Department of Anesthesiology (Qunli Campus), The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R China.
Department of Neurosrugery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, P.R China.
Brain Inj. 2023 Sep 19;37(11):1285-1293. doi: 10.1080/02699052.2023.2237881. Epub 2023 Aug 23.
Ischemia/reperfusion (I/R) is a pathological process that causes severe damage. Propofol is known to alleviate I/R-related injury; however, the exact function and underlying mechanisms are not fully understood.
Using an oxygen glucose deprivation/re-oxygenation (OGD/R) method, an I/R injury model was induced. The cell viability and the level of Fe, glutathione synthetase (GSH), and malondialdehyde (MDA) were evaluated using kits. Luciferase reporter gene assay, chromatin immunoprecipitation, and RNA immunoprecipitation (RIP) were used to verify the interaction between molecules. The m6A level of BECN1 mRNA was determined through methylated RIP.
Propofol-treated OGD/R models showed reduced levels of Fe and MDA, while the cell viability and the level of GSH increased. Propofol inhibited ferroptosis by down-regulating HIF-1α in OGD/R-treated HT22 cells. HIF-1α is bound to the promoter region of YTHDF1 to promote its transcription, and YTHDF1 promoted ferroptosis by stabilizing the mRNA of BECN1. The suppressive effect of propofol on OGD/R-induced ferroptosis was reversed by the overexpression of YTHDF1.
Our study revealed that the HIF-1α/YTHDF1/BECN1 axis in OGD/R-treated HT22 cells promotes ferroptosis, and administration of propofol can inhibit this axis to avoid cell death. This study provides a novel insight for the neuroprotective function of propofol.
缺血再灌注（I/R）是一种导致严重损伤的病理过程。已知异丙酚可减轻与 I/R 相关的损伤；然而，其确切功能和潜在机制尚不完全清楚。
采用氧葡萄糖剥夺/复氧（OGD/R）方法，诱导 I/R 损伤模型。使用试剂盒评估细胞活力以及铁、谷胱甘肽合成酶（GSH）和丙二醛（MDA）的水平。通过荧光素酶报告基因检测、染色质免疫沉淀和 RNA 免疫沉淀（RIP）验证分子间的相互作用。通过甲基化 RIP 测定 BECN1 mRNA 的 m6A 水平。
在 OGD/R 处理的 HT22 细胞中，异丙酚处理的模型显示铁和 MDA 水平降低，而细胞活力和 GSH 水平升高。异丙酚通过下调 OGD/R 处理的 HT22 细胞中的 HIF-1α 抑制铁死亡。HIF-1α 与 YTHDF1 的启动子区域结合以促进其转录，YTHDF1 通过稳定 BECN1 的 mRNA 促进铁死亡。YTHDF1 的过表达逆转了异丙酚对 OGD/R 诱导的铁死亡的抑制作用。
本研究揭示了 OGD/R 处理的 HT22 细胞中 HIF-1α/YTHDF1/BECN1 轴促进铁死亡，而给予异丙酚可以抑制该轴以避免细胞死亡。本研究为异丙酚的神经保护功能提供了新的见解。
