β2-Adrenergic Receptor-Mediated HIF-1α Upregulation Mediates Blood Brain Barrier Damage in Acute Cerebral Ischemia.
β2-Adrenergic Receptor-Mediated HIF-1α Upregulation Mediates Blood Brain Barrier Damage in Acute Cerebral Ischemia.
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beta2-肾上腺素受体介导的 HIF-1α 上调介导急性脑缺血中的血脑屏障损伤。
DOI：
10.3389/fnmol.2017.00257
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发表时间：
2017
影响因子：
4.8
通讯作者：
Jin X
中科院分区：
文献类型：
--
作者：
Sun Y;Chen X;Zhang X;Shen X;Wang M;Wang X;Liu WC;Liu CF;Liu J;Liu W;Jin X
在溶栓时间窗内血脑屏障（BBB）的破坏是缺血性卒中脑出血的前因事件。我们最近的研究表明，脑缺血2小时引起非梗死区血脑屏障损伤，分泌的基质金属蛋白酶-2（MMP-2）解释了这种破坏。然而，影响MMP-2分泌和调节BBB损伤的因素仍然未知。由于缺氧诱导因子-1 α（hypoxia-inducible factor-1 alpha，HIF-1α）被发现是缺氧的主要调节因子，因此我们试图研究HIF-1α在缺血脑中BBB损伤中的作用以及HIF-1α表达的调控因素。采用大鼠大脑中动脉闭塞（MCAO）和体外氧糖剥夺（OGD）模型模拟脑缺血。预先给予HIF-1α抑制剂YC-1可显著抑制MCAO诱导的BBB损伤，并抑制occludin降解和血管内皮生长因子（VEGF）mRNA表达上调。有趣的是，β2-肾上腺素能受体（β2-AR）拮抗剂ICI 118551通过调节HIF-1α表达减轻缺血诱导的BBB损伤。免疫组化双标法显示HIF-1α在缺血神经元中表达上调，而在星形胶质细胞和内皮细胞中表达不明显。值得注意的是，用抑制剂YC-1或siRNA抑制HIF-1α显著阻止了OGD诱导的VEGF上调以及神经元中VEGF和MMP-2的分泌。更重要的是，用ICI 118551阻断β2-AR可抑制缺血神经元中HIF-1α的上调，并减弱OGD处理的神经元条件培养基诱导的occludin降解。总之，阻断β2-AR介导的HIF-1α上调介导了急性脑缺血期间的BBB损伤。这些发现为缺血性卒中早期血脑屏障损伤提供了新的机制理解，并可能有助于减少溶栓相关的出血并发症。
Disruption of the blood brain barrier (BBB) within the thrombolytic time window is an antecedent event to intracerebral hemorrhage in ischemic stroke. Our recent studies showed that 2-h cerebral ischemia induced BBB damage in non-infarcted area and secreted matrix metalloproteinase-2 (MMP-2) accounted for this disruption. However, the factors that affect MMP-2 secretion and regulate BBB damage remains unknown. Since hypoxia-inducible factor-1 alpha (HIF-1α) was discovered as a mater regulator in hypoxia, we sought to investigate the roles of HIF-1α in BBB damage as well as the factors regulating HIF-1α expression in the ischemic brain. in vivo rat middle cerebral artery occlusion (MCAO) and in vitro oxygen glucose deprivation (OGD) models were used to mimic ischemia. Pretreatment with HIF-1α inhibitor YC-1 significantly inhibited 2-h MCAO-induced BBB damage, which was accompanied by suppressed occludin degradation and vascular endothelial growth factor (VEGF) mRNA upregulation. Interestingly, β2-adrenergic receptor (β2-AR) antagonist ICI 118551 attenuated ischemia-induced BBB damage by regulating HIF-1α expression. Double immunostaining showed that HIF-1α was upregulated in ischemic neurons but not in astrocytes andendothelial cells. Of note, HIF-1α inhibition with inhibitor YC-1 or siRNA significantly prevented OGD-induced VEGF upregulation as well as the secretion of VEGF and MMP-2 in neurons. More importantly, blocking β2-AR with ICI 118551 suppressedHIF-1α upregulation in ischemic neurons and attenuated occludin degradation induced by the conditioned media of OGD-treatedneurons. Taken together, blockade of β2-AR-mediated HIF-1α upregulation mediates BBB damage during acute cerebral ischemia. These findings provide new mechanistic understanding of early BBB damage in ischemic stroke and may help reduce thrombolysis-related hemorrhagic complications.
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DOI：
10.1097/00004647-200204000-00003
发表时间：
2002-04-01
影响因子：
6.3
作者：
Bernaudin, M;Nedelec, AS;Schumann-Bard, P
通讯作者：
Schumann-Bard, P
影响因子：
5.5
作者：
Menon, B;Singh, M;Singh, K
通讯作者：
Singh, K
丹参酮 IIA 磺酸钠可提高急性缺血性中风患者 Rt-PA 治疗的有效性，并改善血脑屏障损伤
影响因子：
6.9
作者：
Ji B;Zhou F;Han L;Yang J;Fan H;Li S;Li J;Zhang X;Wang X;Chen X;Xu Y
通讯作者：
Xu Y
影响因子：
8.3
作者：
Kastrup, Andreas;Groeschel, Klaus;Terborg, Christoph
通讯作者：
Terborg, Christoph
影响因子：
158.5
作者：
Hacke, Werner;Kaste, Markku;Toni, Danilo
通讯作者：
Toni, Danilo