もやもや病疾患感受性遺伝子RNF213は内皮細胞において炎症と血管新生のシグナルとを結びつける

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.Moyamoya disease (MMD) represents a specific intracranial vascular disorder characterized by progressive, occlusive lesions of internal carotid arteries and branches in the circle of Willis 1,2 .To compensate the decreased blood flow in the affected brain area, the fine vascular network of Moyamoya, a Japanese word meaning "puffs of smoke", develops as arterial stenosis progress 1,2 .Earlier studies demonstrated that environmental factors including varicella zoster virus infection contributed to the development of MMD 3,4 .On the other hand, population-based studies pointed to the higher incidence of MMD in oriental populations than those in Caucasians, suggesting that certain genetic backgrounds may also confer the risk for the development of the vascular lesions 5 .Genetic studies for MMD patients have been conducted to identify candidate disease susceptibility loci [6][7][8][9][10] .Notably, several groups have demonstrated that single nucleotide variations in the RNF213 gene had a strong association with the onset of MMD in both familial and sporadic cases 11,12 .The human