Sestrin2 Silencing Exacerbates Cerebral Ischemia/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK/PGC-1α Pathway in Rats.
Sestrin2 Silencing Exacerbates Cerebral Ischemia/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK/PGC-1α Pathway in Rats.
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DOI：
10.1038/srep30272
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发表时间：
2016-07-25
影响因子：
4.6
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Li L;Xiao L;Hou Y;He Q;Zhu J;Li Y;Wu J;Zhao J;Yu S;Zhao Y
Sestrin2 （Sesn2）在一些神经退行性疾病中发挥神经保护作用。然而，Sesn2在中风中的作用尚不清楚。amp激活的蛋白激酶/过氧化物酶体增殖体激活受体γ共激活因子-1α (AMPK/PGC-1α)通路在调节线粒体生物发生中起重要作用，有助于预防脑缺血/再灌注（I/R）损伤。在这里，我们旨在确定Sesn2是否通过AMPK/PGC-1α信号通路调节线粒体生物发生，从而减轻I/R损伤。为了验证这一点，我们对Sprague-Dawley大鼠进行了大脑中动脉闭塞（MCAO） 1小时，并使Sesn2沉默。再灌注后24 h，我们发现Sesn2 siRNA组神经功能缺损加重，梗死体积增大，氧化应激和神经元损伤程度高于MCAO组。为了探索其保护机制，我们使用了AMPK激活剂。脑I/R后，Sesn2、p-AMPK、PGC-1α、NRF-1、TFAM、SOD2、UCP2的表达水平显著升高。然而，Sesn2小干扰RNA （siRNA）阻止了这些蛋白的上调。相反，用5′-氨基咪唑-4-羧酰胺核苷激活AMPK会减弱Sesn2 siRNA的作用。上述结果提示，Sesn2沉默可能通过抑制AMPK/PGC-1α通路，抑制线粒体生物发生，降低线粒体生物活性，最终加重脑I/R损伤。
Sestrin2 (Sesn2) exerts neuroprotective properties in some neurodegenerative diseases. However, the role of Sesn2 in stroke is unclear. The AMP-activated protein kinase/peroxisome proliferator-activated receptor γ coactivator-1α (AMPK/PGC-1α) pathway plays an important role in regulating mitochondrial biogenesis, which helps prevent cerebral ischemia/reperfusion (I/R) injury. Here, we aimed to determine whether Sesn2 alleviated I/R damage by regulating mitochondrial biogenesis through the AMPK/PGC-1α signaling pathway. To be able to test this, Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h with Sesn2 silencing. At 24 h after reperfusion, we found that neurological deficits were exacerbated, infarct volume was enlarged, and oxidative stress and neuronal damage were greater in the Sesn2 siRNA group than in the MCAO group. To explore protective mechanisms, an AMPK activator was used. Expression levels of Sesn2, p-AMPK, PGC-1α, NRF-1, TFAM, SOD2, and UCP2 were significantly increased following cerebral I/R. However, upregulation of these proteins was prevented by Sesn2 small interfering RNA (siRNA). In contrast, activation of AMPK with 5′-aminoimidazole-4-carboxamide riboside weakened the effects of Sesn2 siRNA. These results suggest that Sesn2 silencing may suppress mitochondrial biogenesis, reduce mitochondrial biological activity, and finally aggravate cerebral I/R injury through inhibiting the AMPK/PGC-1α pathway.