Cardiovascular Research Advance Access first published online on May 22, 2008
This version [Corrected Proof] published online on June 7, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn130
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The malonyl CoA axis as a potential target for treating ischaemic heart disease
Cardiovascular Research Group, Department of Pediatrics, University of Alberta, Edmonton, Canada
* Corresponding author: 423 Heritage Medical Research Center, University of Alberta, Edmonton, Canada T6G 2S2. Tel: +1 780 492 2170; fax: +1 780 492 9753. E-mail address: gary.lopaschuk{at}ualberta.ca
Cardiovascular disease is the leading cause of death and disability for people living in western societies, with ischaemic heart disease accounting for the majority of this health burden. The primary treatment for ischaemic 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, ischaemic 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 ischaemic heart disease, as it allows the heart to produce energy more efficiently and it reduces the degree of acidosis associated with ischaemia/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 (MCD). Previous studies have shown that inhibiting MCD 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 ischaemia. Hence, the malonyl CoA axis represents an exciting new target for the treatment of ischaemic heart disease.
KEYWORDS Ischaemic heart disease; Malonyl CoA; Malonyl CoA decarboxylase; Acetyl CoA carboxylase; AMP-activated protein kinase; Fatty acid oxidation
Time for primary review: 20 days
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