Kir6.1 Knockdown Aggravates Cerebral Ischemia/Reperfusion-Induced Neural Injury in Mice
Kir6.1 Knockdown Aggravates Cerebral Ischemia/Reperfusion-Induced Neural Injury in Mice
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DOI：
10.1111/cns.12117
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发表时间：
2013-08-01
影响因子：
5.5
通讯作者：
Hu, Gang
中科院分区：
文献类型：
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作者：
Dong, Yin-Feng;Wang, Lin-Xiao;Hu, Gang
背景和目的ATP敏感钾（K-ATP）通道将能量代谢与电活动耦合起来，在包括中风在内的脑部疾病中发挥重要作用。然而，主要在神经胶质细胞上表达的含有Kir6.1的K-ATP通道对中风的影响尚不清楚。方法和结果在本研究中，我们发现C57BL/6J小鼠大脑中动脉闭塞（MCAO）1小时和再灌注24小时后缺血脑区中Kir6.1的表达显着降低。然后，我们对Kir6.1杂合子敲除小鼠（Kir6.1（+/-））进行脑缺血/再灌注（I/R）损伤，发现Kir6.1（+/-）小鼠表现出神经功能紊乱加剧和梗塞面积扩大，并伴有胶质细胞过度激活和血脑屏障（BBB）损伤。此外，我们发现Kir6.1敲低加剧了内质网（ER）应激，从而增加了小鼠大脑中促炎因子肿瘤坏死因子和白介素-1（TNF-和IL-1）的水平。结论我们的研究结果表明，Kir6.1敲低通过增加ER应激和炎症反应加剧了脑缺血再灌注引起的脑损伤，表明含有Kir6.1的K-ATP通道可能是中风的潜在治疗靶点。
Background and PurposeATP-sensitive potassium (K-ATP) channels couple energy metabolism with electric activity, which play important roles in brain diseases including stroke. However, the impacts of Kir6.1-containing K-ATP channels that mainly expressed on glia in stroke remain unclear.Methods and ResultsIn this study, we found that expression of Kir6.1 was significantly decreased in the ischemic brain area of C57BL/6J mice after 1-h middle cerebral artery occlusion (MCAO) and 24-h reperfusion. Then, we subjected Kir6.1 heterozygote knockout (Kir6.1(+/-)) mice to cerebral ischemia/reperfusion (I/R) injury and found that Kir6.1(+/-) mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by glial over-activation and blood-brain barrier (BBB) damages. Furthermore, we showed that Kir6.1 knockdown aggravated endoplasmic reticulum (ER) stress and thereby increased the levels of proinflammatory factors tumor necrosis factor- and interleukin-1 (TNF- and IL-1) in mouse brain.ConclusionsOur findings reveal that Kir6.1 knockdown exacerbates cerebral I/R-induced brain damages via increasing ER stress and inflammatory response, indicating that Kir6.1-containing K-ATP channels may be a potential therapeutic target for stroke.