Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: implications for cerebral ischemic stroke

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.

Current status and potential role of circular RNAs in neurological disorders

“…In addition, no studies have reported on the efficiency of targeting circRNAs through systemic injections in stroke patients. However, previous studies that demonstrated the regulatory properties of circRNAs in stroke models (Bai et al 2018;Han et al 2018) suggest that circRNAs have potential as therapeutic targets for treatment of ischemic stroke.…”

“…CircDLGAP4 over‐expression dramatically attenuated neurological deficits and decreased infarct areas in a mouse stroke model. Furthermore, this group identified circHECTD1, which was increased in the ischemic mouse brain and in the blood of individuals who had suffered a stroke (Han et al ). Knockdown of circHECTD1 expression ameliorated astrocyte activation and decreased infarct areas in mice through regulation of miR‐142 targets.…”

The role of circular RNA HECTD1 expression in disease risk, disease severity, inflammation, and recurrence of acute ischemic stroke

“…7,8 For example, a study discloses that knockdown of circRNA HECTD1 attenuates infract size and decreases neurological deficits in cerebral ischemia transient middle cerebral artery occlusion mouse (tMCAO) stroke models. 7 Besides that, a preliminary study based on primary cultures of alveolar macrophages from silicosis patients demonstrates that circRNA HECTD1 involves in SiO 2 -mediated inflammation cascade. 8 Based on the role of circRNA HECTD1 in enlarging stroke infarct size, accelerating neurological deficits, and inflammation from previous studies, we hypothesized that circRNA HECTD1 may be involved in the development and progression of AIS.…”

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

“…In addition, central excitotoxicity enhanced neuronal autophagy, and autophagy inhibition has been proposed as a potential strategy for neuronal protection (Wang et al, ). Conversely, astrocyte autophagy restrained astrocyte activation and inflammatory cytokine production after cerebral ischemia (Han et al, ), spinal cord injury (Goldshmit et al, ), oxygen–glucose deprivation, and reoxygenation (Li et al, ). The findings from these studies suggest that autophagic mechanisms differ in different cell types.…”