nNOS Translocates into the Nucleus and Interacts with Sox2 to Protect Neurons Against Early Excitotoxicity via Promotion of Shh Transcription

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• 作者：Dongmei Zhang ; Hongmei Wang ; Hanzhang Liu ; Tao Tao ; Ning Wang…
• 关键词：nNOS ; Sox ; 2 ; Shh ; Neuronal injury ; Cerebral ischemia
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：53
• 期：9
• 页码：6444-6458
• 全文大小：7,401 KB
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182
• 卷排序：53

文摘

Cerebral ischemic stroke is a major public health problem leading to high mortality rates and disability in adults. The NMDA receptor (NMDAR)/neuronal nitric oxide synthase (nNOS)/NO-dependent excitotoxicity has been recognized to play an important role in cerebral ischemic stroke pathogenesis. Accumulating evidence suggests that the biological function of nNOS is associated with its ability to couple proteins and its subcellular localization. Previously, we and others determined that nNOS could translocate into the nucleus in cultured astrocytes, but the underlying mechanisms and biological significance remained unclear. In the present study, we identified a specific interaction between nNOS and Sox2 (SRY (sex determining region Y)-box 2), a member of the Sox family of transcription factors, both in vivo and in vitro. Our studies showed that nNOS is transported into the nucleus and interacted with Sox2 to form a nNOS-Sox2 complex in neurons at the early stage following glutamate stimulation. Mechanistically, via activating the transcription of Shh (Sonic hedgehog), the downstream target of Sox2, this nNOS-Sox2 complex exerted a neuroprotective function against glutamate-induced excitotoxicity. Utilizing the MCAO focal ischemia model on rats, we further verified that the ‘nNOS-Sox2-Shh’ axis was involved in the ischemic neuronal injury. Taken together, our studies revealed that the ‘nNOS-Sox2-Shh’ axis functions as a novel feedback compensatory mechanism to protect neurons against the early excitotoxicity and ischemic injury.