Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China.
Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, Jilin Province, China.
Neurochem Res. 2023 Feb;48(2):658-670. doi: 10.1007/s11064-022-03791-x. Epub 2022 Oct 28.
Cerebral ischemia reperfusion injury (CIRI) is the commonest cause of brain dysfunction. Up-regulation of POU domain class 2 transcription factor 2 (POU2F2) has been reported in patients with cerebral ischemia, while the role of POU2F2 in CIRI remains elusive. Middle cerebral artery occlusion/reperfusion (MCAO/R) in mice and oxygen and glucose deprivation/reperfusion (OGD/R) in mouse primary cortical neurons were used as models of CIRI injury in vivo and in vitro. Lentivirus-mediated POU2F2 knockdown further impaired CIRI induced by MCAO/R in mice, which was accompanied by increased-neurological deficits, cerebral infarct volume and neuronal loss. Our evidence suggested that POU2F2 deficiency deteriorated oxidative stress and ferroptosis according to the phenomenon such as the abatement of SOD, GSH, glutathione peroxidase 4 (GPX4) activity and accumulation of ROS, lipid ROS, 4-hydroxynonenal (4-HNE) and MDA. In vivo, primary cortical neurons with POU2F2 knockdown also showed worse neuronal damage, oxidative stress and ferroptosis. Sestrin2 (Sesn2) was reported as a neuroprotection gene and involved in ferroptosis mechanism. Up-regulation of Sesn2 was observed in the ischemic penumbra and OGD/R-induced neuronal cells. Further, we proved that POU2F2, as a transcription factor, could bind to Sesn2 promoter and positively regulate its expression. Sesn2 overexpression relieved oxidative stress and ferroptosis induced by POU2F2 knockdown in OGD/R-treated neurons. This research demonstrated that CIRI induced a compensatory increase of POU2F2 and Sesn2. Down-regulated POU2F2 exacerbated CIRI through the acceleration of oxidative stress and ferroptosis possibly by decreasing Sesn2 expression, which offers new sights into therapeutic mechanisms for CIRI.
脑缺血再灌注损伤（CIRI）是脑功能障碍的最常见原因。已有报道称，脑缺血患者的 POU 结构域类 2 转录因子 2（POU2F2）表达上调，但其在 CIRI 中的作用仍不清楚。本研究采用小鼠大脑中动脉闭塞/再灌注（MCAO/R）和小鼠原代皮质神经元氧葡萄糖剥夺/再灌注（OGD/R）作为体内和体外 CIRI 损伤模型。慢病毒介导的 POU2F2 敲低进一步加重了 MCAO/R 诱导的 CIRI，表现为神经功能缺损加重、脑梗死体积增大和神经元丢失。我们的证据表明，POU2F2 缺乏根据 SOD、GSH、谷胱甘肽过氧化物酶 4（GPX4）活性和 ROS、脂质 ROS、4-羟基壬烯醛（4-HNE）和 MDA 积累等现象加剧氧化应激和铁死亡。在体内，敲低 POU2F2 的原代皮质神经元也表现出更严重的神经元损伤、氧化应激和铁死亡。Sesn2（Sesn2）被报道为一种神经保护基因，参与铁死亡机制。在缺血半影区和 OGD/R 诱导的神经元细胞中观察到 Sesn2 的上调。进一步证明，POU2F2 作为一种转录因子，可以与 Sesn2 启动子结合并正向调节其表达。Sesn2 的过表达缓解了 OGD/R 处理神经元中 POU2F2 敲低诱导的氧化应激和铁死亡。这项研究表明，CIRI 诱导 POU2F2 和 Sesn2 的代偿性增加。下调 POU2F2 通过降低 Sesn2 表达加速氧化应激和铁死亡，从而加重 CIRI，为 CIRI 的治疗机制提供了新的思路。
