. However, pharmacological agents which either inhibit fatty acid use by the heart, or increase carbohydrate use, are beneficial to the heart following a heart attack.
This pharmacological approach can also be beneficial in many other forms of heart disease. To maximally exploit this new approach to treating heart disease, it is important to have a better understanding of how fatty acid used by the heart is regulated. His studies have clarified how fatty acid use is normally controlled at the molecular level in the heart and why control of fatty acid use changes following a heart attack. Researchers also used this new knowlege to develop new pharmacological strategies for treating heart disease. Overall, Dr. Lopaschuk believes that optimizing fuel use by the heart has tremendous potential for treating heart disease. His ongoing research studies could help realize this potential.
In fetal life, the heart obtains most of its energy requirements from the metabolism of carbohydrates. However, within days of birth, fatty acid oxidation increases dramatically (over 10 fold) and becomes the major fuel of the heart. Dr. Lopaschuk's team has defined what molecular changes occur in the heart that are responsible for this switch in energy preference.
Determining the cellular mechanisms responsible for the maturation of fatty acid oxidation following birth not only increases the understanding of the profound physiological changes that occur at birth, but also has direct clinical relevance in the protection of the newborn heart during cardiac surgery. A better understanding of the regulation of energy metabolism in the newborn heart could lead to the development of improved therapeutic approaches for protecting the newborn heart during cardiac surgery.
Heart disease is a major problem in the diabetic. In diabetics almost all of the energy required for heart function is obtained through the metabolism of fatty acids. Dr. Lopaschuk's laboratory and others have shown that decreasing fatty acid use by the heart will increase the use of sugars as a source of energy, which then decreases the likelihood of the diabetic developing heart problems. His team has obtained a better understanding of how fatty acid use by the heart is regulated in the diabetic. His lab has shown that activity of some key enzymes involved in the regulation of fatty acid metabolism is altered. He is presently determining if returning the activity of these enzymes to normal improves heart function in the diabetic. Thiese studies should identify new approaches to decreasing heart problems in the diabetic.
Selected Recent Publications
Lopaschuk GD. (2017) Metabolic Modulators in Heart Disease: Past, Present, and Future. Can J Cardiol [Epub ahead of print] Review. PMID: 28279520.
De Jong KA, Czeczor JK, Sithara S, McEwen K, Lopaschuk GD, Appelbe A, Cukier K, Kotowicz M and McGee SL. (2017) Obesity and type 2 diabetes have additive effects on left ventricular remodelling in normotensive patients-a cross sectional study. Cardiovasc Diabetol 16(1):21. PMID: 28178970.
Rines AK, Chang HC, Wu R, Sato T, Khechaduri A, Kouzu H, Shapiro J, Shang M, Burke MA, Jiang X, Chen C, Rawlings TA, Lopaschuk GD, Schumacker PT, Abel ED and Ardehali H. (2017) Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling. Nat Commun 8:14095. PMID: 28117339.
Lopaschuk GD and Ussher JR. (2016) Evolving Concepts of Myocardial Energy Metabolism: More Than Just Fats and Carbohydrates. Circ Res 119(11):1173-1176. PMID: 28051784.
Lopaschuk GD. (2016) Fatty Acid Oxidation and Its Relation with Insulin Resistance and Associated Disorders. Ann Nutr Metab 68 Suppl 3:15-20PMID: 27931032.
Lopaschuk GD and Verma S. (2016) Empagliflozin's Fuel Hypothesis: Not so Soon. Cell Metab 24(2):200-2. PMID: 27508868.
Fukushima A and Lopaschuk GD. (2016) Acetylation control of cardiac fatty acid β-oxidation and energy metabolism in obesity, diabetes, and heart failure. Biochim Biophys Acta 1862(12):2211-2220. PMID: 27479696.
Groenendyk J, Lee D, Jung J, Dyck JR, Lopaschuk GD, Agellon LB and Michalak M. (2016) Inhibition of the Unfolded Protein Response Mechanism Prevents Cardiac Fibrosis. PLoS One 11(7):e0159682. PMID: 27441395.
Akhnokh MK, Yang FH, Samokhvalov V, Jamieson KL, Cho WJ, Wagg C, Takawale A, Wang X, Lopaschuk GD, Hammock BD, Kassiri Z and Seubert JM. (2016) Inhibition of Soluble Epoxide Hydrolase Limits Mitochondrial Damage and Preserves Function Following Ischemic Injury. Front Pharmacol 7:133. PMID: 27375480.
Fukushima A, Alrob OA, Zhang L, Wagg CS, Altamimi T, Rawat S, Rebeyka IM, Kantor PF and Lopaschuk GD. (2016) Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart. Am J Physiol Heart Circ Physiol 311(2):H347-63. PMID: 27261364.
Lopaschuk GD. (2016) Preface to the BBA special issue "heart lipid metabolism". Biochim Biophys Acta 1860(10):1423-4. PMID: 27208401.
Ussher JR, Fillmore N, Keung W, Zhang L, Mori J, Sidhu VK, Fukushima A, Gopal K, Lopaschuk DG, Wagg CS, Jaswal JS, Dyck JR and Lopaschuk GD. (2016) Genetic and Pharmacological Inhibition of Malonyl CoA Decarboxylase Does Not Exacerbate Age-Related Insulin Resistance in Mice. Diabetes 65(7):1883-91. PMID: 27207536.
Taegtmeyer H, Young ME, Lopaschuk GD, Abel ED, Brunengraber H, Darley-Usmar V, Des Rosiers C, Gerszten R, Glatz JF, Griffin JL, Gropler RJ, Holzhuetter HG, Kizer JR, Lewandowski ED, Malloy CR, Neubauer S, Peterson LR, Portman MA, Recchia FA, Van Eyk JE, Wang TJ; American Heart Association Council on Basic Cardiovascular Sciences. (2016) Assessing Cardiac Metabolism: A Scientific Statement From the American Heart Association. Circ Res 118(10):1659-701. PMID: 27012580.
Fukushima A and Lopaschuk GD. (2016) Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes. Biochim Biophys Acta 1860(10):1525-34. PMID: 26996746.
Lopatin YM, Rosano GM, Fragasso G, Lopaschuk GD, Seferovic PM, Gowdak LH, Vinereanu D, Hamid MA, Jourdain P and Ponikowski P. (2016) Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol 203:909-15. PMID: 26618252.