G. Lopaschuk

 

Dr Gary Lopaschuk

(Adjunct Professor and AHFMR Scientist)

Contact:

Office: 423A Heritage Medical Research Centre  (☎) 780.492.2170
Lab: 423 Heritage Medical Research Centre  (☎) 780.492.8659
gary.lopaschuk@ualberta.ca

Education:
Post-Doctoral Fellowship, The Milton S. Hershey Medical Centre Department of Physiology, 1983-1985
PhD (Pharmacology and Toxicology), University of British Columbia, 1980-1983

Teaching: PMCOL415, PMCOL515

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

 

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.

Azam MA, Wagg CS, Massé S, Farid T, Lai PF, Kusha M, Asta J, Jaimes R 3rd, Kuzmiak-Glancy S, Kay MW, Lopaschuk GD and Nanthakumar K. (2015) Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF. Am J Physiol Heart Circ Physiol 309(9):H1543-53. PMID: 26342067.

Patel VB, Mori J, McLean BA, Basu R, Das SK, Ramprasath T, Parajuli N, Penninger JM, Grant MB, Lopaschuk GD and Oudit GY. (2016) ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity. Diabetes 65(1):85-95. PMID: 26224885.

Fukushima A, Milner K, Gupta A and Lopaschuk GD. (2015) Myocardial Energy Substrate Metabolism in Heart Failure : from Pathways to Therapeutic Targets. Curr Pharm Des 21(25):3654-64. PMID: 26166604.

Masoud WG, Abo Al-Rob O, Yang Y, Lopaschuk GD and Clanachan AS. (2015) Tolerance to ischaemic injury in remodelled mouse hearts: less ischaemic glycogenolysis and preserved metabolic efficiency. Cardiovasc Res 107(4):499-508. PMID: 26150203.

Sankaralingam S and Lopaschuk GD. (2015) Cardiac energy metabolic alterations in pressure overload-induced left and right heart failure (2013 Grover Conference Series). Pulm Circ 5(1):15-28. PMID: 25992268.

Lam VH, Zhang L, Huqi A, Fukushima A, Tanner BA, Onay-Besikci A, Keung W, Kantor PF, Jaswal JS, Rebeyka IM and Lopaschuk GD. (2015) Activating PPARalpha prevents post-ischemic contractile dysfunction in hypertrophied neonatal hearts. Circ Res 117(1):41-51. PMID: 25977309.

Gao S, McMillan RP, Zhu Q, Lopaschuk GD, Hulver MW and Butler AA. (2015) Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance. Mol Metab 4(4):310-24. PMID: 25830094.

Fillmore N, Keung W, Kelly SE, Proctor SD, Lopaschuk GD and Ussher JR. (2015) Accumulation of ceramide in slow-twitch muscle contributes to the development of insulin resistance in the obese JCR:LA-cp rat. Exp Physiol 100(6):730-41. PMID: 25786668.

Opie LH and Lopaschuk GD. (2015) What is good for the circulation also lessens cancer risk. Eur Heart J 36(19):1157-62. PMID: 25776859.

Fillmore N, Huqi A, Jaswal JS, Mori J, Paulin R, Haromy A, Onay-Besikci A, Ionescu L, Thebaud B, Michelakis E and Lopaschuk GD. (2015) Effect of fatty acids on human bone marrow mesenchymal stem cell energy metabolism and survival. PLoS One 10(3):e0120257. PMID: 25768019.

Lopaschuk GD and Ussher JR. (2015) Targeting microRNAs to limit myocardial lipid accumulation. Circ Res 116(2):229-31. PMID: 25593272.

Sankaralingam S, Abo Alrob O, Zhang L, Jaswal JS, Wagg CS, Fukushima A, Padwal RS, Johnstone DE, Sharma AM and Lopaschuk GD. (2014) Lowering Body Weight in Obese Mice With Diastolic Heart Failure Improves Cardiac Insulin Sensitivity and Function: Implications for the Obesity Paradox. Diabetes 64(5):1643-57. PMID: 25524917.

Fillmore N and Lopaschuk GD. (2014) The link between pediatric heart failure and mitochondrial lipids. J Mol Cell Cardiol 76C:71-72. PMID: 25123339.

