二氯乙酸通过抑制自噬减轻心肌缺血/再灌注损伤的机制研究

Ischemia/reperfusion (I/R) injury is the major problem of the treatment of acute myocardial infarction. Prior studies indicated that, Dichloroacetate (DCA), a metabolic modulator, can ameliorate cardiac function following I/R injury, but the specific mechanisms remains unknown. Autophagy plays a critical role in myocardial I/R injury. By suppressing the reperfusion-induced autophagy, I/R injury will be attenuated. Consequently, we speculate that DCA exerts its cardioprotective effect against I/R injury via downstreaming the reperfusion-induced cellular autophagy. Recent studies show that the augmentation of myocardial autophagy will enhance myocardial glucose extraction. Therefore, we assume that DCA may decrease myocardial glucose uptake by repressing the reperfusion-induced autophagy. To confirm the above hypothesis, both ex vivo and in vivo I/R SD rat models are established in this study. Firstly, molecular biology methods and laser confocal microscope and other techniques are used to determine that DCA attenuate I/R injury by suppressing reperfusion-induced autophagy via ROS/Bcl-2 signaling pathway. Secondly, 18F-FDG Micro-PET imaging and molecular biology methods are applied to measure the influence of DCA on myocardial glucose extraction following I/R. This study will clarify the effects and mechanisms of DCA on myocardial autophagy following I/R from a new prospect, and will provide evidence of a potential therapy for treating I/R injury.

心肌缺血/再灌注（ischemia/reperfusion, I/R）损伤是急性心肌梗死再灌注治疗的难题。我们研究证实，二氯乙酸（DCA）可减轻I/R损伤，但作用机制不明。自噬在I/R损伤中发挥着重要作用，抑制再灌注期自噬，可减轻心肌损伤。研究提示，自噬参与调节心肌葡萄糖摄取。据此，我们推测：①DCA可通过抑制自噬减轻心肌I/R损伤；②DCA可通过抑制自噬调节葡萄糖摄取，进而改善心肌能量代谢。为验证假说，本项目拟建立SD大鼠心肌I/R模型：①在细胞和整体水平，采用分子生物学、激光共聚焦显微镜技术，明确DCA可通过抑制自噬减轻I/R损伤；②在细胞水平，采用分子生物学方法明确DCA通过ROS/Bcl-2通路抑制自噬；③在整体水平，结合分子生物学方法及18F-FDG Micro-PET心肌显像，探讨DCA对再灌注心肌葡萄糖摄取的影响。本研究将从新的视角为减轻心肌I/R损伤提供一种新的治疗靶点。

心肌缺血/再灌注（ischemia/reperfusion, I/R）损伤是急性心肌梗死再灌注治疗的难题。二氯乙酸（DCA）可减轻I/R损伤，但作用机制不明。自噬在I/R损伤中发挥着重.要作用，抑制再灌注期自噬，可减轻心肌损伤，自噬参与调节心肌葡萄糖摄取。本项目建立了SD大鼠心肌I/R模型：①在细胞和整体水平，采用分子生物学、激光共聚焦显微镜技术，明确DCA可通过抑制自噬减轻I/R损伤；②在细胞水平，采用分子生物学方法明确DCA通过ROS/Bcl-2通路抑制自噬。本研究证实DCA可通过抑制自噬减轻心肌I/R损伤，进而改善心肌能量代谢，从新的视角为减轻心肌I/R损伤提供一种新的治疗靶点。