Published online before print October 9, 2006, doi: 10.1161/CIRCULATIONAHA.106.642009
(Circulation. 2006;114:1721-1728.)
© 2006 American Heart Association, Inc.
Molecular Cardiology |
Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury
From the Cardiovascular Research Group, Departments of Pediatrics (J.R.B.D., G.D.L.), Pharmacology (J.R.B.D., T.A.H., G.D.L.), and Medicine (S.B., E.D.M.), Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada; USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Department of Pediatrics, Houston, Tex (M.E.Y.); and Chugai Research Institute for Medical Science, Inc, Komakado Gotemba, Japan (M.W., Y.K., K.J.).
Reprint requests to Dr Gary D. Lopaschuk, 423 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2. (e-mail gary.lopaschuk{at}ualberta.ca); or Dr Jason R.B. Dyck, 474 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2. (e-mail Jason.Dyck@UAlberta.ca).
Received June 8, 2006; revision received August 11, 2006; accepted August 18, 2006.
Background— Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabolism, or ischemic cardioprotection.
Methods and Results— Mcd-deficient mice were produced and assessed for in vivo cardiac function as well as ex vivo cardiac function, energy metabolism, and ischemic tolerance. In vivo and ex vivo cardiac function was similar in wild-type and mcd–/– mice. Ex vivo working hearts from mcd–/– and wild-type mice displayed no significant differences in rates of fatty acid oxidation, glucose oxidation, or glycolysis. However, cardiac deletion of mcd resulted in an increased expression of genes regulating fatty acid utilization that may compensate for the loss of MCD protein and likely contributes to the absence of changes in energy metabolism in the aerobic heart. Despite the lack of changes in fatty acid utilization, hearts from mcd–/– mice displayed a marked preference for glucose utilization after ischemia, which correlated with a significant cardioprotection of ischemic hearts from mcd–/– mice compared with wild-type mice.
Conclusions— Deletion of MCD markedly increases glucose oxidation and improves functional recovery of the heart after ischemia. As a result, chronic pharmacological inhibition of MCD may be a viable approach to treat myocardial ischemia.
CLINICAL PERSPECTIVE
This article has been cited by other articles:
 |
|
 |
|
  L. Hue and H. Taegtmeyer The Randle cycle revisited: a new head for an old hat Am J Physiol Endocrinol Metab, September 1, 2009; 297(3): E578 - E591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Ussher, T. R. Koves, J. S. Jaswal, L. Zhang, O. Ilkayeva, J. R.B. Dyck, D. M. Muoio, and G. D. Lopaschuk Insulin-Stimulated Cardiac Glucose Oxidation Is Increased in High-Fat Diet-Induced Obese Mice Lacking Malonyl CoA Decarboxylase Diabetes, August 1, 2009; 58(8): 1766 - 1775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yan, M. E. Young, L. Cui, G. D. Lopaschuk, R. Liao, and R. Tian Increased Glucose Uptake and Oxidation in Mouse Hearts Prevent High Fatty Acid Oxidation but Cause Cardiac Dysfunction in Diet-Induced Obesity Circulation, June 2, 2009; 119(21): 2818 - 2828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W. Dolinsky, A. Y.M. Chan, I. Robillard Frayne, P. E. Light, C. Des Rosiers, and J. R.B. Dyck Resveratrol Prevents the Prohypertrophic Effects of Oxidative Stress on LKB1 Circulation, March 31, 2009; 119(12): 1643 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Ussher and G. D. Lopaschuk The malonyl CoA axis as a potential target for treating ischaemic heart disease Cardiovasc Res, July 15, 2008; 79(2): 259 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Essop, H. S. Camp, C. S. Choi, S. Sharma, R. M. Fryer, G. A. Reinhart, P. H. Guthrie, A. Bentebibel, Z. Gu, G. I. Shulman, et al. Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H256 - H265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Bouzakri, R. Austin, A. Rune, M. E. Lassman, P. M. Garcia-Roves, J. P. Berger, A. Krook, A. V. Chibalin, B. B. Zhang, and J. R. Zierath Malonyl CoenzymeA Decarboxylase Regulates Lipid and Glucose Metabolism in Human Skeletal Muscle Diabetes, June 1, 2008; 57(6): 1508 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Bray, C. A. Shaw, M. W. S. Moore, R. A. P. Garcia, M. M. Zanquetta, D. J. Durgan, W. J. Jeong, J.-Y. Tsai, H. Bugger, D. Zhang, et al. Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H1036 - H1047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P.Y. Koonen, R. L. Jacobs, M. Febbraio, M. E. Young, C.-L. M. Soltys, H. Ong, D. E. Vance, and J. R.B. Dyck Increased Hepatic CD36 Expression Contributes to Dyslipidemia Associated With Diet-Induced Obesity Diabetes, December 1, 2007; 56(12): 2863 - 2871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P.Y. Koonen, M. Febbraio, S. Bonnet, J. Nagendran, M. E. Young, E. D. Michelakis, and J. R.B. Dyck CD36 Expression Contributes to Age-Induced Cardiomyopathy in Mice Circulation, November 6, 2007; 116(19): 2139 - 2147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Abel Glucose for the Aging Heart? Circulation, August 21, 2007; 116(8): 884 - 887. [Full Text] [PDF]
|
|