JNK信号通路在右美托咪定预处理减轻大鼠离体心肌缺血再灌注损伤中的作用

Role of C-Jun N-terminal kinases singnaling pathway in dexmedetomidine preconditioning in reducing myocardial ischemia-reperfusion injury in isolated rat hearts

目的探讨JNK信号通路在右美托咪定(DEX)预处理减轻大鼠离体心肌缺血再灌注损伤(MIRI)中的作用机制。方法将大鼠分为对照(N)组、缺血再灌注(I/R)组、右美托咪定预处理(D)组、JNK信号通路抑制剂SP600125(SP)组、右美托咪定与SP600125(D+SP)组。记录各组大鼠心率(HR)、左心室发展压(LVDP)、左室内压最大上升/下降速率(±dp/dtmax)、左心室舒张末压(LVEDP)、心肌梗死面积、心肌细胞凋亡率(AI)情况,电镜观察心肌超微结构变化,Western blot检测心肌组织GRP78、JNK、p-JNK蛋白表达。结果与N组相比,其余组HR、LVDP、±dp/dtmax降低,LVEDP、心肌梗死面积、AI、GRP78、p-JNK、p-JNK/JNK蛋白表达增加(P<0.05);与I/R组相比,D组、SP组、D+SP组HR、LVDP、±dp/dtmax增加,LVEDP、心肌梗死面积、AI、GRP78、p-JNK、p-JNK/JNK蛋白表达均降低(P<0.05)。电镜下N组心肌细胞超微结构完整,I/R组结构严重破坏,D组、SP组、D+SP组破坏较少。结论右美托咪定预处理可能通过抑制JNK信号通路,减轻大鼠离体心脏过度的内质网应激及其介导的凋亡,从而减轻MIRI。

Objective To investigate the action mechanism of C-Jun N-terminal kinases(JNK)singnaling pathway in dexmedetomidine(DEX)preconditioning-induced reduction of myocardial ischemia-reperfusion injury(MIRI)in the isolated rat hearts.Methods The rats were divided into the control group(N),ischemia-reperfusion group(I/R),dexmedetomidine preconditioning group(D),JNK singnaling pathway inhibitor SP600125 group(SP)and dexmedetomidine+SP600125 group(D+SP).The changes of heart rate(HR),maximum rate of increase of left ventricular pressure(+dp/dtmax),left ventricular developed pressure(LVDP),left ventricular end-diastolic pressure(LVEDP),myocardial infarction size and myocardial cell apoptosis rate(AI)were recorded in each group.The ultrastructural changes of myocardium were observed by electron microscopy.The expressions of GRP78,JNK and p-JNK proteins were detected by Western blot.Results Compared with the group N,HR,LVDP and±dp/dtmax in the other groups were decreased,while LVEDP,myocardial infarct size,AI,GRP78,p-JNK and p-JNK/JNK proteins expressions were increased(P<0.05).Compared with the group I/R,HR,LVDP and±dp/dtmax in the group D,SP and D+SP were increased,LVEDP,myocardial infarct size,AI,GRP78,p-JNK and p-JNK/JNK proteins expressions were decreased(P<0.05).The ultrastructures of cardiomyocytes under the electronic microscope in the group N were integrity,which in the group I/R were severely damaged,and which in the group D,SP and D+SP had little damage.Conclusion Dexmedetomidine preconditioning attenuates MIRI by inhibiting JNK signaling pathway,reducing excessive endoplasmic reticulum stress and its mediated apoptosis.