Abstract 143: Long Non-coding RNA Malat1 Regulates Cerebrovascular Pathologies in Ischemic Stroke

Abstract

Accumulative studies have demonstrated the important regulatory roles of microRNAs in vascular and neural damage after ischemic stroke. However, the functional significance and mechanisms of other classes of non-coding RNAs in cerebrovascular pathophysiology after stroke are less studied. Using RNA-sequencing technology, we previously profiled long non-coding RNAs (lncRNAs) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD), and identified that metastasis associated lung adenocarcinoma transcript 1 (Malat1) is one of the most highly upregulated OGD-responsive endothelial lncRNAs. Here, we sought to determine the role of Malat1 in cerebrovascular pathogenesis of ischemic stroke. Increased Malat1 levels were found in cultured mouse BMECs after OGD as well as in isolated cerebral microvessels in mice after transient middle cerebral artery occlusion (tMCAO) and 24h reperfusion by quantitative PCR. Loss-of-Malat1 function by LNA-GapmeRs significantly increased OGD-induced cell death and Caspase 3 activity in BMECs. It appears that Malat1 plays anti-apoptotic and anti-inflammatory roles in cerebral endothelium, showing that loss-of-Malat1 function significantly aggravated OGD-induced expression of pre-apoptotic factor Bim, pro-inflammatory cytokines MCP-1, IL-6 and E-selectin at both mRNA and protein levels. Moreover, Malat1 KO mice presented larger brain infarct size and worse neurological score after tMCAO compared to WT controls. A battery of behavioral tests, including adhesive tape removal, foot fault, cylinder were performed to assess sensorimotor functions after ischemic stroke. Malat1 KO mice exhibited reduced ability to perform all the above tests. Consistent with in vitro findings, significantly increased expression of Bim, MCP-1, IL-6 and E-selectin at mRNA and protein levels were also found in Malat1 KO mouse cortex after ischemic stroke in comparison with WT controls. Taken together, these findings suggest that Malat1 plays critical vascular and neuroprotective roles in ischemic stroke.