期刊
REDOX BIOLOGY
卷 17, 期 -, 页码 323-337出版社
ELSEVIER
DOI: 10.1016/j.redox.2018.05.001
关键词
Stroke; Neuroprotection; Ischemic tolerance; Electrophile; Lipid peroxidation; VE-cadherin; Conditioning
资金
- US National Institutes of Health [NS092810, NS089534, NS095671, NS105430, NS036736]
- US Department of Veterans Affairs [BX002495]
- American Heart Association [10SDG2560122]
- National Natural Science Foundation of China [81271276, 81228008]
Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3 beta (via GSK3 beta-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3 beta-dependent Nrf2 degradation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据