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(Circulation Research. 2003;93:e33.)
© 2003 American Heart Association, Inc.

Response to Research Commentary

Beneficial Effects of Trimetazidine in Ex Vivo Working Ischemic Hearts Are Due to a Stimulation of Glucose Oxidation Secondary to Inhibition of Long-Chain 3-Ketoacyl Coenzyme A Thiolase

Gary D. Lopaschuk, Rick Barr, Panakkezhum D. Thomas, Jason R.B. Dyck

From the Cardiovascular Research Group, Department of Pediatrics, University of Alberta, Edmonton, Canada.

Correspondence to Dr Gary D. Lopaschuk, 423 Heritage Medical Research Center, University of Alberta, Edmonton, Canada, T6G 2S2. E-mail gary.lopaschuk{at}ualberta.ca

Abstract

High rates of fatty acid oxidation in the heart and subsequent inhibition of glucose oxidation contributes to the severity of myocardial ischemia. These adverse effects of fatty acids can be overcome by stimulating glucose oxidation, either directly or secondary to an inhibition of fatty acid oxidation. We recently demonstrated that trimetazidine stimulates glucose oxidation in the heart secondary to inhibition of fatty acid oxidation. This inhibition of fatty acid oxidation was attributed to an inhibition of mitochondrial long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), an enzyme of fatty acid ß-oxidation. However, the accompanying Research Commentary of MacInnes et al suggests that trimetazidine does not inhibit cardiac LC 3-KAT. This discrepancy with our data can be attributed to the reversible competitive nature of trimetazidine inhibition of LC 3-KAT. In the presence of 2.5 µmol/L 3-keto-hexadecanoyl CoA (KHCoA), trimetazidine resulted in a 50% inhibition of LC-3-KAT activity. However, the inhibition of LC 3-KAT could be completely reversed by increasing substrate (3-keto-hexadecanoyl CoA, KHCoA) concentrations to 15 µmol/L even at high concentrations of trimetazidine (100 µmol/L). The study of MacInnes et al was performed using concentrations of 3K-HCoA in excess of 16 µmol/L, a concentration that would completely overcome 100 µmol/L trimetazidine inhibition of LC 3-KAT. Therefore, the lack of inhibition of LC 3-KAT by trimetazidine in the MacInnes et al study can easily be explained by the high concentration of KHCoA substrate used in their experiments. In isolated working hearts perfused with high levels of fatty acids, we found that trimetazidine (100 µmol/L) significantly improves functional recovery of hearts subjected to a 30-minute period of global no-flow ischemia. This occurred in the absence of changes in oxygen consumption resulting in an improved increase in cardiac efficiency. Combined with our previous studies, we conclude that trimetazidine inhibition of LC 3-KAT decreases fatty acid oxidation and stimulates glucose oxidation, resulting in an improvement in cardiac function and efficiency after ischemia. The full text of this article is available online at http://www.circresaha.org.

Key Words: 3-ketoacyl coenzyme A thiolase • glucose oxidation • fatty acid oxidation • ischemia • trimetazidine

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