The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it is thought to have direct cytoprotective actions on the myocardium, the mechanism(s) by which this occurs is as yet undefined. In this study, we determined what effects trimetazidine has on both fatty acid and glucose metabolism in isolated working rat hearts and on the activities of various enzymes involved in fatty acid oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain lengths. Both glucose and fatty acids were appropriately radiolabeled with either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation.
Kantor
P F
PF
Cardiovascular Research Group and the Division of Pediatric Cardiology, University of Alberta, Edmonton, Canada.
Lucien
A
A
Kozak
R
R
Lopaschuk
G D
GD
D000787:Angina Pectoris / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D004952:Esters / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D004952:Esters; D005227:Fatty Acids; D009097:Multienzyme Complexes; D011768:Pyruvate Dehydrogenase Complex; D014665:Vasodilator Agents; D008316:Malonyl Coenzyme A; D063991:Mitochondrial Trifunctional Protein; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose; D014292:Trimetazidine