Activation of CRHR1 contributes to cerebral endothelial barrier impairment via cPLA2 phosphorylation in experimental ischemic stroke
Activation of CRHR1 contributes to cerebral endothelial barrier impairment via cPLA2 phosphorylation in experimental ischemic stroke
复制标题
DOI：
10.1016/j.cellsig.2019.109467
复制
发表时间：
2020-02-01
影响因子：
4.8
通讯作者：
Li, Shengnan
中科院分区：
文献类型：
--
作者：
Cao, Changchun;Zhou, Jun;Li, Shengnan
促肾上腺皮质激素释放激素受体（CRHR） 1的激活与实验性脑卒中的神经元损伤有关。然而，CRHR1激活与缺血再灌注（I/R）后脑内皮屏障损伤的关系尚不清楚。最近，我们已经证明细胞外信号调节激酶（Erk） 1/2和p38的激活是过氧化氢（H2O2）增加的细胞质磷脂酶A(2) （cPLA(2)）在bEnd3细胞中的磷酸化所必需的。通过体外类缺血模型，我们发现阻断和干扰CRHR1均可抑制h2o2增强的p38、Erk1/2和cPLA(2)磷酸化，进而抑制单层超通透性和ZO-1再分布。然后，通过短暂性大脑中动脉闭塞（tMCAO）小鼠模型，我们发现CRHR1拮抗剂NBI27914预处理可以减轻cPLA(2)磷酸化、Evans蓝染料（EBD）外渗、紧密连接破坏和线粒体细胞色素c释放。CRHR1的干扰也抑制了皮质血管的高通透性。此外，NBI27914可减轻神经血管损伤。MCAO 30 min再灌注7 d后，CRHR1干扰可减轻海马血脑屏障（BBB）渗漏，改善空间认知功能障碍。因此，我们的研究表明，在缺血性卒中期间，内皮细胞CRHR1的激活通过cPLA(2)磷酸化导致血脑屏障损伤。
The activation of corticotrophin-releasing hormone receptor (CRHR) 1 is implicated in neuronal injury in experimental stroke. However, little is known about the relationship between CRHR1 activation and brain endothelial barrier impairment after ischemia and reperfusion (I/R). Recently we have demonstrated that the activation of extracellular signal-regulated kinase (Erk) 1/2 as well as p38 is required for hydrogen peroxide (H2O2)-increased cytosolic phospholipase A(2) (cPLA(2)) phosphorylation in bEnd3 cells. Using this in vitro ischemic-like model, we found that both blockade and interference of CRHR1 inhibited H2O2-enhancd p38, Erk1/2 and cPLA(2) phosphorylation and in turn suppressed monolayer hyperpermeability and ZO-1 redistribution. Then using the transient middle cerebral artery occlusion (tMCAO) mouse model, we revealed that CRHR1 antagonist NBI27914 pretreatment attenuated cPLA(2) phosphorylation, Evans blue dye (EBD) extravasation, tight junction disruption and mitochondrial cytochrome c release. CRHR1 interference also inhibited cortical vascular hyperpermeability. Furthermore, NBI27914 administration attenuated neurovascular injury. After 30 min MCAO with 7 days reperfusion CRHR1 interference alleviated hippocampal blood-brain barrier (BBB) leakage and improved spatial cognitive dysfunction. Thus, our study demonstrates that during ischemic stroke the activation of endothelial CRHR1 contributes to BBB impairment via cPLA(2) phosphorylation.