The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury.
The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury.
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DOI：
10.1097/tp.0000000000001032
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发表时间：
2016-02
期刊：
影响因子：
6.2
通讯作者：
Zhai Y
中科院分区：
文献类型：
--
作者：
Zhou H;Zhu J;Yue S;Lu L;Busuttil RW;Kupiec-Weglinski JW;Wang X;Zhai Y
内质网（ER）应激在肝脏缺血再灌注损伤（IRI）的发病机制中发挥着关键作用。由于 ER 应激会触发适应性细胞反应，因此决定其在肝脏 IRI 中功能结果的问题仍有待确定。在小鼠肝脏部分热缺血模型中，我们研究了短暂（30m）或长时间（90m）肝脏缺血如何调节局部内质网应激反应和自噬活性及其与肝脏IRI的关系。评估了化学伴侣 4-苯基丁酸 (4-PBA) 或自噬抑制剂 3-甲基腺嘌呤 (3-MA) 的作用。我们的结果表明，虽然两种类型的缺血都会在肝脏中诱导 ER 应激反应的 ATF6 分支，但短暂的缺血会激活肝脏自噬，但长时间的缺血会抑制肝脏自噬。虽然3-MA对长时间缺血后的肝脏IRI没有影响，但它在短暂缺血后显着增加肝脏IRI。 4-PBA 治疗通过恢复自噬通量来保护长期缺血后的肝脏免受 IRI，而辅助 3-MA 治疗则消除了其肝脏保护作用。然而，相同的 4-PBA 治疗会增加肝脏 IRI，并在短暂缺血后扰乱自噬通量。虽然两种类型的缺血都会激活 5' 单磷酸腺苷激活蛋白激酶 (AMPK) 和失活的蛋白激酶 B (Akt)，但长时间缺血也会导致缺血肝脏中自噬相关基因 (Atg) 3 和 Atg5 的下调。这些结果表明肝脏 IRI 中 ER 应激反应通过其自噬调节而存在功能二分性。短暂缺血会激活自噬，保护肝脏免受IRI的影响，而长时间缺血会抑制自噬，促进肝脏IRI的发生。
Endoplasmic reticulum (ER) stress plays critical roles in the pathogenesis of liver ischemia and reperfusion injury (IRI). As ER stress triggers an adaptive cellular response, the question of what determines its functional outcome in liver IRI remains to be defined. In a murine liver partial warm ischemia model, we studied how transient (30m) or prolonged (90m) liver ischemia regulated local ER stress response and autophagy activities and their relationship with liver IRI. Effects of chemical chaperon 4-phenylbutyrate (4-PBA) or autophagy inhibitor 3-methyladenine (3-MA) was evaluated. Our results showed that while the ATF6 branch of ER stress response was induced in livers by both types of ischemia, liver autophagy was activated by transient, but inhibited by prolonged, ischemia. Although 3-MA had no effects on liver IRI after prolonged ischemia, it significantly increased liver IRI after transient ischemia. The 4-PBA treatment protected livers from IRI after prolonged ischemia by restoring autophagy flux, and the adjunctive 3-MA treatment abrogated its liver protective effect. The same 4-PBA treatment, however, increased liver IRI and disrupted autophagy flux after transient ischemia. Although both types of ischemia activated 5′ adenosine monophosphate-activated protein kinase (AMPK) and inactivated protein kinase B (Akt), prolonged ischemia also resulted in downregulations of autophagy-related gene (Atg) 3 and Atg5 in ischemic livers. These results indicate a functional dichotomy of ER stress response in liver IRI via its regulation of autophagy. Transient ischemia activates autophagy to protect livers from IRI, while prolonged ischemia inhibits autophagy to promote the development of liver IRI.