Genome-wide microRNA changes in human intracranial aneurysms

BMC Neurology, Oct 2014

Background Intracranial aneurysms are pathological dilatations of the cerebral artery, while rupture of intracranial aneurysms causes life-threatening subarachnoid hemorrhage. The molecular mechanisms of pathogenesis of intracranial aneurysms are poorly understood. MicroRNAs have fundamental roles in modulating vascular biology and disease. In the present study, we carried out a genome-wide characterization on expressions of microRNAs, and performed integrative analyses in conjunction with changes of the transcriptome in human intracranial aneurysms. Methods Genome-wide microRNA screening was performed in 6 intracranial aneurysmal samples and 6 normal superficial temporal arteries. Each case and control pair was individually matched with gender, age (�5 years), and high blood pressure history. Microarray analysis was performed using Agilent Human miRNA arrays. Results As compared to normal arteries, we identified 157 microRNAs that were differentially expressed in the aneurysmal tissue (P?<?0.05 and fold change???2), including 72 upregulated and 85 downregulated. The changed microRNAs included endothelium-enriched microRNAs such as members of the let-7 family, miR-17, miR-23b, miR-126, hsa-miR-24-1 and miR-222, and vascular smooth muscle-enriched miRNAs such as miR-143 and miR-145. Moreover, miR-1, miR-10a, miR-125b, and miR-26a, which were implicated in modulating vascular smooth muscle cell functions such as proliferation, apoptosis and shift of phenotype, were also changed. In contrast, microRNAs involved in monocyte and macrophage functions, such as miR-155, miR-146a, miR-223, and miR-124a, were not significantly changed. Bioinformatic analysis revealed that the changed microRNAs were associated with several biological processes related to aneurysm formation, including inflammation, dysregulation of extracellular matrix, smooth muscle cell proliferation, programmed cell death, and response to oxidative stress. Interestingly, we found that a subset of the potential microRNA target genes belonged to the protein translation machinery, including various eukaryotic translation initiation factors and ribosomal proteins, and this finding was highly correlated with our previous transcriptome data showing that multiple genes of the ribosomal proteins and translation initiation and elongation factors were significantly downregulated in human intracranial aneurysms. Conclusions Our results support that dysregulated microRNAs may have a pathogenic role in intracranial aneurysms. Disruption of the protein translation process may have a pathogenic role in the development of intracranial aneurysms.

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Genome-wide microRNA changes in human intracranial aneurysms

Dehua Liu Liang Han Xiao Wu 0 Xinjian Yang Qunye Zhang 0 Fan Jiang 0 0 Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital , 107 Wenhuaxi Road, Jinan 250012, Shandong Province , China Background: Intracranial aneurysms are pathological dilatations of the cerebral artery, while rupture of intracranial aneurysms causes life-threatening subarachnoid hemorrhage. The molecular mechanisms of pathogenesis of intracranial aneurysms are poorly understood. MicroRNAs have fundamental roles in modulating vascular biology and disease. In the present study, we carried out a genome-wide characterization on expressions of microRNAs, and performed integrative analyses in conjunction with changes of the transcriptome in human intracranial aneurysms. Methods: Genome-wide microRNA screening was performed in 6 intracranial aneurysmal samples and 6 normal superficial temporal arteries. Each case and control pair was individually matched with gender, age (5 years), and high blood pressure history. Microarray analysis was performed using Agilent Human miRNA arrays. Results: As compared to normal arteries, we identified 157 microRNAs that were differentially expressed in the aneurysmal tissue (P < 0.05 and fold change 2), including 72 upregulated and 85 downregulated. The changed microRNAs included endothelium-enriched microRNAs such as members of the let-7 family, miR-17, miR-23b, miR-126, hsa-miR-24-1 and miR-222, and vascular smooth muscle-enriched miRNAs such as miR-143 and miR-145. Moreover, miR-1, miR-10a, miR-125b, and miR-26a, which were implicated in modulating vascular smooth muscle cell functions such as proliferation, apoptosis and shift of phenotype, were also changed. In contrast, microRNAs involved in monocyte and macrophage functions, such as miR-155, miR-146a, miR-223, and miR-124a, were not significantly changed. Bioinformatic analysis revealed that the changed microRNAs were associated with several biological processes related to aneurysm formation, including inflammation, dysregulation of extracellular matrix, smooth muscle cell proliferation, programmed cell death, and response to oxidative stress. Interestingly, we found that a subset of the potential microRNA target genes belonged to the protein translation machinery, including various eukaryotic translation initiation factors and ribosomal proteins, and this finding was highly correlated with our previous transcriptome data showing that multiple genes of the ribosomal proteins and translation initiation and elongation factors were significantly downregulated in human intracranial aneurysms. Conclusions: Our results support that dysregulated microRNAs may have a pathogenic role in intracranial aneurysms. Disruption of the protein translation process may have a pathogenic role in the development of intracranial aneurysms. - Background Intracranial aneurysms (IAs) are pathological dilatations of the cerebral artery; rupture of IAs is the primary cause of life-threatening subarachnoid hemorrhage (SAH) [1-3]. The cellular and molecular mechanisms underlying the pathogenesis of IA formation are still poorly understood. Factors including smoking, hypertension, excessive alcohol consumption, vascular inflammation, nutritional factors and mechanical forces produced by the blood flow may all contribute to the formation and/or rupture of IAs [4-10]. On the other hand, mounting evidence has suggested that genetic factors (such as gene polymorphisms) also have important roles in the etiology of IAs [11,12]. Throughout IA research, identification of aberrantly expressed genes in IA tissues remains to be a core approach to understanding the molecular regulatory mechanisms underlying IA development and rupture. In line with this, several groups have employed high-throughput microarray methods to study gene expression changes at the whole genome level [13-17]. For example, in a previous study, we identified 1,160 genes whose expression levels were significantly changed in un-ruptured aneurysmal tissues as compared to normal blood vessels [15]. We found that a cluster of extracellular matrix related genes (including collagens type I, III, V, and XI and metalloproteinases) were significantly changed. Moreover, we found that a number of immune/inflammation-related genes were also differentially expressed in IA tissues [15]. Collectively, these functional genomic studies provided important information regarding the potential molecular mechanisms implicated in this multifactorial cerebral vascular disease [18]. MicroRNAs (miRNAs) are a class of short (1825 nucleotides), non-coding RNAs that have fundamental roles in post-transcriptional regulation of gene expression. Regulation of gene expression by miRNAs may be achieved via either sequence-specific interactions with target mRNAs and subsequent mRNA degradation, or miRNA-mediated translational repression [19,20]. Therefore, miRNAs represent another layer of regulation of gene expression in a (...truncated)


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Dehua Liu, Liang Han, Xiao Wu, Xinjian Yang, Qunye Zhang, Fan Jiang. Genome-wide microRNA changes in human intracranial aneurysms, BMC Neurology, 2014, pp. 188, 14, DOI: 10.1186/s12883-014-0188-x