LncRNA BIRF Promotes Brain Ischemic Tolerance Induced By Cerebral Ischemic Preconditioning Through Upregulating GLT-1 via Sponging miR-330-5p

Abstract

Long noncoding RNAs (lncRNAs) play an important regulatory role in various diseases. However, the role of lncRNAs in brain ischemic tolerance (BIT) induced by cerebral ischemic preconditioning (CIPC) is still unknown. The lncRNA profile of rat cortical astrocytes pretreated with ischemic preconditioning was analyzed by high-throughput sequencing. The results of Cell-Counting Kit-8 (CCK-8) assay showed that a novel lncRNA, NONRATT009133.2, which we referred to as brain ischemia–related factor (BIRF), was highly correlated with BIT. Through bioinformatics analysis, we predicted that BIRF, miR-330-5p, and GLT-1 (also named Slc1a2) might constitute a ceRNA regulatory network in the induction of BIT. We found that BIRF was upregulated by CIPC, which promoted GLT-1 expression and BIT induction. BIRF could directly bind to miR-330-5p. Furthermore, miR-330-5p directly targeted GLT-1, and miR-330-5p inhibited both GLT-1 expression and BIT induction in vitro and in vivo. Moreover, BIRF acts as a molecular sponge to competitively bind to miR-330-5p with GLT-1 mRNA, while the miR-330-5p inhibitor reversed all the effects of BIRF siRNA on GLT-1 expression and neuronal vitality. Taken together, our results demonstrate the important roles of the BIRF/miR-330-5p/GLT-1 axis in the induction of BIT by CIPC. BIRF may be a potentially effective therapeutic strategy against stroke injury.

Regulation of rat HspB5/alphaB-Crystallin by microRNAs miR-101a-3p, miR-140-5p, miR-330-5p, and miR-376b-3p

“…HspB5 is upregulated by several transcription factors, the most important being heat shock factor 1 (HSF1)(De Thonel et al 2012 ). Among validated target genes for miR-330-5p that might be relevant in the CNS are the NMDA receptor GRIN2A (Yan et al 2022 ) and the glial glutamate transporter GLT-1 (Li et al 2022 ). GRIN2A is known to activate the PI3K/Akt pathway under stress conditions (Wu and Tymianski 2018 ).…”

New role of astrocytes in neuroprotective mechanisms after ischemic stroke

“…Many studies have showed that GLT-1 upregulation plays a vital role in inducing ischemic tolerance by preventing excessive glutamate accumulation and terminating multiple downstream death-signalingcascades. 83,84 Compared with normal astrocytes, activated astrocytes in the ischemic area are closely related to the spatiotemporal pattern of ischemic tolerance after IPC. 65,85 The P2X7 receptor, as an ion channel forming ATP receptor, is selectively upregulated in activated astrocytes.…”