Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Neuroscience. 2022 Jan 1;480:155-166. doi: 10.1016/j.neuroscience.2021.11.013. Epub 2021 Nov 12.
P2Y purinoceptor 2 (P2RY2) is involved in the regulation of cell proliferation and apoptosis. The aim of this study was to explore the effects of P2RY2 on cerebral ischemia/reperfusion (I/R) injury and its molecular mechanism. Middle cerebral artery occlusion (MCAO) model in rats and OXYGEN and oxygen-glucose deprivation/reoxygenation (OGD/R) model in PC12 cells were established. P2RY2 expressions in I/R injury model in vitro and in vivo were up-regulated. In the OGD/R group, ROS level, cyto-CytC and mitochondrial fission factors expressions and cell apoptosis were increased, while SOD activity, mito-CytC and mitochondrial fusion factors expressions were decreased. P2RY2 overexpression could reverse these results. Up-regulated P2RY2 expression decreased Yes-associated protein (YAP) phosphorylation level, promote the nuclear translocation of YAP, and inhibit cell apoptosis, which can be reversed by YAP inhibitor verteporfin. The addition of PI3K/AKT inhibitor LY294002 could reverse the decrease of YAP phosphorylation level and cell apoptosis, and the increase of nuclear translocation caused by P2RY2 overexpression. Further in vivo studies validated that interference with P2RY2 increased the cerebral infarction area, decreased AKT expression, enhanced YAP phosphorylation, and inhibited the nuclear translocation of YAP. In conclusion, P2RY2 can alleviate cerebral I/R injury by inhibiting YAP phosphorylation and reducing mitochondrial fission.
P2Y 嘌呤能受体 2 (P2RY2) 参与细胞增殖和凋亡的调节。本研究旨在探讨 P2RY2 对脑缺血/再灌注 (I/R) 损伤的影响及其分子机制。建立了大鼠大脑中动脉闭塞 (MCAO) 模型和 PC12 细胞的 OXYGEN 和氧葡萄糖剥夺/再氧合 (OGD/R) 模型。体外和体内 I/R 损伤模型中 P2RY2 的表达上调。在 OGD/R 组中，ROS 水平、Cyt-CytC 和线粒体分裂因子的表达以及细胞凋亡增加，而 SOD 活性、mito-CytC 和线粒体融合因子的表达降低。P2RY2 的过表达可以逆转这些结果。上调的 P2RY2 表达降低了 Yes 相关蛋白 (YAP) 的磷酸化水平，促进了 YAP 的核转位，并抑制了细胞凋亡，而 YAP 抑制剂 verteporfin 可以逆转这种作用。添加 PI3K/AKT 抑制剂 LY294002 可以逆转 P2RY2 过表达引起的 YAP 磷酸化水平和细胞凋亡降低以及核转位增加。进一步的体内研究验证了干扰 P2RY2 可增加脑梗死面积，降低 AKT 表达，增强 YAP 磷酸化，并抑制 YAP 的核转位。总之，P2RY2 可以通过抑制 YAP 磷酸化和减少线粒体分裂来减轻脑 I/R 损伤。
