title: Downregulation of Securin by the variant RNF213 R4810K (rs112735431, G>A) reduces angiogenic activity of induced pluripotent stem cell-derived vascular endothelial cells from moyamoya patients.
abstract: Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. Induced pluripotent stem cells (iPSCs) were established from unaffected fibroblast donors with wild-type RNF213 alleles, and from carriers/patients with one or two RNF213 R4810K alleles. Angiogenic activities of iPSC-derived vascular endothelial cells (iPSECs) from patients and carriers were lower (49.0 ± 19.4%) than from wild-type subjects (p<0.01). Gene expression profiles in iPSECs showed that Securin was down-regulated (p<0.01) in carriers and patients. Overexpression of RNF213 R4810K downregulated Securin, inhibited angiogenic activity (36.0 ± 16.9%) and proliferation of humanumbilical vein endothelial cells (HUVECs) while overexpression of RNF213 wild type did not. Securin expression was downregulated using RNA interference techniques, which reduced the level of tube formation in iPSECs and HUVECs without inhibition of proliferation. RNF213 R4810K reduced angiogenic activities of iPSECs from patients with MMD, suggesting that it is a promising in vitro model for MMD.
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Habu
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okuda
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.forename: Kenji
authors.initials: K
authors.lastname: Osafune
authors.forename: Daisuke
authors.initials: D
authors.lastname: Taura
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.forename: Isao
authors.initials: I
authors.lastname: Asaka
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ameku
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kasahara
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sudo
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Shiota
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Hashikata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takagi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morito
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000251:Adenosine Triphosphatases; D002478:Cells, Cultured; D002648:Child; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D039904:Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D064249:Securin; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: Angiogenesis; Endothelium; Moyamoya disease; RNF213; Securin; iPS cells