Published Online
on October 9, 2006

A more recent version of this article appeared on October 17, 2006

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Submitted on June 8, 2006
Revised on August 11, 2006
Accepted on August 18, 2006

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

Jason R.B. Dyck PhD, Teresa A. Hopkins PhD, Sebastien Bonnet PhD, Evangelos D. Michelakis MD, Martin E. Young PhD, Miho Watanabe PhD, Yosuke Kawase PhD, Kou-ichi Jishage PhD, and Gary D. Lopaschuk PhD^*

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.).

^* To whom correspondence should be addressed. E-mail: gary.lopaschuk{at}ualberta.ca.

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.

Key words: drugs • fatty acids • glucose • ischemia • malonyl coenzyme A • metabolism • reperfusion

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