Inhibition of miR-181a protects female mice from transient focal cerebral ischemia by targeting astrocyte estrogen receptor-α.
Inhibition of miR-181a protects female mice from transient focal cerebral ischemia by targeting astrocyte estrogen receptor-α.
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DOI：
10.1016/j.mcn.2017.05.004
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Giffard RG
中科院分区：
文献类型：
--
作者：
Stary CM;Xu L;Li L;Sun X;Ouyang YB;Xiong X;Zhao J;Giffard RG
miR-181 a在中风中的作用是否具有性别二态性尚不清楚。先前的工作显示了miR-181 a抑制对雄性小鼠的保护作用。雌激素受体-α（ERα）是miR 181在子宫内膜中的一个确定的靶点。因此，我们研究了卵巢切除术后miR-181 a抑制和17β-雌二醇（E2）替代的单独和联合作用。成年雌性小鼠切除卵巢，并植入E2或载体含有胶囊14天前1小时大脑中动脉闭塞（MCAO）。各组在MCAO前24 h侧脑室注射miR-181 a或错配对照。MCAO后，评估神经功能缺损和梗死体积。对原代雄性和雌性星形胶质细胞培养物进行葡萄糖剥夺，使用miR-181 a抑制剂或转染对照，以及E2或溶剂对照，使用/不使用小干扰RNA敲低ESRα。通过碘化丙啶染色和乳酸脱氢酶测定来评估细胞死亡。使用miR-181 a/ERα靶位点阻断剂（TSB）（含/不含miR-181 a模拟物）证实miR-181 a在星形胶质细胞中靶向ERα。单独地，miR-181 a抑制或E2减少了雌性小鼠的梗死体积并改善了神经评分，并保护了雄性和雌性星形胶质细胞培养物。联合miR-181 a抑制加E2对雌性小鼠和雌性星形胶质细胞培养物提供了更大的保护，但在雄性星形胶质细胞培养物中没有。MiR-181 a抑制仅增加体内和雌性培养物中的ERα水平，而用siRNA敲除ERα增加两种性别中的细胞死亡。ERα TSB给药在两种性别动物中均具有较强的保护作用。总之，本研究的结果表明，miR-181 a抑制增强了E2介导的雌性卒中保护作用，部分原因是增加了ERα的产生，这是在雌性小鼠和雌性星形胶质细胞中检测到的一种机制。在联合miR-181 a抑制/E2治疗和miR-181 a靶向ERα治疗中观察到性别差异。
Whether the effect of miR-181a is sexually dimorphic in stroke is unknown. Prior work showed protection of male mice with miR-181a inhibition. Estrogen receptor-α (ERα) is an identified target of miR181 in endometrium. Therefore we investigated the separate and joint effects of miR-181a inhibition and 17β-estradiol (E2) replacement after ovariectomy. Adult female mice were ovariectomized and implanted with an E2- or vehicle-containing capsule for 14d prior to 1h middle cerebral artery occlusion (MCAO). Each group received either miR-181a antagomir or mismatch control by intracerebroventricular injection 24h before MCAO. After MCAO neurologic deficit and infarct volume were assessed. Primary male and female astrocyte cultures were subjected to glucose deprivation with miR-181a inhibitor or transfection control, and E2 or vehicle control, with/without ESRα knockdown with small interfering RNA. Cell death was assessed by propidium iodide staining, and lactate dehydrogenase assay. A miR-181a/ERα target site blocker (TSB), with/without miR-181a mimic, was used to confirm targeting of ERα by miR-181a in astrocytes. Individually, miR-181a inhibition or E2 decreased infarct volume and improved neurologic score in female mice, and protected male and female astrocyte cultures. Combined miR-181a inhibition plus E2 afforded greater protection of female mice and female astrocyte cultures, but not in male astrocyte cultures. MiR-181a inhibition only increased ERα levels in vivo and in female cultures, while ERα knockdown with siRNA increased cell death in both sexes. Treatment with ERα TSB was strongly protective in both sexes. In conclusion, the results of the present study suggest miR-181a inhibition enhances E2-mediated stroke protection in females in part by augmenting ERα production, a mechanism detected in female mice and female astrocytes. Sex differences were observed with combined miR-181a inhibition/E2 treatment, and miR-181a targeting of ERα.
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影响因子：
6.2
作者：
Hutchison ER;Kawamoto EM;Taub DD;Lal A;Abdelmohsen K;Zhang Y;Wood WH 3rd;Lehrmann E;Camandola S;Becker KG;Gorospe M;Mattson MP
通讯作者：
Mattson MP
影响因子：
4.7
作者：
Dai, Xiaoniu;Chen, Ling;Sokabe, Masahiro
通讯作者：
Sokabe, Masahiro
影响因子：
4.8
作者：
Coleman, KM;Dutertre, M;Smith, CL
通讯作者：
Smith, CL
影响因子：
2.5
作者：
Cimarosti, H;Jones, NM;Beart, PM
通讯作者：
Beart, PM
影响因子：
2.5
作者：
Liao, SL;Chen, WY;Chen, CJ
通讯作者：
Chen, CJ