Alrob OA and Lopaschuk GD. (2014) Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation. Biochem Soc Trans 42(4):1043-1051. PMID: 25110000.

Aksentijevic D, McAndrew DJ, Karlstadt A, Zervou S, Sebag-Montefiore L, Cross R, Douglas G, Regitz-Zagrosek V, Lopaschuk GD, Neubauer S and Lygate CA. (2014) Cardiac dysfunction and peri-weaning mortality in malonyl-coenzyme A decarboxylase (MCD) knockout mice as a consequence of restricting substrate plasticity. J Mol Cell Cardiol 75:76-87. PMID: 25066696.

Ussher JR, Fillmore N, Keung W, Mori J, Beker DL, Wagg CS, Jaswal JS and Lopaschuk GD. (2014) Trimetazidine therapy prevents obesity-induced cardiomyopathy in mice. Can J Cardiol 30(8):940-944. PMID: 25064584.

Ezekowitz JA, Becher H, Belenkie I, Clark AM, Duff HJ, Friedrich MG, Haykowsky MJ, Howlett JG, Kassiri Z, Kaul P, Kim DH, Knudtson ML, Light PE, Lopaschuk GD, McAlister FA, Noga ML, Oudit GY, Paterson DI, Quan H, Schulz R, Thompson RB, Weeks SG, Anderson TJ and Dyck JR. (2014) The Alberta Heart Failure Etiology and Analysis Research Team (HEART) study. BMC Cardiovasc Disord. 14:91. PMID: 25063541.

Alrob OA, Sankaralingam S, Ma C, Wagg CS, Fillmore N, Jaswal JS, Sack MN, Lehner R, Gupta MP, Michelakis ED, Padwal RS, Johnstone DE, Sharma AM and Lopaschuk GD. (2014) Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling. Cardiovasc Res 103(4):485-497. PMID: 24966184.

Gao S, McMillan RP, Jacas J, Zhu Q, Li X, Kumar GK, Casals N, Hegardt FG, Robbins PD, Lopaschuk GD, Hulver MW and Butler AA. (2014) Regulation of Substrate Oxidation Preferences in Muscle by the Peptide Hormone Adropin. Diabetes 2014 May 21 [Epub ahead of print]. PMID: 24848071.

Lee CT, Ussher JR, Mohammad A, Lam A and Lopaschuk GD. (2014) 5'-AMP-activated protein kinase increases glucose uptake independent of GLUT4 translocation in cardiac myocytes. Can J Physiol Pharmacol 92(4):307-314. PMID: 24708213.

Ussher JR, Keung W, Fillmore N, Koves TR, Mori J, Zhang L, Lopaschuk DG, Ilkayeva OR, Wagg CS, Jaswal JS, Muoio DM and Lopaschuk GD. (2014) Treatment with the 3-Ketoacyl-CoA Thiolase Inhibitor Trimetazidine Does Not Exacerbate Whole-Body Insulin Resistance in Obese Mice. J Pharmacol Exp Ther 349 (3):487-496. PMID: 24700885.

Fillmore N and Lopaschuk GD. (2014) Malonyl CoA: A promising target for the treatment of cardiac disease. IUBMB Life 2014 Mar 3. PMID: 24591219.

Mori J, Patel VB, Ramprasath T, Alrob OA, Desaulniers J, Scholey JW, Lopaschuk GD and Oudit GY. (2014) Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation and lipotoxicity. Am J Physiol Renal Physiol 306(8):F812-21. PMID: 24553436.

Mori J, Patel VB, Abo AO, Basu R, Altamimi T, Desaulniers J, Wagg CS, Kassiri Z, Lopaschuk GD and Oudit GY. (2014) Angiotensin 1-7 Ameliorates Diabetic Cardiomyopathy and Diastolic Dysfunction in db/db Mice by Reducing Lipotoxicity and Inflammation. Circ Heart Fail 7(2):327-39. PMID: 24389129.

Lopaschuk GD, Keehan KH, Taegtmeyer H, Des Rosiers C, William (Bill) C. Stanley (1957-2013). (2014) Am J Physiol Heart Circ Physiol 306 (2):H161-H162. PMID: 24322618.