Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: implications for cerebral ischemic stroke
- 3 July 2018
- journal article
- research article
- Published by Informa UK Limited in Autophagy
- Vol. 14 (7), 1164-1184
- https://doi.org/10.1080/15548627.2018.1458173
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 typeKeywords
Funding Information
- National Natural Science Foundation of China (81673410)
- National Natural Science Foundation of China (81473190)
- National Natural Science Foundation of China (81603090)
- Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYZZ16_0127)
- Major State Basic Research Developmen (2013CB733800/2013CB733803)
This publication has 72 references indexed in Scilit:
- Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancerCancer Letters, 2017
- Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunityProceedings of the National Academy of Sciences, 2016
- Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAsNature Communications, 2016
- Circular RNA expression alterations are involved in OGD/R-induced neuron injuryBiochemical and Biophysical Research Communications, 2016
- A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223European Heart Journal, 2016
- Detecting and characterizing circular RNAsNature Biotechnology, 2014
- miR-142-3p Controls the Specification of Definitive Hemangioblasts during OntogenyDevelopmental Cell, 2013
- NAD+ administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemiaNeuroscience Letters, 2012
- Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioningAutophagy, 2010
- In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic toleranceBlood, 2009