Data_Sheet_1_Ras-related protein Rab-20 inhibition alleviates cerebral ischemia/reperfusion injury by inhibiting mitochondrial fission and dysfunction.PDF

Ras-related protein Rab-20 (Rab20) is induced in hypoxia and contributes to hypoxia-induced apoptosis. However, the role and mechanism of Rab20 in cerebral ischemia/reperfusion (I/R) injury need to be elucidated. We established a cerebral I/R injury model in the mice and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT22 cells to determine the effects of Rab20 in cerebral I/R injury. Rab20 expression was upregulated in mice after I/R and in HT22 cells after OGD/R. Upregulated Rab20 was mainly located in neurons. Rab20 inhibition significantly alleviated brain infarct volume, neurological deficits, and neuronal apoptosis in mice after I/R. Moreover, Rab20 knockdown significantly ameliorated the OGD/R-induced inhibition of cell viability and apoptotic cell death in HT22 cells. Rab20 knockdown significantly alleviated OGD/R-induced mitochondrial fission by repressing mitochondrial dynamin-related protein 1 (Drp-1) recruitment and increasing Drp-1 (Ser637) phosphorylation and ameliorated mitochondrial dysfunction by reducing the mitochondrial reactive oxygen species (ROS) and cellular calcium accumulation and increasing the mitochondrial membrane potential. In addition, Rab20 knockdown significantly alleviated cytochrome c release from the mitochondria into the cytosol in HT22 cells after OGD/R. Rab20 contributes to cerebral I/R injury by regulating mitochondria-associated apoptosis pathways. Targeting Rab20 may be an attractive strategy for the treatment of cerebral I/R injury.

Ras相关蛋白Rab-20（Rab20）在缺氧状态下被诱导，并参与缺氧诱导的细胞凋亡。然而，Rab20在脑缺血/再灌注（I/R）损伤中的作用及其机制尚需阐明。本研究构建了小鼠脑缺血/再灌注损伤模型及HT22细胞的氧糖剥夺/再氧合（OGD/R）模型，以探究Rab20在脑缺血/再灌注损伤中的作用。Rab20在I/R损伤后的小鼠中以及OGD/R损伤后的HT22细胞中表达上调，主要定位于神经元。Rab20的抑制显著减轻了小鼠脑缺血/再灌注后的脑梗死体积、神经功能缺损和神经元凋亡。此外，Rab20敲低显著改善了OGD/R诱导的细胞活力抑制和细胞凋亡死亡。Rab20敲低通过抑制线粒体动力蛋白1（Drp-1）的募集并增加Drp-1（Ser637）磷酸化，显著减轻了OGD/R诱导的线粒体分裂，并通过减少线粒体活性氧（ROS）和细胞钙积累，增加线粒体膜电位，改善了线粒体功能障碍。此外，Rab20敲低在OGD/R损伤后的HT22细胞中显著减轻了细胞色素c从线粒体释放到细胞质。Rab20通过调节与线粒体相关的凋亡通路参与脑缺血/再灌注损伤。针对Rab20可能成为治疗脑缺血/再灌注损伤的有吸引力的策略。