TY - JOUR
T1 - Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP
T2 - implications for cerebral ischemic stroke
AU - Han, Bing
AU - Zhang, Yuan
AU - Zhang, Yanhong
AU - Bai, Ying
AU - Chen, Xufeng
AU - Huang, Rongrong
AU - Wu, Fangfang
AU - Leng, Shuo
AU - Chao, Jie
AU - Zhang, John H.
AU - Hu, Gang
AU - Yao, Honghong
N1 - Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2018/7/3
Y1 - 2018/7/3
N2 - UNLABELLED: 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: 4',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.
AB - UNLABELLED: 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: 4',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.
KW - Astrocyte activation
KW - MIR142
KW - TIPARP
KW - autophagy
KW - circHECTD1
KW - stroke
KW - tMCAO
KW - MicroRNAs/genetics
KW - Astrocytes/metabolism
KW - Humans
KW - Male
KW - Autophagy
KW - Brain Ischemia/complications
KW - Infarction, Middle Cerebral Artery/pathology
KW - Nucleoside Transport Proteins
KW - Base Sequence
KW - Female
KW - RNA, Circular
KW - Stroke/complications
KW - Brain Infarction/genetics
KW - Mice, Inbred C57BL
KW - RNA/genetics
KW - Animals
KW - Aged
KW - Poly(ADP-ribose) Polymerases/genetics
KW - Up-Regulation/genetics
UR - http://www.scopus.com/inward/record.url?scp=85050354210&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85050354210&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/4afc117f-06fe-371c-a489-c67a5a9519b9/
U2 - 10.1080/15548627.2018.1458173
DO - 10.1080/15548627.2018.1458173
M3 - Article
C2 - 29938598
SN - 1554-8627
VL - 14
SP - 1164
EP - 1184
JO - Autophagy
JF - Autophagy
IS - 7
ER -