Pannexin1 knockout and blockade reduces ischemic stroke injury in female, but not in male mice.
Pannexin1 knockout and blockade reduces ischemic stroke injury in female, but not in male mice.
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DOI：
10.18632/oncotarget.16937
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发表时间：
2017-06-06
期刊：
影响因子：
--
通讯作者：
Naus CC
中科院分区：
文献类型：
--
作者：
Freitas-Andrade M;Bechberger JF;MacVicar BA;Viau V;Naus CC
膜通道Pannexin 1（Panx 1）介导损伤神经元中的凋亡和炎症信号级联，先前显示在缺血条件下的反应是性二态的。我们检验了Panx 1在介导卒中结局反应的性别差异中起潜在作用的假设。使中年、8-9月龄的雄性和雌性野生型和Panx 1 KO小鼠经受永久性大脑中动脉（MCA）闭塞，并在4天后评估梗死面积以及星形胶质细胞和小胶质细胞活化。通过测试丙磺舒（一种已知的Panx 1阻断剂）改变每搏输出量的效果，也探讨了Panx 1缺失的性二态性。与野生型对应物相比，Panx 1 KO雌性动物显示出显著较小的梗死体积（减少约50%），而雄性动物中未发生此类KO效应。Panx 1 KO的这种性别特异性效应通过梗死周围炎症和星形胶质细胞反应性的显著降低以及丙磺舒治疗的雌性动物（而非雄性动物）的较小梗死体积来重现。最后，女性表现出整体，较高的Panx 1蛋白水平比男性缺血条件下。这些发现揭示了Panx 1在永久性MCA闭塞中的有害作用，这是女性独有的，并为理解卒中结局的性别差异提供了几个新的框架。
The membrane channel Pannexin 1 (Panx1) mediates apoptotic and inflammatory signaling cascades in injured neurons, responses previously shown to be sexually dimorphic under ischemic conditions. We tested the hypothesis that Panx1 plays an underlying role in mediating sex differences in stroke outcome responses. Middle-aged, 8-9 month old male and female wild type and Panx1 KO mice were subjected to permanent middle cerebral artery (MCA) occlusion, and infarct size and astrocyte and microglia activation were assessed 4 days later. The sexually dimorphic nature of Panx1 deletion was also explored by testing the effect of probenecid a known Panx1 blocker to alter stroke volume. Panx1 KO females displayed significantly smaller infarct volumes (~ 50 % reduction) compared to their wild-type counterparts, whereas no such KO effect occurred in males. This sex-specific effect of Panx1 KO was recapitulated by significant reductions in peri-infarct inflammation and astrocyte reactivity, as well as smaller infarct volumes in probenecid treated females, but not males. Finally, females showed overall, higher Panx1 protein levels than males under ischemic conditions. These findings unmask a deleterious role for Panx1 in response to permanent MCA occlusion, that is unique to females, and provide several new frameworks for understanding sex differences in stroke outcome.
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