Original articleTrimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia–reperfusion injury
Introduction
Trimetazidine or 1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride (TMZ) is the first of a promising new class of metabolic agents that act by optimizing energy metabolism in the heart. TMZ is a clinically effective anti-ischemic drug, that is currently used in some European countries for the treatment of stable angina pectoris [1], [2]. It has recently been demonstrated that this anti-ischemic effect of TMZ may involve the inhibition of long-chain 3-ketoacyl CoA thiolase activity, with subsequent reduction in fatty acid oxidation and stimulation of glucose oxidation [3]. This mechanism may explain the significant improvement in postischemic functional recovery observed in rat hearts pre-treated with TMZ [4].
Besides this metabolic effect, in vitro evidence suggests that TMZ might also modulate mitochondrial permeability transition [5]. Mitochondrial permeability transition represents a crucial event in both necrotic and apoptotic cardiomyocyte death following a prolonged myocardial ischemia–reperfusion [6], [7]. It is due to the opening of a non-specific megachannel (called the mitochondrial permeability transition pore (mPTP)) in the inner mitochondrial membrane. The mPTP, that remains closed throughout ischemia, opens at the time of reperfusion as a consequence of abrupt restoration of pH, Ca2+ overload, adenine nucleotide depletion, accumulation of inorganic phosphate, and production of reactive oxygen species (ROS) [7], [8]. Opening of the mPTP results in a collapse of the inner membrane potential (ΔΨm), uncoupling of the respiratory chain, and efflux of small molecules such as cytochrome c and other proapoptotic factors [9]. Recent evidence indicates that inhibition of mPTP opening by cyclosporin A (CsA), induce a potent cardioprotection in both in vitro and in vivo experimental models of myocardial infarction [10], [11], [12]. Inhibition of mitochondrial permeability transition may explain, at least in part, the cardioprotective effect of ischemic preconditioning (PC) [11], [13].
We postulated that TMZ might modulate mPTP opening and limit lethal ischemia–reperfusion injury. Our objective was to determine:
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whether in vivo administration of TMZ might protect the ischemic-reperfused myocardium from necrosis and apoptosis;
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whether any cardioprotective effect of TMZ may be related to an inhibition of mPTP opening.
Section snippets
Materials and methods
The investigation confirms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Hemodynamics
HR and MBP were comparable at baseline among all three groups (Table 1). In all experimental groups, sustained ischemia–reperfusion resulted in a comparable decrease in MBP. TMZ had no significant hemodynamic effect (Table 1).
Infarct size
AR was comparable among the three groups of rabbits, with mean values averaging 1.14 ± 0.12 g, 1.04 ± 0.10 g, 1.36 ± 0.14 g, in C, PC, and TMZ groups respectively (P = ns among groups). As expected, ischemic PC significantly reduced infarct size that averaged 21 ± 4% of the AR
Discussion
In the present study, we demonstrated, that in vivo TMZ attenuates myocardial apoptosis and necrosis to a similar extent than ischemic PC, and inhibits mPTP opening in the rabbit heart model of myocardial infarction.
The present findings are in agreement with previous studies, performed in the anesthetized rat or rabbit heart models, demonstrated that TMZ reduces infarct size following a prolonged ischemic insult [23], [24], [25]. In the present study, we further showed that infarct size
Acknowledgments
We thank Servier® (Neuilly-sur-Seine France) for providing TMZ.
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