Abstract
Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes. However, their functions in cerebral ischemia remain largely unknown. Through an lncRNA array analysis in a rat model of focal cerebral ischemia/reperfusion (I/R), we have identified CAMK2D-associated transcript 1 (C2dat1) as a novel I/R-induced lncRNA that regulated the expression of CaMKIIδ in murine models of focal cerebral ischemia. C2dat1 mRNA was upregulated in a time-dependent manner in mouse cortical penumbra after focal ischemic brain injury, which was accompanied by increased expression of CaMKIIδ at transcript and protein levels. The expression patterns of C2dat1 and CAMK2D were confirmed in mouse Neuro-2a cells in response to in vitro ischemia (oxygen-glucose deprivation/reoxygenation, OGD/R). Knockdown of C2dat1 resulted in a significant blockade of CaMKIIδ expression, and potentiated OGD/R-induced cell death. Mechanistically, reduced CaMKIIδ expression upon silencing C2dat1 inhibited OGD/R-induced activation of the NF-κB signaling pathway. Further analysis showed that the downregulation of IKKα and IKKβ expression and phosphorylation, and subsequent inhibition of IκBα degradation accounted for the inhibition of the NF-κB signaling activity caused by silencing C2dat1. In summary, we discovered a novel I/R-induced lncRNA C2dat1 that modulates the expression of CaMKIIδ to impact neuronal survival, and may be a potential target for therapeutic intervention of ischemic brain injury.
Highlights
Non-coding RNAs comprise a large portion of the transcribed genome and regulate many important biological processes
We report the discovery of a novel CAMK2D-associated long ncRNAs (lncRNAs), CAMK2D-associated transcript 1 (C2dat1)
This lncRNA was upregulated in murine ischemia/ reperfusion (I/R) models and in mouse neuronal cells upon in vitro ischemia oxygen-glucose deprivation/reoxygenation (OGD/R)
Summary
Non-coding RNAs (ncRNAs) comprise a large portion of the transcribed genome and regulate many important biological processes. Increasing evidence has demonstrated an important role of ncRNAs, such as microRNAs (miRNAs), as critical regulators of stroke-associated biological processes.[1,2] the expression and function of long ncRNAs (lncRNAs) in stroke and neuroprotection remain largely unknown.[3] LncRNAs are ncRNAs 4200 nucleotides long and do not encode proteins. Despite extensive studies on the abundantly expressed CaMKIIα or CaMKII holoenzyme, the function of CaMKIIδ, one of the most ubiquitous CaMKII isoforms expressed both in neuronal and non-neuronal cells, remains largely unknown in the CNS.[10,25]. We report the discovery of a novel CAMK2D-associated lncRNA, CAMK2D-associated transcript 1 (C2dat[1]) This lncRNA was upregulated in murine ischemia/ reperfusion (I/R) models and in mouse neuronal cells upon in vitro ischemia oxygen-glucose deprivation/reoxygenation (OGD/R). The neuroprotective role of C2dat[1] may be exploited for therapeutic intervention of I/R-induced neuronal injury
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