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

Abstract

Background/Aims: LncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was reported to be highly expressed in an in vitro mimic of ischemic stroke conditions. However, the exact biological role of MALAT1 and its underlying mechanism in ischemic stroke remain to be elucidated. Methods: The roles of MALAT1 and miR-30a on cell death and infarct volume and autophagy were evaluated in experimental ischemic stroke. The relationships between miR-30a and MALAT1, Beclin1 were confirmed by luciferase reporter assay. The autophagy inhibitor 3-methyadenine (3-MA) was used to examine the impact of autophagy on ischemic injury. Results: We found that MALAT1, along with the levels of conversion from autophagy-related protein microtubule-associated protein light chain 3-I (LC3-I) to LC3-phosphatidylethanolamine conjugate (LC3-II), as well as Beclin1 were up-regulated and miR-30a was down-regulated in cerebral cortex neurons after oxygen-glucose deprivation (OGD) and mouse brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Down-regulation of MALAT1 suppressed ischemic injury and autophagy in vitro and in vivo. Furthermore, MALAT1 may serve as a molecular sponge for miR-30a and negatively regulate its expression. In addition, MALAT1 overturned the inhibitory effect of miR-30a on ischemic injury and autophagy in vitro and in vivo, which might be involved in the derepression of Beclin1, a direct target of miR-30a. Mechanistic analyses further revealed that autophagy inhibitor 3-methyadenine (3-MA) markedly suppressed OGD-induced neuronal cell death and MCAO-induced ischemic brain infarction. Conclusion: Taken together, our study first revealed that down-regulation of MALAT1 attenuated neuronal cell death through suppressing Beclin1-dependent autophagy by regulating miR-30a expression in cerebral ischemic stroke. Besides, our study demonstrated a novel lncRNA-miRNA-mRNA regulatory network that is MALAT1-miR-30a-Beclin1 in ischemic stroke, contributing to a better understanding the pathogenesis and progression of ischemic stroke.

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

“…Up regulated MALAT1 expression is correlated with poor overall survival in various cancers [4,22]. We found that its expression was up regulated in stroke tissues in our study in accordance with results from Guo et al [23]. Furthermore, we demonstrated that down regulation of MALAT1 suppresses ischemic injury both in vitro and in vivo, further attenuating neuronal cell death in cerebral ischemic stroke.…”

By Activating Akt/eNOS Bilobalide B Inhibits Autophagy and Promotes Angiogenesis Following Focal Cerebral Ischemia Reperfusion

“…Since apoptosis and autophagy are now relatively well defined mechanisms of stroke mediated brain injury [25,26], readily available compounds that are able to combat these pathways are desirable subjects of further studies to develop therapeutic strategies to treat stroke patients. In this study, we subjected rats to transient MCAO and studied the effects of bilobalide in post MCAO recovery.…”

Whole Blood Gene Expression Reveals Specific Transcriptome Changes in Neonatal Encephalopathy

“…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]. …”