We recently showed that inhibition of hypoxia-induced factor-1α (HIF-1α) decreased acute ischemic stroke-induced blood-brain barrier (BBB) damage. However, factors that induce the upregulation of HIF-1α expression remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase played a critical role in reperfusion-induced BBB damage after stroke. However, the role of NADPH oxidase in BBB injury during the acute ischemia stage remains unclear. This study is aimed at investigating the role of NADPH oxidase in BBB injury and the expression of HIF-1α after acute ischemic stroke. A sutured middle cerebral artery occlusion (MCAO) model was used to mimic ischemic stroke in rats. Our results show that the inhibition of NADPH oxidase by apocynin can significantly reduce the BBB damage caused by 2 h ischemic stroke accompanied by reducing the degradation of tight junction protein occludin. In addition, treatment with apocynin significantly decreased the upregulation of HIF-1α induced by 2 h MCAO. More importantly, apocynin could also inhibit the MMP-2 upregulation. Of note, HIF-1α was not colocalized with a bigger blood vessel. Taken together, our results showed that inhibition of NADPH oxidase-mediated HIF-1α upregulation reduced BBB damage accompanied by downregulating MMP-2 expression and occludin degradation after 2 h ischemia stroke. These results explored the mechanism of BBB damage after acute ischemic stroke and may help reduce the associated cerebral hemorrhage transformation after thrombolysis and endovascular treatment after ischemic stroke.

中文翻译：

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NADPH 氧化酶诱导的缺氧诱导因子 1α 增加在大鼠 2 小时局灶性缺血性卒中后血脑屏障破坏中的作用

我们最近表明，抑制缺氧诱导的因子 1 α (HIF-1 α ) 可降低急性缺血性中风诱导的血脑屏障 (BBB) 损伤。然而，诱导 HIF-1 α表达上调的因素仍不清楚。烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶在中风后再灌注诱导的 BBB 损伤中起关键作用。然而，NADPH 氧化酶在急性缺血阶段 BBB 损伤中的作用仍不清楚。这项研究的目的是调查NADPH氧化酶的BBB损伤中的作用和HIF-1的表达α急性缺血性脑卒中后。缝合的大脑中动脉闭塞 (MCAO) 模型用于模拟大鼠的缺血性中风。我们的研究结果表明，夹竹桃苷对 NADPH 氧化酶的抑制作用可以显着减少 2 h 缺血性卒中引起的 BBB 损伤，同时减少紧密连接蛋白 occludin 的降解。此外，夹竹桃麻素处理显着降低了2 小时 MCAO 诱导的 HIF-1 α的上调。更重要的是，夹竹桃麻素还可以抑制 MMP-2 上调。值得注意的是，HIF-1 α没有与更大的血管共定位。总之，我们的结果表明抑制 NADPH 氧化酶介导的 HIF-1 α在缺血性卒中 2 小时后，上调可减少 BBB 损伤，同时下调 MMP-2 表达和 occludin 降解。这些结果探讨了急性缺血性卒中后 BBB 损伤的机制，可能有助于减少缺血性卒中后溶栓和血管内治疗后相关的脑出血转化。