title: Neuroprotective effect of microRNA-99a against focal cerebral ischemia-reperfusion injury in mice.
abstract: MicroRNA-99a (miR-99a) has been reported to function as a tumor suppressor through regulating cell cycle and apoptosis. But its clinical significance in ischemic stroke and its function in cerebral ischemia-reperfusion (I/R) injury remained unknown. Herein transient middle cerebral artery occlusion was built on C57BL/6 mice, followed by intracerebroventricular injection of miR-99a agomir or antagomir before reperfusion for 24h. Our clinical analysis indicates that plasma miR-99a level was significantly decreased in ischemic stroke patients as compared to healthy subjects, and a significant correlation was observed between miR-99a and clinical parameters. And miR-99a overexpression mitigated I/R injury in mice, as evidenced by reduced brain infarct volume and neural apoptosis, whereas miR-99a downregulation aggravates brain injury. In vitro, miR-99a protected neuro-2a cells against hydrogen peroxide-induced oxidative stress injury, by improving cell viability, suppressing LDH release and cell apoptosis. In addition, miR-99a overexpression inhibited H2O2 induced G1/S phase transition in neuro-2a cells, accompanied by a significant decrease in cyclin D1 level and a tendency of down-regulation of CDK6. It was further proved in mice that miR-99a inhibited cyclin D1 and CDK6 expressions following cerebral I/R injury. These findings indicate that miR-99a reduces neuronal damage following cerebral I/R through regulating cell cycle progression and preventing apoptosis, suggesting that miR-99a could be used as a new therapeutic agent targeting neuronal cell cycle re-entry following stroke.
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China.
authors.forename: Rongliang
authors.initials: R
authors.lastname: Wang
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China.
authors.forename: Chencheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China; Beijing Institute for Brain Disorders, Beijing 100053, China; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing 100053, China; Beijing Geriatric Medical Research Center, Beijing 100053, China; Beijing Institute for Brain Disorders, Beijing 100053, China; Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing 100053, China. Electronic address: yumin111@ccmu.edu.cn.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016877:Oxidants / Q000494:pharmacology; D015427:Reperfusion Injury / Q000097:blood / Q000517:prevention & control*; D018709:Statistics, Nonparametric; D014162:Transfection
chemical_list: D035683:MicroRNAs; C573158:Mirn99 microRNA, mouse; D018696:Neuroprotective Agents; D016877:Oxidants; D019938:Cyclin D1; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D051361:Cyclin-Dependent Kinase 6; D053148:Caspase 3
keywords: CDK6; Cell cycle; Cerebral ischemia; Cyclin D1; MiR-99a; Oxidative stress