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RNA sequencing analysis revealed the induction of CCL3 expression in human intracranial aneurysms.

ABSTRACT: Intracranial aneurysm (IA) is a socially important disease as a major cause of subarachnoid hemorrhage. Recent experimental studies mainly using animal models have revealed a crucial role of macrophage-mediated chronic inflammatory responses in its pathogenesis. However, as findings from comprehensive analysis of unruptured human IAs are limited, factors regulating progression and rupture of IAs in humans remain unclear. Using surgically dissected human unruptured IA lesions and control arterial walls, gene expression profiles were obtained by RNA sequence analysis. RNA sequencing analysis was done with read count about 60~100 million which yielded 6~10 billion bases per sample. 79 over-expressed and 329 under-expressed genes in IA lesions were identified. Through Gene Ontology analysis, 'chemokine activity', 'defense response' and 'extracellular region' were picked up as over-represented terms which included CCL3 and CCL4 in common. Among these genes, quantitative RT-PCR analysis using another set of samples reproduced the above result. Finally, increase of CCL3 protein compared with that in control arterial walls was clarified in IA lesions. Findings of the present study again highlight importance of macrophage recruitment via CCL3 in the pathogenesis of IA progression.

SUBMITTER: Aoki T

PROVIDER: S-EPMC6637171 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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RNA sequencing analysis revealed the induction of CCL3 expression in human intracranial aneurysms.

Aoki Tomohiro T Koseki Hirokazu H Miyata Haruka H Itoh Masayoshi M Kawaji Hideya H Takizawa Katsumi K Kawashima Akitsugu A Ujiie Hiroshi H Higa Takashi T Minamimura Kenzo K Kimura Toshikazu T Kasuya Hidetoshi H Nozaki Kazuhiko K Morita Akio A Sano Hirotoshi H Narumiya Shuh S

Scientific reports 20190717 1

Intracranial aneurysm (IA) is a socially important disease as a major cause of subarachnoid hemorrhage. Recent experimental studies mainly using animal models have revealed a crucial role of macrophage-mediated chronic inflammatory responses in its pathogenesis. However, as findings from comprehensive analysis of unruptured human IAs are limited, factors regulating progression and rupture of IAs in humans remain unclear. Using surgically dissected human unruptured IA lesions and control arterial ...[more]

PMID: 31316152

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Project description:BackgroundThe present study aims to investigate the complete long non-coding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in Intracranial aneurysm (IA) patients and controls by RNA sequencing, which reveals the lncRNA with predictive value for IA risk.MethodsThe comprehensive lncRNA and mRNA expression profiles were detected by RNA-Seq in human IA walls and superficial temporal arteries (STAs), followed by bioinformatics analyses, such as GO analysis, KEGG pathway analysis, and CNC network construction. Subsequently, qRT-PCR was used to profile the expression levels of selected lncRNA (lncRNA ENST000000576153, lncRNA ENST00000607042, lncRNA ENST00000471220, lncRNA ENST00000478738, lncRNA MALAT1, lncRNA ENST00000508090 and lncRNA ENST00000579688) in 30 (small) or 130 (large) peripheral blood leukocytes, respectively. Multivariate logistic regression was utilized to analyze the effects of lncRNA on IA. Receiver operating characteristic (ROC) curve was further drawn to explore the value of lncRNA in predicting IA.ResultsTotally 900 up-regulated and 293 down-regulated lncRNAs, as well as 1297 up-regulated and 831 down-regulated mRNAs were discovered in sequencing. Enrichment analyses revealed that they were actively involved in immune/inflammatory response and cell adhesion/extracellular matrix. Co-expression analysis and further enrichment analyses showed that five candidate lncRNAs might participate in IA's inflammatory response. Besides, after controlling other conventional risk factors, multivariate logistic regression analysis disclosed that low expression of lncRNA ENST00000607042, lncRNA ENST00000471220, lncRNA ENST00000478738, lncRNA MALAT1 in peripheral blood leukocytes were independent risk factors for IA. LncRNA ENST00000607042 has superior diagnostic value for IA.ConclusionsThis study reveals the complete lncRNAs expression profiles in IA. The inflammatory response was closely related to IA. Besides, lncRNA ENST00000607042 might be a novel biomarker for IA risk.

Project description:BackgroundIntracranial non-branching site blood blister-like aneurysms (BBA) are extremely rare and vicious. Their etiology remains elusive, and no molecular study has been carried out to reveal its pathogenic relevance to intracranial atherosclerosis. To investigate its transcriptomic landscape and underlying potential pathogenesis, we performed single-cell RNA sequencing with extensive pathological validation.MethodsIn total, 12,245 cells were recovered for single-cell RNA sequencing analysis from 1 BBA and 2 saccular intracranial aneurysms (IAs). Unbiased clustering using Seurat-based pipeline was used for cellular landscape profiling. Cellchat was used to understand intracellular communications. Furthermore, 10 BBAs and 30 IAs were retrospectively collected for pathological validations like scanning electron microscopy, H&E stain, Masson stain, Verhoeff Van Gielson stain, and immunofluorescence.ResultsSingle-cell transcriptome profiled 14 total subclusters in 6 major groups, namely, 6 monocyte/macrophage clusters, 2 T&NK clusters, 3 vascular smooth muscle cell (VSMC) clusters, 1 dendritic cell, 1 B cell, and 1 endothelial cell cluster. The only mural cell identified in BBAs was VSMC-2 cluster, while mural cells in IAs comprise most clusters of VSMCs and endothelial cells. Upregulated genes in BBA-derived VSMCs are related to arterial mineralization and atherosclerosis, such as PTX3, SPP1, LOX, etc., whereas vasodilation and physiological regulatory genes such as MGP, ACTA2, and MYL9 were conversely enriched in conventional IA-derived VSMCs. Immune cells in the BBA were predominantly macrophages, with a low fraction of T&NK cells, while conventional IAs had a higher percentage of T&NK. Gene enrichment analysis suggested that macrophages in BBA were highly enriched in lipid metabolism as well as atherosclerosis. Ligand-receptor interaction suggested that secretory phosphoprotein 1 (also known as osteopontin) played a major role in mediating the intracellular communication between VSMC and macrophages, especially in BBA. Pathological experiments corroborate with the bioinformatic findings and further characterized BBAs as a thin-walled thrombotic aneurysm with severe atherosclerotic lesions, where ApoE+ macrophages and OPN+ mural cells are intimately involved in the inflammation process.ConclusionsThe preexisting intracranial atherosclerosis might predispose the parent artery to the pathogenic occurrence of BBAs. These data shed light on the pathophysiology of intracranial aneurysms and might assist in the further resolution of the complexity in aneurysm pathogenesis.

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RNA sequencing analysis revealed the induction of CCL3 expression in human intracranial aneurysms.

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RNA sequencing analysis revealed the induction of CCL3 expression in human intracranial aneurysms.

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