© 2000 American Heart Association, Inc.
Integrative Physiology |
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
From the Cardiovascular Research Group and the Division of Pediatric Cardiology (P.F.K., R.K., G.D.L.), University of Alberta, Edmonton, Canada, and Institut De Recherches Internationales Servier (A.L.), Courbevoie, France.
Correspondence to Gary D. Lopaschuk, 423 Heritage Medical Research Center, University of Alberta, Edmonton, Canada, T6G 2S2. E-mail gary.lopaschuk{at}ualberta.ca
Abstract—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 µU/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 3H or 14C 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 · g dry weight-1 · minute-1 (P<0.05), whereas it increased rates of glucose oxidation from 1889±119 to 2378±166 nmol · g dry weight-1 · 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 ß-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC50 of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 µmol/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.
Key Words: glycolysis • mitochondria • trimetazidine
This article has been cited by other articles:
 |
|
 |
|
  S. Sajapitak, K. Iwata, M. Shahab, Y. Uenoyama, S. Yamada, M. Kinoshita, F. Y. Bari, H. I'Anson, H. Tsukamura, and K.-i. Maeda Central Lipoprivation-Induced Suppression of Luteinizing Hormone Pulses Is Mediated by Paraventricular Catecholaminergic Inputs in Female Rats Endocrinology, June 1, 2008; 149(6): 3016 - 3024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Doenst, H. Bugger, M. Schwarzer, G. Faerber, M. A. Borger, and F. W. Mohr Three good reasons for heart surgeons to understand cardiac metabolism Eur. J. Cardiothorac. Surg., May 1, 2008; 33(5): 862 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Wu, F. Yang, K. C. Vinnakota, and D. A. Beard Computer Modeling of Mitochondrial Tricarboxylic Acid Cycle, Oxidative Phosphorylation, Metabolite Transport, and Electrophysiology J. Biol. Chem., August 24, 2007; 282(34): 24525 - 24537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Lopaschuk, C. D.L. Folmes, and W. C. Stanley Cardiac Energy Metabolism in Obesity Circ. Res., August 17, 2007; 101(4): 335 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. O Onbasili, Y. Yeniceriglu, P. Agaoglu, A. Karul, T. Tekten, H. Akar, and G. Discigil Trimetazidine in the prevention of contrast-induced nephropathy after coronary procedures Heart, June 1, 2007; 93(6): 698 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bonello, P. Sbragia, N. Amabile, O. Com, S. V Pierre, S. Levy, and F. Paganelli Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention Heart, June 1, 2007; 93(6): 703 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Belardinelli, M. Solenghi, L. Volpe, and A. Purcaro Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect Eur. Heart J., May 1, 2007; 28(9): 1102 - 1108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Jayle, F. Favreau, K. Zhang, C. Doucet, J. M. Goujon, W. Hebrard, M. Carretier, M. Eugene, G. Mauco, J. P. Tillement, et al. Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model Am J Physiol Renal Physiol, March 1, 2007; 292(3): F1082 - F1093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gambert, C. Helies-Toussaint, and A. Grynberg Extracellular glycerol regulates the cardiac energy balance in a working rat heart model Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1600 - H1606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Horowitz and J. A. Kennedy Time to Address the Cardiac Metabolic "Triple Whammy": Ischemic Heart Failure in Diabetic Patients J. Am. Coll. Cardiol., December 5, 2006; 48(11): 2232 - 2234. [Full Text] [PDF]
|
|
|
|
|
|
G. Fragasso, A. Palloshi, P. Puccetti, C. Silipigni, A. Rossodivita, M. Pala, G. Calori, O. Alfieri, and A. Margonato A Randomized Clinical Trial of Trimetazidine, a Partial Free Fatty Acid Oxidation Inhibitor, in Patients With Heart Failure J. Am. Coll. Cardiol., September 5, 2006; 48(5): 992 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. K. Kutala, M. Khan, R. Mandal, L. P. Ganesan, S. Tridandapani, T. Kalai, K. Hideg, and P. Kuppusamy Attenuation of Myocardial Ischemia-Reperfusion Injury by Trimetazidine Derivatives Functionalized with Antioxidant Properties J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 921 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Meng, L. Feng, X.-J. Chen, D. Yang, and J.-N. Zhang Trimetazidine improved Ca2+ handling in isoprenalinemediated myocardial injury of rats Exp Physiol, May 1, 2006; 91(3): 591 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Fragasso, G. Perseghin, F. De Cobelli, A. Esposito, A. Palloshi, G. Lattuada, P. Scifo, G. Calori, A. Del Maschio, and A. Margonato Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure Eur. Heart J., April 2, 2006; 27(8): 942 - 948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. D. Monti, E. Setola, G. Fragasso, R. P. Camisasca, P. Lucotti, E. Galluccio, A. Origgi, A. Margonato, and P. Piatti Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E54 - E59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sambandam, D. Morabito, C. Wagg, B. N. Finck, D. P. Kelly, and G. D. Lopaschuk Chronic activation of PPAR{alpha} is detrimental to cardiac recovery after ischemia Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H87 - H95. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Parang, B. Singh, and R. Arora Metabolic Modulators for Chronic Cardiac Ischemia Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2005; 10(4): 217 - 223. [Abstract] [PDF]
