Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia

Abstract

The brain endothelium is an important therapeutic target for the inhibition of cerebrovascular dysfunction in ischemic stroke. Previously, we documented the important regulatory roles of microRNAs in the cerebral vasculature, in particular the cerebral vascular endothelium. However, the functional significance and molecular mechanisms of other classes of non-coding RNAs in the regulation of cerebrovascular endothelial pathophysiology after stroke are completely unknown. Using RNA sequencing (RNA-seq) technology, we profiled long non-coding RNA (lncRNA) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD), an in vitro mimic of ischemic stroke conditions. After 16h of OGD exposure, the expression levels for 362 of the 10,677 lncRNAs analyzed changed significantly, including a total of 147 lncRNAs increased and 70 lncRNAs decreased by more than 2-fold. Among them, the most highly upregulated lncRNAs include Snhg12, Malat1, and lnc-OGD 1006, whereas the most highly downregulated lncRNAs include 281008D09Rik, Peg13, and lnc-OGD 3916. Alteration of the most highly upregulated/downregulated ODG-responsive lncRNAs was further confirmed in cultured BMECs after OGD as well as isolated cerebral microvessels in mice following transient middle cerebral artery occlusion (MCAO) and 24h reperfusion by the quantitative real-time PCR approach. Moreover, promoter analysis of altered ODG-responsive endothelial lncRNA genes by bioinformatics showed substantial transcription factor binding sites on lncRNAs, implying potential transcriptional regulation of those lncRNAs. These findings are the first to identify OGD-responsive brain endothelial lncRNAs, which suggest potential pathological roles for these lncRNAs in mediating endothelial responses to ischemic stimuli. Endothelial-selective lncRNAs may function as a class of novel master regulators in cerebrovascular endothelial pathologies after ischemic stroke.

Down-Regulation of Lncrna MALAT1 Attenuates Neuronal Cell Death Through Suppressing Beclin1-Dependent Autophagy by Regulating Mir-30a in Cerebral Ischemic Stroke

“…Wu et al found that lncRNA-N1LR promoted neuroprotection against ischemic stroke by inhibiting p53 phosphorylation and served as a potential target for therapeutic intervention following ischemic brain injury [35]. In the present study, we found that MALAT1 was significantly up-regulated in MCAO mice and cortical neurons subjected to OGD, consistent with a previous study [17]. More importantly, MALAT1 down-regulation dramatically restrained the conversion of LC3-I to LC3-II and Beclin1 level in vitro and in vivo , indicating MALAT1 down-regulation suppressed autophagy in ischemic stroke.…”

“…Accumulating evidence reveals that MALAT1 is up-regulated in many solid tumors and associated with cancer metastasis and recurrence [16]. More interestingly, MALAT1 was reported to be highly expressed in an in vitro mimic of ischemic stroke conditions [17]. However, the role of MALAT1 in ischemic stroke and its underlying mechanism have not been elucidated.…”

Maternally Expressed Gene 3 (MEG3) Enhances PC12 Cell Hypoxia Injury by Targeting MiR-147

“…It has become increasingly important to elucidate the molecular mechanisms of acute cerebral ischemia-related neuronal injury [26]. As we have discussed previously, there are studies which have reported that cerebral miRNA and lncRNAs control epigenetic silencing or activation in mammal also get altered due to cerebral ischemia [27-29]. Moreover, long non-coding RNAs (LncRNAs), also go through changes in the post-stroke brain [30].…”

Whole Blood Gene Expression Reveals Specific Transcriptome Changes in Neonatal Encephalopathy

“…In HeLa cells, it has been shown to control the HIF-1α axis under hypoxic conditions in a positive feedback loop [20]. After ische­mic stroke, it regulates gene expression in cerebrovascular endothelial cells [21, 22], where it is proposed to protect against hypoxia-reperfusion-induced apoptosis [23]. MALAT1 has been of interest as a therapeutic target after its downregulation was found to suppress ischemic injury and autophagy in vitro and in vivo, which makes its strong upregulation in our data of particular interest [24].…”