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Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion
Laurent Argaud1, Ludovic Gomez, Odile Gateau-Roesch
1Inserm, E0226, 69003 Lyon, France.
Abstract:
Trimetazidine (TMZ) affects mitochondrial function during ischemia. Mitochondrial permeability transition is a pivotal event in cardiomyocyte death following acute ischemia. The aim of the present study was to determine whether the anti-ischemic agent TMZ might modulate mitochondrial permeability transition pore (mPTP) opening and limit lethal ischemia-reperfusion injury. Anesthetized NZW rabbits underwent 30 min of coronary artery occlusion followed by 4 hours of reperfusion. Prior to this, they underwent either no intervention (control, C), ischemic preconditioning (PC), or an IV injection of 5 mg kg(-1) TMZ 10 min before ischemia (TMZ). Additional rabbits (Sham group) underwent no ischemia/reperfusion throughout the experiment. Infarct size was assessed by triphenyltetrazolium staining, and apoptosis via measurement of caspase 3 activity. Ca(2+)-induced mPTP opening was assessed in mitochondria isolated from ischemic myocardium. TMZ and PC significantly reduced infarct size that averaged 34 +/- 4% and 21 +/- 4% of the risk region respectively, versus 63 +/- 6% in controls (P<0.005). Caspase 3 activity was reduced in both TMZ and PC groups: 37 +/- 11 and 29 +/- 7 respectively, versus 68 +/- 9 nmol min(-1) mg(-1) mitochondrial protein in controls (P=0.01 versus TMZ and PC). In controls, Ca(2+) load required for mPTP opening averaged 11 +/- 4 microM mg(-1) mitochondrial protein versus 116 +/- 6 in shams (P<0.0001). Pre-treatment by TMZ or PC attenuated this, with Ca(2+) loads averaging 45 +/- 4 and 46 +/- 4 microM mg(-1) mitochondrial proteins, respectively (P<0.005 versus C). These data suggest that TMZ inhibits mPTP opening and protects the rabbit heart from prolonged ischemia-reperfusion injury.
Insights
Trimetazidine (TMZ) protects the heart from ischemia-reperfusion injury by inhibiting the mitochondrial permeability transition pore (mPTP). This anti-ischemic agent significantly reduces infarct size and cardiomyocyte apoptosis in rabbits.
Area of Science:
- Cardiovascular Science
- Mitochondrial Biology
- Pharmacology
Background:
- Mitochondrial permeability transition pore (mPTP) opening is critical in cardiomyocyte death during ischemia.
- Trimetazidine (TMZ) is an anti-ischemic agent known to affect mitochondrial function.
- Investigating TMZ's effect on mPTP opening is crucial for understanding its cardioprotective mechanisms.
Purpose of the Study:
- To determine if Trimetazidine (TMZ) modulates mitochondrial permeability transition pore (mPTP) opening.
- To assess TMZ's efficacy in limiting lethal ischemia-reperfusion injury in a rabbit model.
- To compare the effects of TMZ with ischemic preconditioning (PC).
Main Methods:
- Anesthetized rabbits underwent 30 minutes of coronary artery occlusion followed by 4 hours of reperfusion.
- Groups included control, ischemic preconditioning (PC), and Trimetazidine (TMZ) pre-treatment (5 mg/kg IV).
- Infarct size, caspase 3 activity (apoptosis marker), and Ca(2+)-induced mPTP opening in isolated mitochondria were measured.
Main Results:
- TMZ and PC significantly reduced infarct size compared to controls (34% and 21% vs. 63%, respectively).
- Caspase 3 activity was significantly lower in TMZ and PC groups compared to controls (37 and 29 vs. 68 nmol/min/mg).
- TMZ and PC attenuated Ca(2+)-induced mPTP opening, requiring higher Ca(2+) loads (45 and 46 µM/mg vs. 11 µM/mg in controls).
Conclusions:
- Trimetazidine (TMZ) inhibits mitochondrial permeability transition pore (mPTP) opening.
- TMZ provides significant cardioprotection against prolonged ischemia-reperfusion injury in rabbits.
- TMZ's protective effects are comparable to ischemic preconditioning.
