Li Qian, He Quanwei, Baral Suraj, Mao Ling, Li Yanan, Jin Huijuan, Chen Shengcai, An Tianhui, Xia Yuanpeng, Hu Bo
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
FEBS J. 2016 May;283(9):1720-33. doi: 10.1111/febs.13697. Epub 2016 Mar 31.
MicroRNA-493 (miR-493) is known to suppress tumour metastasis and angiogenesis and its expression is decreased in stroke patients. In the present study, we investigated a role for miR-493 in regulating post-stroke angiogenesis. We found decreased expression of miR-493 in the ischemic boundary zone (IBZ) of rats subjected to middle cerebral artery occlusion (MCAO), and in rat brain microvascular endothelial cells (RBMECs) exposed to oxygen glucose deprivation. Down-regulating miR-493 with a lateral ventricular injection of antagomir-493, a synthetic miR-493 inhibitor, increased capillary density in the IBZ, decreased focal infarct volume and ameliorated neurologic deficits in rats subjected to MCAO. Intriguingly, MCAO also increased the expression of macrophage migration inhibitory factor (MIF) in the IBZ of rats; MIF expression was also increased in RBMECs exposed to oxygen glucose deprivation. We found that miR-493 directly targeted MIF, and that the protective effect of miR-493 inhibition in angiogenesis was attenuated by knocking down MIF. This effect could then be rescued by administration of recombinant MIF. Our findings highlight the importance of miR-493 in regulating angiogenesis after MCAO, and indicate that miR-493 is a potential therapeutic target in the treatment of stroke.
已知微小RNA-493（miR-493）可抑制肿瘤转移和血管生成，且其在中风患者中表达降低。在本研究中，我们探究了miR-493在调节中风后血管生成中的作用。我们发现，在大脑中动脉闭塞（MCAO）的大鼠缺血边界区（IBZ）以及暴露于氧糖剥夺的大鼠脑微血管内皮细胞（RBMECs）中，miR-493表达降低。通过侧脑室注射抗miR-493（一种合成的miR-493抑制剂）下调miR-493，可增加MCAO大鼠IBZ中的毛细血管密度，减小局灶性梗死体积并改善神经功能缺损。有趣的是，MCAO还增加了大鼠IBZ中巨噬细胞迁移抑制因子（MIF）的表达；在暴露于氧糖剥夺的RBMECs中，MIF表达也增加。我们发现miR-493直接靶向MIF，并且通过敲低MIF可减弱miR-493抑制对血管生成的保护作用。然后，通过给予重组MIF可挽救此效应。我们的研究结果突出了miR-493在调节MCAO后血管生成中的重要性，并表明miR-493是中风治疗中的一个潜在治疗靶点。
