Long Noncoding RNA Malat1 Regulates Cerebrovascular Pathologies in Ischemic Stroke

Abstract

The study was designed to determine the role of long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (Malat1), in ischemic stroke outcome. Primary mouse brain microvascular endothelial cells (BMECs) were cultured and treated with Malat1 GapmeR before 16 h oxygen and glucose depravation (OGD). Cell death was assayed by LDH and MTT methods. Malat1 knock-out and wild-type mice were subjected to 1 h of middle cerebral artery occlusion (MCAO) and 24 -72 h of reperfusion. To explore the underlying mechanism, apoptotic and inflammatory factors were measured by qPCR, ELISA, and Western blotting. The physical interaction between Malat1 and apoptotic or inflammatory factors was measured by RNA immunoprecipitation. Increased Malat1 levels were found in cultured mouse BMECs after OGD as well as in isolated cerebral microvessels in mice after MCAO. Silencing of Malat1 by Malat1 GapmeR significantly increased OGD-induced cell death and Caspase 3 activity in BMECs. Silencing of Malat1 also significantly aggravated OGD-induced expression of the proapoptotic factor Bim and proinflammatory cytokines MCP-1, IL-6, and E-selectin. Moreover, Malat1 KO mice presented larger brain infarct size, worsened neurological scores, and reduced sensorimotor functions. Consistent with in vitro findings, significantly increased expression of proapoptotic and proinflammatory factors was also found in the cerebral cortex of Malat1 KO mice after ischemic stroke compared with WT controls. Finally, we demonstrated that Malat1 binds to Bim and E-selectin both in vitro and in vivo. Our study suggests that Malat1 plays critical protective roles in ischemic stroke.

MALAT1 Activates the P53 Signaling Pathway by Regulating MDM2 to Promote Ischemic Stroke

“…Overall, these results reveal that up regulation of MALAT1 exerts its biological roles through regulation of MDM2 expression in ischemic stroke. A previous study indicated that Malat1 plays anti-apoptotic and anti-inflammatory roles in the brain microvasculature to reduce ischemic stroke [7]. In addition, studies have uncovered the regulation pattern of Malat1 expression mediated by p53 in hematopoietic differentiation [26].…”

“…LncRNAs are potential novel biomarkers that should be explored further for use in the diagnosis, treatment and prognosis of stroke [6]. Metastasisassociated lung adenocarcinoma transcript 1 (MALAT1) is a highly abundant lncRNA that exerts anti-inflammatory and anti-apoptotic roles in the brain microvasculature to reduce ischemia in the cerebral vasculature [7]. Studies have shown that MALAT1 regulates the function of endothelial cells and vessel growth [8,9].…”

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].…”

Analysis of Long Noncoding RNA and mRNA Expression Profiles in IL-9-Activated Astrocytes and EAE Mice

“…Recent work points to the role of lncRNAs in oligodendrocyte precursor cell (OPC) differentiation from neural stem cells (NSCs), myelination and remyelination in the CNS [29, 30]. lncRNA (Malat1) displays anti–apoptotic and anti-inflammatory roles in microvasculature structure of the brain to reduce ischemic brain injury [31]. However, there is a large gap between the number of existing lncRNAs and their known association with a particular molecular or cellular function in MS/EAE.…”