Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: implications for cerebral ischemic stroke
Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: implications for cerebral ischemic stroke
复制标题
通过靶向 MIR142-TIPARP 通过自噬激活星形胶质细胞的环状 RNA HECTD1 的新见解：对脑缺血性中风的影响
DOI：
10.1080/15548627.2018.1458173
复制
发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Yao, Honghong
中科院分区：
文献类型：
--
作者：
Han, Bing;Zhang, Yuan;Yao, Honghong
摘要环状RNA在中枢神经系统中高度表达，参与生理和病理生理过程的调控。然而，circRNA在中风中的潜在作用在很大程度上仍然未知。在这里，使用circRNA微阵列，我们发现，在短暂性大脑中动脉闭塞（tMCAO）小鼠中风模型中，缺血性脑组织中的环状RNA Hectd 1（circHectd 1）水平显著增加，并在急性缺血性中风（AIS）患者的血浆样本中进一步验证了这一发现。敲低circHectd 1表达显著减少梗死面积，减弱神经元缺损，并改善tMCAO小鼠星形胶质细胞活化。从机制上讲，circHECTD 1作为内源性MIR 142（microRNA 142）海绵发挥作用，以抑制MIR 142活性，从而抑制TIPARP（TCDD诱导型聚[ADP-核糖]聚合酶）表达，随后抑制星形胶质细胞通过大自噬/自噬活化。总而言之，我们的研究结果表明circHECTD 1及其偶联机制参与了脑缺血，从而提供了circHECTD 1可以作为中风的新型生物标志物和治疗靶点的转化证据。缩略语：3-甲基丙烯酸：3-甲基腺嘌呤; ACTB：肌动蛋白β; AIS：急性缺血性卒中;助理秘书：原代小鼠星形胶质细胞; BECN 1：beclin 1，自噬相关; BMI：体重指数; circHECTD 1：circRNA HECTD 1; circRNA：环状RNA; CBF：脑血流量; Con：对照; DAPI：4 β，6-二脒基-2-苯基吲哚; ECA：颈外动脉; FISH：荧光原位杂交; GAPDH：甘油醛-3-磷酸脱氢酶; Gdna：基因组DNA; GFAP：胶质细胞酸性蛋白; GO：基因本体; HDL：高密度脂蛋白; IOD：积分光密度; LDL：低密度脂蛋白; LPA：脂蛋白（a）; MAP 1 LC 3 B：微管相关蛋白1轻链3 β; MIR 142：microRNA 142; mNSS：改良神经系统严重程度评分; MRI：磁共振成像; NIHSS：美国国立卫生研究院斯托克量表; OGD-R：氧糖剥夺-再灌注; PCR：聚合酶链反应; PFA：多聚甲醛; SQSTM 1：隔离体1; TIPARP：TCDD诱导型聚（ADP-核糖）聚合酶; tMCAO：短暂性大脑中动脉闭塞; TTC：氯化2，3，5-三苯基四唑; UTR：非翻译区; WT：野生型
ABSTRACT Circular RNAs (circRNAs) are highly expressed in the central nervous system and are involved in the regulation of physiological and pathophysiological processes. However, the potential role of circRNAs in stroke remains largely unknown. Here, using a circRNA microarray, we showed that circular RNA Hectd1 (circHectd1) levels were significantly increased in ischemic brain tissues in transient middle cerebral artery occlusion (tMCAO) mouse stroke models and further validated this finding in plasma samples from acute ischemic stroke (AIS) patients. Knockdown of circHectd1 expression significantly decreased infarct areas, attenuated neuronal deficits, and ameliorated astrocyte activation in tMCAO mice. Mechanistically, circHECTD1 functions as an endogenous MIR142 (microRNA 142) sponge to inhibit MIR142 activity, resulting in the inhibition of TIPARP (TCDD inducible poly[ADP-ribose] polymerase) expression with subsequent inhibition of astrocyte activation via macroautophagy/autophagy. Taken together, the results of our study indicate that circHECTD1 and its coupling mechanism are involved in cerebral ischemia, thus providing translational evidence that circHECTD1 can serve as a novel biomarker of and therapeutic target for stroke. Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AIS: acute ischemic stroke; AS: primary mouse astrocytes; BECN1: beclin 1, autophagy related; BMI: body mass index; circHECTD1: circRNA HECTD1; circRNAs: circular RNAs; CBF: cerebral blood flow; Con: control; DAPI: 4ʹ,6-diamidino-2-phenylindole; ECA: external carotid artery; FISH: fluorescence in situ hybridization; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; Gdna: genomic DNA; GFAP: glial fibrillary acidic protein; GO: gene ontology; HDL: high-density lipoprotein; IOD: integrated optical density; LDL: low-density lipoprotein; LPA: lipoprotein(a); MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MIR142: microRNA 142; mNSS: modified neurological severity scores; MRI: magnetic resonance imaging; NIHSS: National Institute of Health Stoke Scale; OGD-R: oxygen glucose deprivation-reperfusion; PCR: polymerase chain reaction; PFA: paraformaldehyde; SQSTM1: sequestosome 1; TIPARP: TCDD inducible poly(ADP-ribose) polymerase; tMCAO: transient middle cerebral artery occlusion; TTC: 2,3,5-triphenyltetrazolium chloride; UTR: untranslated region; WT: wild type