The regulatory role of NF-κB in autophagy-like cell death after focal cerebral ischemia in mice.
The regulatory role of NF-κB in autophagy-like cell death after focal cerebral ischemia in mice.
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DOI：
10.1016/j.neuroscience.2013.03.045
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发表时间：
2013-08-06
期刊：
影响因子：
3.3
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Li WL;Yu SP;Chen D;Yu SS;Jiang YJ;Genetta T;Wei L
自噬可能有助于脑缺血诱导的细胞死亡，但自噬细胞死亡的调节在很大程度上是未知的。核因子-kappaB(NF-κB)是脑缺血后细胞凋亡的调节因子。在成年野生型(WT)和NF-κB p50基因敲除(p50−/−)小鼠中，通过结扎大脑中动脉远端分支诱导桶状皮质局灶性脑缺血。12~24 h后，缺血中心区和/或半暗带区Beclin-1和Lc3表达增强，自噬活性增强。这种自噬增加导致细胞损伤，末端脱氧核苷酸转移酶(TdT)介导的dUTP-生物素缺口末端标记(TUNEL)共染色和自噬抑制剂3-甲基腺嘌呤的保护作用证明了这一点。P50−/−小鼠的Beclin-1/TUNEL阳性细胞数明显多于WT小鼠。神经细胞和血管细胞死亡，通过与NeuN或IV型胶原共染色的TUNEL阳性细胞检测，在p50−/−小鼠中更为丰富。内皮细胞紧密连接标记阻滞素的免疫染色显示p50−/−小鼠血脑屏障受到更多损害。Western blotting显示，脑缺血后p50−/−小鼠脑梗塞周围组织中雷帕霉素(MTor)信号的哺乳动物靶点Akt减少。这些发现首次提供了脑缺血诱导的自噬样损伤受NF-κB途径调控的证据，这可能为缺血性卒中提供潜在的治疗方法。
Autophagy may contribute to ischemia-induced cell death in the brain, but the regulation of autophagic cell death is largely unknown. Nuclear factor kappa B (NF-κB) is a regulator of apoptosis in cerebral ischemia. We examined the hypothesis that autophagy-like cell death could contribute to ischemia-induced brain damage and the process was regulated by NF-κB. In adult wild-type (WT) and NF-κB p50 knockout (p50−/−) mice, focal ischemia in the barrel cortex was induced by ligation of distal branches of the middle cerebral artery. Twelve to 24 h later, autophagic activity increased as indicated by enhanced expression of Beclin-1 and LC3 in the ischemic core and/or penumbra regions. This increased autophagy contributed to cell injury, evidenced by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) co-staining and a protective effect achieved by the autophagy inhibitor 3-methyladenine. The number of Beclin-1/TUNEL-positive cells was significantly more in p50−/− mice than in WT mice. Neuronal and vascular cell death, as determined by TUNEL-positive cells co-staining with NeuN or Collagen IV, was more abundant in p50−/− mice. Immunostaining of the endothelial cell tight junction marker occludin revealed more damage to the blood–brain barrier in p50−/− mice. Western blotting of the peri-infarct tissue showed a reduction of Akt-the mammalian target of rapamycin (mTOR) signaling in p50−/− mice after ischemia. These findings provide the first evidence that cerebral ischemia induced autophagy-like injury is regulated by the NF-κB pathway, which may suggest potential treatments for ischemic stroke.
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影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
影响因子：
4.8
作者：
Choi, Ko-Eun;Hall, Casey L.;Yu, Shan P.
通讯作者：
Yu, Shan P.
DOI：
10.2174/187152506778520691
发表时间：
2006-10-01
影响因子：
--
作者：
Curin, Y.;Ritz, M. F.;Andriantsitohaina, R.
通讯作者：
Andriantsitohaina, R.
影响因子：
2.9
作者：
Li, Jimei;Lu, Zhongyang;Wei, Ling
通讯作者：
Wei, Ling
影响因子：
8
作者：
Fabre, C.;Carvalho, G.;Kroemer, G.
通讯作者：
Kroemer, G.