Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats.
Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats.
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DOI：
10.1177/0271678x15610786
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Sharp FR
中科院分区：
文献类型：
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作者：
Liu da Z;Jickling GC;Ander BP;Hull H;Zhan X;Cox C;Shroff N;Dykstra-Aiello C;Stamova B;Sharp FR
由于我们最近的研究表明，缺血性卒中后患者全血和大鼠全血中的miR-122降低，我们测试了升高血液miR-122是否会改善大鼠卒中结局。年轻成年大鼠进行暂时性大脑中动脉闭塞（MCAO）或假手术。使用基于聚乙二醇-脂质体的转染系统在MCAO后施用miR-122模拟物。在有或没有miR-122治疗的情况下，在MCAO后24 h检查血液中的神经功能缺损、脑梗死、脑血管完整性、粘附分子表达以及miR-122靶基因和间接靶基因的表达。MCAO后血液中的miR-122降低，而MCAO后24 h血液中的miR-122模拟物升高。静脉注射而非脑室内注射miR-122模拟物可减少神经功能缺损和脑梗死，减弱ICAM-1表达，并维持MCAO后血管完整性。miR-122模拟物还下调了MCAO后血液中的直接靶基因（例如Vcam 1、Nos 2、Pla 2g 2a）和间接靶基因（例如Alox 5、Itga 2b、Timp 3、Illb、Il 2、Mmp 8），这些基因被预测影响细胞粘附、渗出、白细胞外渗、类花生酸和动脉粥样硬化信号传导。数据显示，升高miR-122可改善卒中结局，我们推测这是通过下调血液白细胞中的miR-122靶基因实现的。
Because our recent studies have demonstrated that miR-122 decreased in whole blood of patients and in whole blood of rats following ischemic stroke, we tested whether elevating blood miR-122 would improve stroke outcomes in rats. Young adult rats were subjected to a temporary middle cerebral artery occlusion (MCAO) or sham operation. A polyethylene glycol-liposome-based transfection system was used to administer a miR-122 mimic after MCAO. Neurological deficits, brain infarction, brain vessel integrity, adhesion molecule expression and expression of miR-122 target and indirect-target genes were examined in blood at 24 h after MCAO with or without miR-122 treatment. miR-122 decreased in blood after MCAO, whereas miR-122 mimic elevated miR-122 in blood 24 h after MCAO. Intravenous but not intracerebroventricular injection of miR-122 mimic decreased neurological deficits and brain infarction, attenuated ICAM-1 expression, and maintained vessel integrity after MCAO. The miR-122 mimic also down-regulated direct target genes (e.g. Vcam1, Nos2, Pla2g2a) and indirect target genes (e.g. Alox5, Itga2b, Timp3, Il1b, Il2, Mmp8) in blood after MCAO which are predicted to affect cell adhesion, diapedesis, leukocyte extravasation, eicosanoid and atherosclerosis signaling. The data show that elevating miR-122 improves stroke outcomes and we postulate this occurs via downregulating miR-122 target genes in blood leukocytes.