慢性低灌注诱导海马CA1区PERK/eIF2α/ATF4/CHOP-JNK/c-Jun信号通路及雌激素的保护作用
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国家自然科学基金(30970664,31171354);唐山市老年医学重点实验室(14140221B)


PERK/eIF2/ATF4/CHOP-JNK/c-Jun signaling pathway induced by chronic hypoperfusion and the protection of estrogen following BCCAO in hippocampal CA1 region
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    摘要:

    目的:观察慢性低灌注后海马CA1区内质网应激信号通路PERK-eIF2α-ATF4-促凋亡信号CHOP-JNK/c-Jun的变化及17-雌二醇(E2)的影响-方法:成年雌性大鼠行双侧卵巢切除,术后1周结扎双侧颈总动脉(bilateral common caroticl arterises occlusion,BCCAO)从而诱导慢性低灌注模型,实验动物随机分为sham(14 d-21 d)组,BCCAO(14 d-21 d-28 d)组,持续生理剂量E2处理组,SP600125处理组和溶剂对照组-Western blot法检测海马CA1区GRP78-ATF4-CHOP蛋白表达和PERK-eIF2α-JNK-c-Jun的磷酸化水平-结果:与sham 14 d组相比,BCCAO后14-21-28 d GRP78蛋白水平无显著差异,但PERK-eIF2α-ATF4及CHOP的蛋白表达均显著升高;而且JNK-c-Jun的磷酸化水平于BCCAO后各时间点均较sham组14 d显著升高-JNK抑制剂SP600125和E2不但显著阻断JNK/c-Jun信号通路的激活,也显著降低BCCAO后21 d诱导的PERK-eIF2α-ATF4-CHOP信号-结论:脑慢性低灌注可诱导海马CA1区内质网应激,其可能通过激活JNK/c-Jun信号通路及CHOP活性从而导致神经元损伤,长期生理剂量E2可显著降低此变化-

    Abstract:

    Objective:To investigate the changes of PERK-eIF2-ATF4 signaling pathway, pro-apoptosis CHOP, and JNK-c-Jun, as well as the effect of 17-estradiol (E2) following cerebral chronic hypoperfusion in the hippocampal CA1 region. Methods: Female rats were bilaterally ovariectomized, and 1 week later, chronic hypoperfusion was induced by occlusion bilateral common carotid arteries. The rats were randomly divided into the sham (14 d and 21 d)groups, the hypoperfusion (BCCAO 14 d, 21 d and 28 d) groups, the continuous physiological dose of E2 group, the JNK inhibitor SP600125 group and the solvent control group. GRP78, ATF4, CHOP, and phosphorylation levels of PERK, eIF2α, JNK and c-Jun were detected using Western blotting in the hippocampal CA1 region. Results: Compared to the sham 14 d group, phosphorylation levels of PERK and eIF2α, as well as ATF4 and CHOP expressions were significantly increased at 14 d, 21 d and 28 d after BCCAO, although there was no statistic difference in GRP78 protein expression. Furthermore, p-JNK and p-c-Jun significantly increased after BCCAO compared with the sham 14 d group. Either E2 or SP600125 not only significangly prevented the activation of JNK/c-Jun pathway, but also attenuated PERK-eIF2α-ATF4-CHOP stress signaling induced by BCCAO after 21 d in the hippocampal CA1 region. Conclusion: Chronic hypoperfusion induced by BCCAO could cause long term ER stress in the hippocampal CA1 region, which might include activation of JNK/c-Jun signaling pathway and CHOP transcriptional activity, and ultimately induce neuron damage. Continuously administration of physiological dose E2 could significantly prevent the damage.

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代永鑫,朱 莹,李 宁,张文丽,唐 慧,王瑞敏.慢性低灌注诱导海马CA1区PERK/eIF2α/ATF4/CHOP-JNK/c-Jun信号通路及雌激素的保护作用[J].南京医科大学学报(自然科学版),2016,(1):33-38

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  • 收稿日期:2015-03-16
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  • 在线发布日期: 2016-01-30
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