Canonical Notch Pathway Protects Hepatocytes from Ischemia/Reperfusion Injury in Mice by Repressing Reactive Oxygen Species Production Through JAK2/STAT3 Signaling
Canonical Notch Pathway Protects Hepatocytes from Ischemia/Reperfusion Injury in Mice by Repressing Reactive Oxygen Species Production Through JAK2/STAT3 Signaling
复制标题
经典Notch通路通过JAK2/STAT3信号传导抑制活性氧的产生，保护小鼠肝细胞免受缺血/再灌注损伤
DOI：
10.1002/hep.24469
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发表时间：
2011-09-01
期刊：
影响因子：
13.5
通讯作者：
Han, Hua
中科院分区：
文献类型：
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作者：
Yu, Heng-Chao;Qin, Hong-Yan;Han, Hua
肝脏缺血再灌注损伤是由缺血后再灌注早期活性氧（ROS）的积累引起的，但控制ROS产生和清除的细胞机制尚不完全清楚。在这项研究中，我们表明，通过敲除转录因子RBP-J或药物抑制剂来阻断Notch信号会导致肝脏I/R损伤加剧，表现为体外和体内肝功能恶化以及细胞凋亡、坏死和炎症增加。阻断Notch信号导致肝细胞内ROS增加，阻断Notch信号后ROS清除剂可治疗加重的肝I/R损伤，提示Notch信号缺乏通过增加ROS水平加重I/R损伤。Notch信号阻断导致Hes 5的下调，导致Hes 5-STAT 3复合物的形成减少和STAT 3的低磷酸化，这进一步减弱了锰超氧化物歧化酶（MnSOD）的表达并增加了ROS和细胞凋亡。事实上，组成型活性STAT 3的过表达在Notch信号传导不存在的情况下拯救了MnSOD表达和I/R损伤诱导的细胞凋亡。最后，通过配体刺激或Hes 5过表达的强制Notch激活减少了细胞内ROS，并通过激活STAT 3和MnSOD表达保护肝细胞免于I/R损伤后的凋亡。
Hepatic ischemia/reperfusion (I/R) injury is initiated by reactive oxygen species (ROS) accumulated during the early reperfusion phase after ischemia, but cellular mechanisms controlling ROS production and scavenging have not been fully understood. In this study, we show that blocking Notch signal by knockout of the transcription factor RBP‐J or a pharmacological inhibitor led to aggravated hepatic I/R injury, as manifested by deteriorated liver function and increased apoptosis, necrosis, and inflammation, both in vitro and in vivo. Interruption of Notch signaling resulted in increased intracellular ROS in hepatocytes, and a ROS scavenger cured exacerbated hepatic I/R injury after Notch signaling blockade, suggesting that Notch signal deficiency aggravated I/R injury through increased ROS levels. Notch signal blockade resulted in down‐regulation of Hes5, leading to reduced formation of the Hes5‐STAT3 complex and hypophosphorylation of STAT3, which further attenuated manganese superoxide dismutase (MnSOD) expression and increased ROS and apoptosis. Indeed, overexpression of a constitutively active STAT3 rescued MnSOD expression and I/R injury–induced apoptosis in the absence of Notch signaling. Finally, forced Notch activation by ligand stimulation or Hes5 overexpression reduced intracellular ROS and protected hepatocytes from apoptosis after I/R injury through the activation of STAT3 and MnSOD expression.