Published online before print April 22, 2004, doi: 10.1161/01.RES.0000129255.19569.8f
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Submitted on January 22, 2004
Accepted on April 13, 2004
Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation
Jason R.B. Dyck *;
From the Cardiovascular Research Group (J.R.B.D., G.D.L.), Departments of Pediatrics and Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada; Chugai Pharma USA LLC (J.-F.C., S.B., D.W., T.A., C.H., G.Y., A.M.N.), San Diego, Calif; Department of Physiology and Biophysics (W.C.S., M.P.C.), Case Western Reserve University, Cleveland, Ohio; Metabolic Modulators Research Ltd. (J.R.B.D., R.B., G.D.L.) 2020 Research Transition Facility, University of Alberta, Edmonton, Alberta, Canada.
* To whom correspondence should be addressed. E-mail: Jason.Dyck{at}UAlberta.ca or Gary.Lopaschuk{at}UAlberta.ca.
Abnormally high rates of fatty acid oxidation and low rates of glucose oxidation are important contributors to the severity of ischemic heart disease. Malonyl coenzyme A (CoA) regulates fatty acid oxidation by inhibiting mitochondrial uptake of fatty acids. Malonyl CoA decarboxylase (MCD) is involved in the decarboxylation of malonyl CoA to acetyl CoA. Therefore, inhibition of MCD may decrease fatty acid oxidation and protect the ischemic heart, secondary to increasing malonyl CoA levels. Ex vivo working rat hearts aerobically perfused in the presence of newly developed MCD inhibitors showed an increase in malonyl CoA levels, which was accompanied by both a significant decrease in fatty acid oxidation rates and an increase in glucose oxidation rates compared with controls. Using a model of demand-induced ischemia in pigs, MCD inhibition significantly increased glucose oxidation rates and reduced lactate production compared with vehicle-treated hearts, which was accompanied by a significant increase in cardiac work compared with controls. In a more severe rat heart global ischemia/reperfusion model, glucose oxidation was significantly increased and cardiac function was significantly improved during reperfusion in hearts treated with the MCD inhibitor compared with controls. Together, our data show that MCD inhibitors, which increase myocardial malonyl CoA levels, decrease fatty acid oxidation and accelerate glucose oxidation in both ex vivo rat hearts and in vivo pig hearts. This switch in energy substrate preference improves cardiac function during and after ischemia, suggesting that pharmacological inhibition of MCD may be a novel approach to treating ischemic heart disease.
Key words: metabolism • fatty acids • glucose • ischemia • malonyl CoA decarboxylase
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