JNK信号途径通过内质网应激反应介导心肌梗死后心力衰竭小鼠心肌组织的凋亡

c-Jun N-terminal protein kinase signaling pathway mediates cardiac myocyte apoptosis in mouse congestive heart failure after myocardial infraction via endoplasmic reticulum stress

目的探讨在心肌梗死后心力衰竭诱导的内质网应激反应中c-Jun氨基端激酶(c-Jun N-terminal kinase,JNK)通路介导心肌细胞凋亡可能的作用及机制。方法结扎小鼠左冠状动脉主干建立心肌梗死后心力衰竭(心衰)模型,32只小鼠采用随机数字法分4组:假手术组、心肌梗死后2、4、6周组,采用超声心动图观察心室扩张及心功能变化情况,Western blot检测内质网分子伴侣GRP78蛋白以及JNK蛋白及其磷酸化水平的表达。采用TUNEL法观察心肌细胞的凋亡情况。结果与假手术组相比较,心肌梗死后心力衰竭的小鼠左心室扩大,心功能下降。小鼠心肌组织GRP78表达明显增高(P<0.05),JNK蛋白表达没有明显变化,但其活化形式磷酸化JNK表达增高(P<0.05)。TUNEL染色显示心肌梗死后心力衰竭的小鼠心肌组织凋亡明显增多(P<0.05)。结论心肌梗死后心力衰竭诱导内质网应激反应,并激活JNK信号途径促进了心肌细胞的凋亡。

Objective To explore the contribution of the c-Jun N-terminal protein kinase （JNK） signaling pathway to cardiac myocyte apoptosis in mouse congestive heart failure due to myocardial infraction. Methods The mouse heart failure model was induced by acute myocardial infarction through ligating the left coronary artery. Thirty-two health male mice were randomly divided into 4 groups ： sham operated group, 2-week postoperative group, d-week postoperative group arid 6-week postoperative group. The ventricular dilatation and left ventricular function were assessed by echocardiography. The expressions of GRP78, JNK and phosphorylated JNK were assessed by Western blot assay. The cardiac myocyte apoptosis were assessed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling （TUNEL）. Results Compared with the sham group, cardiac expression of endoplasmic reticulum chaperones GRP78 and phosphorylated JNK were significantly up-regulated in the operation groups （ P 〈 0. 05 ）. The number of TUNEL positive ceils were markedly increased in the operation group compared with the sham group （P 〈 0.05）. Conclusion These findings suggest that the CNK signaling pathway partly mediates cardiac myocyte apoptosis in mouse congestive heart failure due to myocardial infraction via endoplasmic reticulum stress.