School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China.
College of Intelligence and Information Engineering, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
Stroke Vasc Neurol. 2022 Dec;7(6):500-509. doi: 10.1136/svn-2021-001396. Epub 2022 Jun 20.
Postsynaptic density protein-95 (PSD95) plays an important role in cerebral ischaemia injury, but its mechanism needs further research. This study aimed to explore the role of PSD95 in (Ang-(1-7))-Mas-mediated cerebral ischaemia protection and its regulatory mechanism.
Oxygen-glucose deprivation (OGD) neuron and rat middle cerebral artery occlusion (MCAO) models were used as in vitro and in vivo models, respectively. TAT-MAS9C was used to disrupt the interaction between PSD95 and Mas. The recombinant PSD95 adenovirus (Ad-PSD95) was used to overexpress PSD95 in neurons.
Results showed that in OGD neurons, Ang-(1-7) could promote cell viability; reduce cell apoptosis; reduce the cell membrane localisation of Mas; upregulate the expression levels of pAKT, bcl-2 and I-κB; and downregulate the expression levels of Bax, pI-κB, tumour necrosis factor alpha and interleukin-1β. TAT-MAS9C could enhance the aforementioned effects of Ang-(1-7). However, the PSD95 overexpression inhibited the aforementioned effects of Ang-(1-7). In the MCAO rat model, the 2,3,5-triphenyltetrazolium chloride (TTC) staining showed that Ang-(1-7) reduced the infarct volume. The Morris water maze test showed that the number of crossings over the platform area in the Ang-(1-7) group was significantly increased. TAT-MAS9C could promote the protective effect of Ang-(1-7).
Results suggested that PSD95 alleviated the activation of AKT and the inhibition of nuclear factor kappa B signalling pathway mediated by the Ang-(1-7)-Mas complex, thereby reducing neuronal activity, increasing apoptosis and inhibiting the Ang-(1-7)-Mas-mediated cerebral ischaemia protection.
突触后密度蛋白-95（PSD95）在脑缺血损伤中发挥重要作用，但具体机制仍需进一步研究。本研究旨在探讨 PSD95 在（Ang-（1-7））-Mas 介导的脑缺血保护中的作用及其调控机制。
采用氧葡萄糖剥夺（OGD）神经元和大鼠大脑中动脉闭塞（MCAO）模型分别作为体外和体内模型。采用 TAT-MAS9C 破坏 PSD95 与 Mas 的相互作用。采用重组 PSD95 腺病毒（Ad-PSD95）过表达神经元中的 PSD95。
结果表明，在 OGD 神经元中，Ang-（1-7）可促进细胞活力；减少细胞凋亡；减少 Mas 的细胞膜定位；上调 pAKT、bcl-2 和 I-κB 的表达水平；下调 Bax、pI-κB、肿瘤坏死因子-α和白细胞介素-1β的表达水平。TAT-MAS9C 可增强 Ang-（1-7）的上述作用。然而，PSD95 的过表达抑制了 Ang-（1-7）的上述作用。在 MCAO 大鼠模型中，2,3,5-三苯基四氮唑氯化物（TTC）染色显示 Ang-（1-7）减少了梗死体积。Morris 水迷宫试验显示 Ang-（1-7）组穿越平台区域的次数明显增加。TAT-MAS9C 可促进 Ang-（1-7）的保护作用。
结果表明，PSD95 减轻了 Ang-（1-7）-Mas 复合物介导的 AKT 激活和核因子 kappa B 信号通路的抑制，从而减少神经元活性，增加凋亡，并抑制 Ang-（1-7）-Mas 介导的脑缺血保护。
