摘要
Objectives: Trimetazidine(TMZ) can optimize energy metabolism via inhibition of long-chain 3-ketoacyl Co A thiolase(3-KAT) in the heart, with subsequent decrease in fatty acid oxidation and stimulation of glucose oxidation. TMZ changes the cardiac AMP/ATP ratio by modulating fatty acid oxidation, thereby triggering AMPK signaling cascade that contributes to the protection of the heart from ischemia/reperfusion(I/R) injury. Methods: The mouse model of in vivo regional ischemia and reperfusion by the ligation of the left anterior descending coronary artery(LAD) was used for determination of myocardial infarction. The infarct size was compared between C57BL/6J WT mice and AMPK kinase dead(KD) transgenic mice with or without TMZ treatment. The ex vivo working heart perfusion system was used to monitor the effect of TMZ on glucose oxidation and fatty acid oxidation in the heart. Results: TMZ treatment significantly stimulates cardiac AMPK and extracellular signal regulated kinase(ERK) signaling pathways(p < 0.05 vs. vehicle group). The ex vivo working heart perfusion data demonstrated that TMZ treatment significantly activates AMPK signaling and modulating the substrate metabolism by shifting fatty acid oxidation to glucose oxidation during reperfusion, leading to reduction of oxidative stress in the I/R hearts. Therefore, both AMPK and ERK signaling pathways mediate the cardioprotection of TMZ against ischemic injury. Conclusion: We demonstrate that trimetazidine regulate metabolism during myocardial ischemia/reperfusion injury through regulating AMPK signaling pathway, and trimetazidine can reduce myocardial infarction size through AMPK and ERK signaling pathways. The result that AMPK KD mice or AMPK inhibitor compound C, ERK inhibitor PD98059 abolished the cardioprotective effect of trimetazidine further confirmed the hypothesis that trimetazidine exerts its protective effect through activating AMPK signaling pathway as well as trimetazidine's protective effect through regulating ERK signaling pathway.
Objectives: Trimetazidine(TMZ) can optimize energy metabolism via inhibition of long-chain 3-ketoacyl Co A thiolase(3-KAT) in the heart, with subsequent decrease in fatty acid oxidation and stimulation of glucose oxidation. TMZ changes the cardiac AMP/ATP ratio by modulating fatty acid oxidation, thereby triggering AMPK signaling cascade that contributes to the protection of the heart from ischemia/reperfusion(I/R) injury. Methods: The mouse model of in vivo regional ischemia and reperfusion by the ligation of the left anterior descending coronary artery(LAD) was used for determination of myocardial infarction. The infarct size was compared between C57BL/6J WT mice and AMPK kinase dead(KD) transgenic mice with or without TMZ treatment. The ex vivo working heart perfusion system was used to monitor the effect of TMZ on glucose oxidation and fatty acid oxidation in the heart. Results: TMZ treatment significantly stimulates cardiac AMPK and extracellular signal regulated kinase(ERK) signaling pathways(p < 0.05 vs. vehicle group). The ex vivo working heart perfusion data demonstrated that TMZ treatment significantly activates AMPK signaling and modulating the substrate metabolism by shifting fatty acid oxidation to glucose oxidation during reperfusion, leading to reduction of oxidative stress in the I/R hearts. Therefore, both AMPK and ERK signaling pathways mediate the cardioprotection of TMZ against ischemic injury. Conclusion: We demonstrate that trimetazidine regulate metabolism during myocardial ischemia/reperfusion injury through regulating AMPK signaling pathway, and trimetazidine can reduce myocardial infarction size through AMPK and ERK signaling pathways. The result that AMPK KD mice or AMPK inhibitor compound C, ERK inhibitor PD98059 abolished the cardioprotective effect of trimetazidine further confirmed the hypothesis that trimetazidine exerts its protective effect through activating AMPK signaling pathway as well as trimetazidine's protective effect through regulating ERK signaling pathway.
引文