Abstract
Intracranial aneurysm (IA) is vascular enlargement occurred on the wall of cerebral vessels and can result in fatal subarachnoid hemorrhage when ruptured. Recent studies have supported the important role of long non-coding RNAs (lncRNAs) in IA treatment. This study identified functional significance of lncRNA myocardial infarction associated transcript (MIAT) in IA. Myocardial infarction associated transcript and ectodermal-neural cortex 1 (ENC1) expression was detected by reverse transcription quantitative polymerase chain reaction. Cell counting kit 8 assay flow cytometry were conducted to detect cell viability and apoptosis of endothelial cells in IA. The interaction among MIAT, ENC1, and myelocytomatosis oncogene (MYC) was analyzed by RNA pull down, RNA immunoprecipitation assay, chromatin immunoprecipitation assay, and dual luciferase reporter assay. Intracranial aneurysm was induced by ligating the left carotid artery and the bilateral posterior branch of the renal artery in rats for studying the role of MIAT and ENC1 in vivo. Myocardial infarction associated transcript and ENC1 were upregulated in IA. Endothelial cells in IA presented a decreased cell viability and an increased apoptotic rate. Myocardial infarction associated transcript could regulate the expression of ENC1, and MYC could bind to the promoter region of ENC1. High expression of MIAT increased endothelial cell apoptosis and vascular endothelial injury, while MIAT knockdown was identified to reduce the risk of IA both in vitro and in vivo through regulating ENC1. To sum up, MIAT silencing is preventive for IA occurrence by decreasing the MYC-mediated ENC1 expression, which represents a novel therapeutic target for IA.
Highlights
Intracranial aneurysm (IA) is a life-threatening disorder leading to subarachnoid hemorrhage with an incidence of approximately 1–2%
To explore the key long non-coding RNAs (lncRNAs) that promote IA, analysis of the microarray dataset GSE75436 by R language revealed the presence of 267 genes highly expressed and 298 genes poorly expressed in IA (Figure 1A)
Nine differentially expressed lncRNAs were obtained from the Venn diagram (Figure 1B), among them, myocardial infarction associated transcript (MIAT) was selected for subsequent experimentation as it had been previously identified as a potential pharmacological target for the treatment of neurovascular diseases (Jiang et al, 2016) that MIAT was associated with the pathogenesis underlying the formation and rupture of IA
Summary
Intracranial aneurysm (IA) is a life-threatening disorder leading to subarachnoid hemorrhage with an incidence of approximately 1–2%. Role of MIAT in IA aneurysm growth leading to IA recurrence arise after endovascular treatment (Abdihalim et al, 2014). Initial bioinformatic analysis of this study identified differentially expressed lncRNA myocardial infarction associated transcript (MIAT) related to neurovascular disease. Existing evidence has suggested the potential of MIAT to modulate the endothelial cell function via interactions with vascular endothelial growth factors (Yan et al, 2015). We predicted that MIAT was involved in the pathogenesis of IA via interaction with ectodermal-neural cortex 1 (ENC1) and transcription factor (TF) myelocytomatosis oncogene (MYC). A recent study revealed the potential of ENC1 as a favorable candidate for ovarian cancer treatment (Fan et al, 2019). Our study was performed to clarify the functional relevance of MIAT in IA, which was involved with the interaction with ENC1 and MYC.
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