Zhang Yang, Guo Xun, Peng Zhifeng, Liu Chang, Ren Lili, Liang Jia, Wang Peng
Department of Neurobiology and Key Laboratory of Neurodegenerative Diseases of Liaoning Province, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
Department of Physiology, Shanxi Datong University, Datong, 037009, Shanxi, China.
Mol Neurobiol. 2022 Aug;59(8):4879-4891. doi: 10.1007/s12035-022-02903-6. Epub 2022 Jun 3.
The molecular mechanisms of blood-brain barrier (BBB) disruption in the early stage after ischemic stroke are poorly understood. In the present study, we investigated the potential role of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) in ischemia-induced BBB damage using an animal middle cerebral artery occlusion (MCAO) model of ischemic stroke. Recombinant human NMNAT1 (rh-NMNAT1) was administered intranasally and Sirtuin 1 (SIRT1) siRNA was administered by intracerebroventricular injection. Our results indicate that rh-NMNAT1 reduced infarct volume, improved functional outcome, and decreased BBB permeability in mice after ischemic stroke. Furthermore, rh-NMNAT1 prevented the loss of tight junction proteins (occludin and claudin-5) and reduced cell apoptosis in ischemic microvessels. NMNAT1-mediated BBB permeability was correlated with the elevation of nicotinamide adenine dinucleotide (NAD)/NADH ratio and SIRT1 level in brain microvascular endothelial cells. In addition, rh-NMNAT1 treatment significantly decreased the levels of acetylated nuclear factor-κB, acetylated p53, and matrix metalloproteinase-9 in ischemic microvessels. Moreover, the protective effects of rh-NMNAT1 could be reversed by SIRT1 siRNA. In conclusion, these findings indicate that rh-NMNAT1 protects BBB integrity after cerebral ischemia via the NAD/SIRT1 signaling pathway in brain microvascular endothelial cells. NMNAT1 may be a novel potential therapeutic target for reducing BBB disruption after ischemic stroke.
缺血性中风早期血脑屏障（BBB）破坏的分子机制尚不清楚。在本研究中，我们使用缺血性中风的动物大脑中动脉闭塞（MCAO）模型，研究了烟酰胺单核苷酸腺苷酸转移酶1（NMNAT1）在缺血诱导的血脑屏障损伤中的潜在作用。通过鼻内给予重组人NMNAT1（rh-NMNAT1），并通过脑室内注射给予沉默信息调节因子1（SIRT1）小干扰RNA（siRNA）。我们的结果表明，rh-NMNAT1可减少缺血性中风后小鼠的梗死体积，改善功能结局，并降低血脑屏障通透性。此外，rh-NMNAT1可防止紧密连接蛋白（闭合蛋白和Claudin-5）的丢失，并减少缺血性微血管中的细胞凋亡。NMNAT1介导的血脑屏障通透性与脑微血管内皮细胞中烟酰胺腺嘌呤二核苷酸（NAD）/还原型烟酰胺腺嘌呤二核苷酸（NADH）比值的升高和SIRT1水平相关。此外，rh-NMNAT1治疗可显著降低缺血性微血管中乙酰化核因子κB、乙酰化p53和基质金属蛋白酶9的水平。此外，SIRT1 siRNA可逆转rh-NMNAT1的保护作用。总之，这些发现表明，rh-NMNAT1通过脑微血管内皮细胞中的NAD/SIRT1信号通路保护脑缺血后的血脑屏障完整性。NMNAT1可能是减少缺血性中风后血脑屏障破坏的一种新的潜在治疗靶点。