|
|
|
|
 |
|
 W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk Myocardial Substrate Metabolism in the Normal and Failing Heart Physiol Rev, July 1, 2005; 85(3): 1093 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Saeedi, M. Grist, R. B. Wambolt, A. Bescond-Jacquet, A. Lucien, and M. F. Allard Trimetazidine Normalizes Postischemic Function of Hypertrophied Rat Hearts J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 446 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Thiele, N. D. Price, T. D. Vo, and B. O. Palsson Candidate Metabolic Network States in Human Mitochondria: IMPACT OF DIABETES, ISCHEMIA, AND DIET J. Biol. Chem., March 25, 2005; 280(12): 11683 - 11695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E O'Meara and J J V McMurray Myocardial metabolic manipulation: a new therapeutic approach in heart failure? Heart, February 1, 2005; 91(2): 131 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P Di Napoli, A A Taccardi, and A Barsotti Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy Heart, February 1, 2005; 91(2): 161 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Hanley, S. Drose, U. Brandt, R. A. Lareau, A. L. Banerjee, D. K. Srivastava, L. J. Banaszak, J. J. Barycki, P. P. Van Veldhoven, and J. Daut 5-Hydroxydecanoate is metabolised in mitochondria and creates a rate-limiting bottleneck for {beta}-oxidation of fatty acids J. Physiol., January 15, 2005; 562(2): 307 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vitale, M. Wajngaten, B. Sposato, O. Gebara, P. Rossini, M. Fini, M. Volterrani, and G. M.C. Rosano Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease Eur. Heart J., October 2, 2004; 25(20): 1814 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Huss and D. P. Kelly Nuclear Receptor Signaling and Cardiac Energetics Circ. Res., September 17, 2004; 95(6): 568 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Taegtmeyer Cardiac Metabolism as a Target for the Treatment of Heart Failure Circulation, August 24, 2004; 110(8): 894 - 896. [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Magner and D. Royston Heart failure Br. J. Anaesth., July 1, 2004; 93(1): 74 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R.B. Dyck, J.-F. Cheng, W. C. Stanley, R. Barr, M. P. Chandler, S. Brown, D. Wallace, T. Arrhenius, C. Harmon, G. Yang, et al. Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation Circ. Res., May 14, 2004; 94(9): e78 - e84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lee, J. Horowitz, and M. Frenneaux Metabolic manipulation in ischaemic heart disease, a novel approach to treatment Eur. Heart J., April 2, 2004; 25(8): 634 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Khairallah, F. Labarthe, B. Bouchard, G. Danialou, B. J. Petrof, and C. Des Rosiers Profiling substrate fluxes in the isolated working mouse heart using 13C-labeled substrates: focusing on the origin and fate of pyruvate and citrate carbons Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1461 - H1470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Opie Angina Pectoris: The Evolution of Concepts Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S3 - S9. [PDF]
|
|
|
|
|
|
U. Thadani Current Medical Management of Chronic Stable Angina Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S11 - S29. [Abstract] [PDF]
|
|
|
|
|
|
W. C. Stanley Myocardial Energy Metabolism During Ischemia and the Mechanisms of Metabolic Therapies Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S31 - S45. [Abstract] [PDF]
|
|
|
|
|
|
L. H. Opie Preconditioning and metabolic anti-ischaemic agents Eur. Heart J., October 2, 2003; 24(20): 1854 - 1856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. MacInnes, D. A. Fairman, P. Binding, J. a. Rhodes, M. J. Wyatt, A. Phelan, P. S. Haddock, and E. H. Karran The Antianginal Agent Trimetazidine Does Not Exert Its Functional Benefit via Inhibition of Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A Thiolase Circ. Res., August 8, 2003; 93 (3): e26 - e32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Lopaschuk, R. Barr, P. D. Thomas, and J. R.B. Dyck 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 Circ. Res., August 8, 2003; 93 (3): e33 - e37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Chandler, P. N. Chavez, T. A. McElfresh, H. Huang, C. S. Harmon, and W. C. Stanley Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia Cardiovasc Res, July 1, 2003; 59(1): 143 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Lopaschuk and M. Marzilli Mode of Action of Trimetazidine and Other New Metabolic Agents in the Treatment of Ischemic Heart Disease Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2003; 7(1): 91 - 96. [PDF]
