Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells

Kazuhiro Okubo, Yasunari Sakai, Hirosuke Inoue, Satoshi Akamine, Yoshito Ishizaki, Yuki Matsushita, Masafumi Sanefuji, Hiroyuki Torisu, Kenji Ihara, Marco Sardiello, Toshiro Hara

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Abstract

Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.

Original languageEnglish
Article number13191
JournalScientific reports
Volume5
DOIs
Publication statusPublished - Aug 17 2015

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Moyamoya Disease
Disease Susceptibility
Endothelial Cells
Genes
Circle of Willis
Cerebrovascular Disorders
cdc Genes
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Metalloproteases
Gene Expression Profiling
Transcriptional Activation
Cultured Cells
Fibroblasts
Cytokines
Gene Expression
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • General

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Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. / Okubo, Kazuhiro; Sakai, Yasunari; Inoue, Hirosuke; Akamine, Satoshi; Ishizaki, Yoshito; Matsushita, Yuki; Sanefuji, Masafumi; Torisu, Hiroyuki; Ihara, Kenji; Sardiello, Marco; Hara, Toshiro.

In: Scientific reports, Vol. 5, 13191, 17.08.2015.

Research output: Contribution to journalArticle

Okubo, K, Sakai, Y, Inoue, H, Akamine, S, Ishizaki, Y, Matsushita, Y, Sanefuji, M, Torisu, H, Ihara, K, Sardiello, M & Hara, T 2015, 'Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells', Scientific reports, vol. 5, 13191. https://doi.org/10.1038/srep13191
Okubo, Kazuhiro ; Sakai, Yasunari ; Inoue, Hirosuke ; Akamine, Satoshi ; Ishizaki, Yoshito ; Matsushita, Yuki ; Sanefuji, Masafumi ; Torisu, Hiroyuki ; Ihara, Kenji ; Sardiello, Marco ; Hara, Toshiro. / Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. In: Scientific reports. 2015 ; Vol. 5.
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