Gary LopaschukGary Lopaschuk, PhD

Office:       450, Heritage Medical Research Centre
Mail:         University of Alberta, Edmonton AB, T6G 2S2
Phone:      780-492-1236 (Office) 
               780-492-8659 (Lab)
Fax:        780-492-9753
Email:     gary.lopaschuk@ualberta.ca

 

 

 

 

Current Position

Scientific Director, Mazankowski Alberta Heart Institute

Professor, Department of Pediatrics

Adjunct Professor, Department of Pharmacology

 

Research Area

Dr. Gary Lopaschuk focuses on the regulatory pathways involved in energy metabolism in the heart, particularly the integrated regulation of fatty acid oxidation and carbohydrate metabolism in both the normal heart, the heart of a diabetic, and the reperfused ischemic heart.


Current Research Activities

 

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 knowledge 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. These studies should identify new approaches to decreasing heart problems in the diabetic.

 

Other Activities and Affiliations

 

President and CEO of Metabolic Modulators Research Ltd. (MMRL)

 

Biography

PhD, University of British Columbia

 

Selected Publications

 

Koves, T.R., Ussher, J.R., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J., Newgard CB, Lopaschuk GD and Muoio DM. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metabolism. 7: 45-56 (2008)

Lopaschuk, G.D., Folmes, C., Stanley, W. Cardiac energy metabolism in obesity. Circ. Res. 102:335-347 (2007).

Carley, A.N., Atkinson, L.L., Bonen, A., Harper, M.E., Kunnathu, S., Lopaschuk, G.D.,      Severson, D.L. Mechanisms responsible for enhanced fatty acid utilization by perfused hearts       from type 2 diabetic db/db mice. Arch. Physiol. Biochem. 113 :65-75 (2007).

 

Lopaschuk, G.D., Stanley, W. Malonyl-CoA decarboxylase inhibition as a novel approach to treat ischemic heart disease. Cardiovasc. Drugs Ther. 20:433-439 (2006).

 

Bonnet, S., Archer, S.L., Allalunis-Turner, J., Haromy, A., Beaulieu, C., Thompson, R., Lee, C.T., Lopaschuk, G., Puttagunta, L., Bonnet, S.N., Harry, G., Hashimoto, K., Thebaud, B., Michelakis, E. A Mitochondria-K+ Channel Axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 11:37-51 (2007).

Putnam, CT., Martins, KJ., Gallo, ME., Lopaschuk, GD., Pearcey JA.,  Maclean Im., Saranchuk RJ., Pette D. {alpha}-Catalytic Subunits of  5’AMP-Activated protein kinase display fiber specific expression and are upregulated by chronic low-frequency stimulation in rat muscle. Am. J. Physiol. 293:R1325-R1334 (2007).

 

Szczesna-Cordary, D., Jones, M., Moore, J.R., Watt, J., Kerrick, W.G., Wu, Y., Wang, Y., Wagg, C., Lopaschuk, G.D. Myosin regulatory light chain E22k mutation results in decreased cardiac intracellular calcium and force transients. FASEB J. 21:3974-85 (2007).

 

Wallis, GA., Friedlander, A.L., Jacobs, K.A., Horning, M.A., Fattor, J.A.,  Wolfel, E.E., Lopaschuk, G.D., Brooks, G.A. Substantial working muscle glycerol turnover during two-legged cycle ergometry. Am. J. Physiol. 293:E950-E957 (2007).

Gao, S., Kinzig, K.P., Aja, S., Scott, K.A., Keung, W., Kelly, S., Strynadka, K., Chohan, S., Smith, W.W., Tamashiro, K.L., Ladenheim, E.E., Ronnett, G.V., Tu, Y., Birnbaum, M.J., Lopaschuk, G.D., Moran, T.H. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc. Natl. Acad. Sci. 104: 17358-63 (2007).

Zhou, L., Huang, H., Yuan, C.L., Keung, W., Lopaschuk, G.D., Stanley, W.C. Metabolic response to an acute jump in cardiac worklaod: Effects on Malonyl-CoA, mechanical efficiency , fatty acid oxidation an acute jump in cardiac workload. Am. J. Physiol. 294: H954-H960(2007).

Onay-Besikci, A., Wagg, C., Lopaschuk, T.P., Keung, W., Lopaschuk G.D. Alpha-lipoic acid        increases cardiac glucose oxidation independant of AMP-activated protein kinase in isolated             working rate hearts. Basic. Res. Cardiol. 102:436-444 (2007).

Dyck, J.R.B., Hopkins, T.A., Bonnet, S., Michelakis, E., Young, M.E., Watanabe, Y., Kawase, Y., Jishage, K., Lopaschuk, G.D. Absence of malonyl CoA decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation 114:1721-1728 (2006).

CL Folmes, AS Clanachan, GD Lopaschuk. Fatty acids attenuate insulin regulation of 5'-AMP activated protein kinase and insulin cardioprotection after ischemia. Circ Res. 99(1):61-68, 2006.

 

JR Dyck, GD Lopaschuk. AMPK alterations in cardiac physiology and pathology: enemy or ally?  J Physiol. 574:95-112, 2006.

 

WC Stanley, FA Recchia, GD Lopaschuk.  Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85:1093-1129, 2005.

 

A Onay-Besikci, JY Altarejos, GD Lopaschuk.  gAd-globular head domain of adiponectin increases fatty acid oxidation in newborn rabbit hearts.  J. Biol. Chem. 279:44320-44326, 2004.

 

JR Dyck, JF Cheng, WC Stanley,R Barr, MP Chandler, S Brown, D Wallace, T Arhenios, C Harmon, G Yang, AM Nazdan, GD Lopaschuk.  Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and glucose oxidation.  Circ. Res. 194:e78-84, 2004.

 

A Onay-Besikci, FM Campbell, TA Hopkins, JR Dyck, GD Lopaschuk. Relative importance of malonyl CoA and carnitine in maturation of fatty acid oxidation in newborn rabbit heart. Am J Physiol Heart Circ Physiol. Jan;284(1):H283-9, 2003.

 

G Fragasso, PM Piatti, L Monti, A Palloshi, E Setola, P Puccetti, G Calori, GD Lopaschuk, A Margonato. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J. 146:18, 2003.

 

JA Bamford, GD Lopaschuk, IM MacLean, ML Reinhart, WT Dixon, CT Putman. Effects of chronic AICAR administration on the metabolic and contractile phenotypes of rat slow- and fast-twitch skeletal muscles. Can J Physiol Pharmacol. Nov;81:1-11, 2003.

 

N Sambandam, GD Lopaschuk. AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. Prog Lipid Res. May;42(3):238-56, 2003.

 

WC Stanley, SR Meadows, KM Kivilo, BA Roth, GD Lopaschuk. beta-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content. Am J Physiol Heart Circ Physiol. Oct;285(4):H1626-31, 2003.

 

GD Lopaschuk, R Barr, PD Thomas, JR Dyck. Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme a thiolase. Circ Res. Aug 8;93(3):e33-7, 2003.

 

TA Hopkins, MC Sugden, MJ Holness, R Kozak, JR Dyck, GD Lopaschuk. Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-alpha transgenic mice. Am J Physiol Heart Circ Physiol. Jul;285(1):H270-6, 2003.

 

Website links

 

Metabolic Modulators Research Inc.