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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn130
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

The Malonyl CoA Axis as a Potential Target for Treating Ischemic Heart Disease

John R. Ussher and Gary D. Lopaschu{dagger}

Cardiovascular Research Group, Department of Pediatrics, University of Alberta, Edmonton, Canada

{dagger} Address for correspondence: Dr. Gary Lopaschuk, 423 Heritage Medical Research Center, University of Alberta, Edmonton, Canada, T6G 2S2, tel: (780) 492-2170, fax: (780) 492-9753, email: gary.lopaschuk{at}ualberta.ca

Cardiovascular disease is the leading cause of death and disability for people living in Western Societies, with ischemic heart disease accounting for the majority of this health burden. The primary treatment for ischemic heart disease consists of either improving blood and oxygen supply to the heart, or reducing the heart's oxygen demand. Unfortunately, despite recent advances with these approaches, ischemic heart disease still remains a major health problem. Therefore, the development of new treatment strategies is still required. One exciting new approach, is to optimize cardiac energy metabolism, particularly by decreasing the use of fatty acids as a fuel and by increasing the use of glucose as a fuel. This approach is beneficial in the setting of ischemic heart disease as it allows the heart to produce energy more efficiently, and it reduces the degree of acidosis associated with ischemia/reperfusion. Malonyl CoA is a potent endogenous inhibitor of cardiac fatty acid oxidation, secondary to inhibiting carnitine palmitoyl transferase-I, the rate-limiting enzyme in the mitochondrial uptake of fatty acids. Malonyl CoA is synthesized in the heart by acetyl CoA carboxylase, which in turn is phosphorylated and inhibited by 5'AMP activated protein kinase. The degradation of myocardial malonyl CoA occurs via malonyl CoA decarboxylase. Previous studies have shown that inhibiting malonyl CoA decarboxylase will significantly increase cardiac malonyl CoA levels. This is associated with an increase in glucose oxidation, a decrease in acidosis, and an improvement in cardiac function and efficiency during and following ischemia. Hence, the malonyl CoA axis represents an exciting new target for the treatment of ischemic heart disease.

Time for primary review: 20


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