Wang Lihua, Li Mingjie, Liu Bing, Zheng Ruihan, Zhang Xinyi, Yu Shuoyi
Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, Heilongjiang 150086, China.
Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, Heilongjiang 150086, China.
Brain Res Bull. 2024 Jun 15;212:110953. doi: 10.1016/j.brainresbull.2024.110953. Epub 2024 Apr 16.
Chronic cerebral hypoperfusion (CCH) is a common cause of brain dysfunction. As a microRNA (also known as miRNAs or miRs), miR-30a-5p participates in neuronal damage and relates to ferroptosis. We explored the in vivo and in vitro effects and functional mechanism of miR-30a-5p in CCH-triggered cognitive impairment through the silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway.
After 1 month of CCH modeling through bilateral common carotid artery stenosis, mice were injected with 2 μL antagomir (also known as anti-miRNAs) miR-30a-5p, with cognitive function evaluated by Morris water maze and novel object recognition tests. In vitro HT-22 cell oxygen glucose deprivation (OGD) model was established, followed by miR-30a-5p inhibitor and/or si-SIRT1 transfections, with Fe concentration, malonaldehyde (MDA) and glutathione (GSH) contents, reactive oxygen species (ROS), miR-30a-5p and SIRT1 and glutathione peroxidase 4 (GPX4) protein levels, NRF2 nuclear translocation, and miR-30a-5p-SIRT1 targeting relationship assessed.
CCH-induced mice showed obvious cognitive impairment, up-regulated miR-30a-5p, and down-regulated SIRT1. Ferroptosis occurred in hippocampal neurons, manifested by elevated Fe concentration and ROS and MDA levels, mitochondrial atrophy, and diminished GSH content. Antagomir miR-30a-5p or miR-30a-5p inhibitor promoted SIRT1 expression and NRF2 nuclear translocation, increased GPX4, cell viability and GSH content, and reduced Fe concentration and ROS and MDA levels. miR-30a-5p negatively regulated SIRT1. In vitro, miR-30a-5p knockout increased NRF2 nuclear translocation by up-regulating SIRT1, inhibiting OGD-induced ferroptosis in HT-22 cells.
miR-30a-5p induces hippocampal neuronal ferroptosis and exacerbates post-CCH cognitive dysfunction by targeting SIRT1 and reducing NRF2 nuclear translocation.
慢性脑灌注不足（CCH）是脑功能障碍的常见原因。作为一种微小RNA（也称为miRNA或miR），miR-30a-5p参与神经元损伤并与铁死亡相关。我们通过沉默信息调节因子1（SIRT1）/核因子红细胞2相关因子2（NRF2）途径，探讨了miR-30a-5p在CCH引发的认知障碍中的体内和体外作用及功能机制。
通过双侧颈总动脉狭窄进行CCH建模1个月后，给小鼠注射2 μL抗miR-30a-5p（也称为抗miRNA），通过莫里斯水迷宫和新物体识别测试评估认知功能。建立体外HT-22细胞氧糖剥夺（OGD）模型，随后进行miR-30a-5p抑制剂和/或si-SIRT1转染，评估铁浓度、丙二醛（MDA）和谷胱甘肽（GSH）含量、活性氧（ROS）、miR-30a-5p和SIRT1以及谷胱甘肽过氧化物酶4（GPX4）蛋白水平、NRF2核转位以及miR-30a-5p-SIRT1靶向关系。
CCH诱导的小鼠表现出明显的认知障碍，miR-30a-5p上调，SIRT1下调。海马神经元发生铁死亡，表现为铁浓度、ROS和MDA水平升高，线粒体萎缩，GSH含量降低。抗miR-30a-5p或miR-30a-5p抑制剂促进SIRT1表达和NRF2核转位，增加GPX4、细胞活力和GSH含量，并降低铁浓度、ROS和MDA水平。miR-30a-5p对SIRT1起负调节作用。在体外，miR-30a-5p敲除通过上调SIRT1增加NRF2核转位，抑制OGD诱导的HT-22细胞铁死亡。
miR-30a-5p通过靶向SIRT1并减少NRF2核转位，诱导海马神经元铁死亡并加重CCH后的认知功能障碍。
