P2RY2 Alleviates Cerebral Ischemia–Reperfusion Injury by Inhibiting YAP Phosphorylation and Reducing Mitochondrial Fission

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.