|
|
|
|
 |
|
 D. Tallarico, V. Rizzo, F. di Maio, F. Petretto, G. Bianco, G. Placanica, M. Marziali, V. Paravati, N. Gueli, F. Meloni, et al. Myocardial Cytoprotection by Trimetazidine Against Anthracycline-Induced Cardiotoxicity in Anticancer Chemotherapy Angiology, March 1, 2003; 54(2): 219 - 227. [Abstract] [PDF]
|
|
|
|
|
|
I. Tabbi-Anneni, C. Helies-Toussaint, D. Morin, A. Bescond-Jacquet, A. Lucien, and A. Grynberg Prevention of Heart Failure in Rats by Trimetazidine Treatment: A Consequence of Accelerated Phospholipid Turnover? J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1003 - 1009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ferrara, G. Guardigli, and R. Ferrari Myocardial metabolism: the diabetic heart Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B15 - B18. [Abstract] [PDF]
|
|
|
|
|
|
M. Frenneaux New tricks for an old drug Eur. Heart J., December 2, 2002; 23(24): 1898 - 1899. [PDF]
|
|
|
|
|
|
R. K. Kudej, L. T. White, A. B. Kudej, S. F. Vatner, and E. D. Lewandowski Brief Increase in Carbohydrate Oxidation After Reperfusion Reverses Myocardial Stunning in Conscious Pigs Circulation, November 26, 2002; 106(22): 2836 - 2841. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Taegtmeyer, D. M. Cohen, M. Allard, R. Brownsey, and G. Lopaschuk Overestimating glycolysis in rat heart Am J Physiol Endocrinol Metab, November 1, 2002; 283(5): E1102 - E1104. [Full Text] [PDF]
|
|
|
|
|
|
R. Liao, M. Jain, L. Cui, J. D'Agostino, F. Aiello, I. Luptak, S. Ngoy, R. M. Mortensen, and R. Tian Cardiac-Specific Overexpression of GLUT1 Prevents the Development of Heart Failure Attributable to Pressure Overload in Mice Circulation, October 15, 2002; 106(16): 2125 - 2131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Rottman, D. Bracy, C. Malabanan, Z. Yue, J. Clanton, and D. H. Wasserman Contrasting effects of exercise and NOS inhibition on tissue-specific fatty acid and glucose uptake in mice Am J Physiol Endocrinol Metab, July 1, 2002; 283(1): E116 - E123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Fragasso, P. M. Piatti, L. Monti, A. Palloshi, C. Lu, G. Valsecchi, E. Setola, G. Calori, G. Pozza, A. Margonato, et al. Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease: Evaluation of the protective role of the metabolic modulator trimetazidine J. Am. Coll. Cardiol., February 6, 2002; 39(3): 413 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Michelakis, M. S. McMurtry, X.-C. Wu, J. R.B. Dyck, R. Moudgil, T. A. Hopkins, G. D. Lopaschuk, L. Puttagunta, R. Waite, and S. L. Archer Dichloroacetate, a Metabolic Modulator, Prevents and Reverses Chronic Hypoxic Pulmonary Hypertension in Rats: Role of Increased Expression and Activity of Voltage-Gated Potassium Channels Circulation, January 15, 2002; 105(2): 244 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Szwed, Z. Sadowski, W. Elikowski, A. Koronkiewicz, A. Mamcarz, W. Orszulak, E. Skibinska, K. Szymczak, J. Swiatek, and M. Winter Combination treatment in stable effort angina using trimetazidine and metoprolol. Results of a randomized, double-blind, multicentre study (TRIMPOL II) Eur. Heart J., December 2, 2001; 22(24): 2267 - 2274. [Abstract] [PDF]
|
|
|
|
|
|
D.V. Cokkinos Can metabolic manipulation reverse myocardial dysfunction? Eur. Heart J., December 1, 2001; 22(23): 2138 - 2139. [PDF]
|
|
|
|
|
|
R. Belardinelli and A. Purcaro Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischaemic cardiomyopathy Eur. Heart J., December 1, 2001; 22(23): 2164 - 2170. [Abstract] [PDF]
|
|
|
|
|
|
Y. Iwado, K. Mizushige, K. Manabe, Y. Wada, I. Kondo, K. Ohmori, and M. Kohno Suppression of Fatty Acid Metabolism After Exercise Stress in Patients with No Electrocardiographic ST Segment Shift During Balloon Angioplasty Angiology, December 1, 2001; 52(12): 841 - 849. [Abstract] [PDF]
|
|
|
|
|
|
N. Rosenblatt-Velin, C. Montessuit, I. Papageorgiou, J. Terrand, and R. Lerch Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism Cardiovasc Res, December 1, 2001; 52(3): 407 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.C. Stanley Changes in cardiac metabolism: a critical step from stable angina to ischaemic cardiomyopathy Eur. Heart J. Suppl., November 1, 2001; 3(suppl_O): O2 - O7. [Abstract] [PDF]
|
|
|
|
|
|
M. Marzilli Trimetazidine: a metabolic agent for the treatment of stable angina Eur. Heart J. Suppl., November 1, 2001; 3(suppl_O): O12 - O15. [Abstract] [PDF]
|
|
|
|
|
|
S.L. Chierchia Trimetazidine and left ventricular ischaemic dysfunction: an overview of clinical evidence Eur. Heart J. Suppl., November 1, 2001; 3(suppl_O): O16 - O20. [Abstract] [PDF]
|
|
|
|
|
|
|