{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T23:59:36Z","timestamp":1792886376764,"version":"4.5.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2015,7,17]]},"abstract":"\n Background<\/jats:title>\n \n P.R4810K of\n \n RNF<\/jats:styled-content>\n 213\n <\/jats:italic>\n (mysterin: rs112735431), which is an\n AAA<\/jats:styled-content>\n +<\/jats:sup>\n ATP<\/jats:styled-content>\n ase, is the susceptibility polymorphism for moyamoya disease (\n MMD<\/jats:styled-content>\n ) in East Asians. However, the role of\n RNF<\/jats:styled-content>\n 213 R4810K in the etiology of\n MMD<\/jats:styled-content>\n is unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n To clarify the role of\n RNF<\/jats:styled-content>\n 213 in known angiogenic pathways,\n RNF<\/jats:styled-content>\n 213 expression was analyzed in endothelial cells (\n EC<\/jats:styled-content>\n s) treated with several angiogenic and antiangiogenic factors, including interferons (\n IFN<\/jats:styled-content>\n s).\n RNF<\/jats:styled-content>\n 213 was upregulated by\n IFN<\/jats:styled-content>\n \u2010\u03b2 through signal transducer and activator of transcription x in the promoter and mediated antiangiogenic activity of\n IFN<\/jats:styled-content>\n \u2010\u03b2.\n RNF<\/jats:styled-content>\n 213 wild\u2010type (\n WT<\/jats:styled-content>\n ) overexpression could not lower angiogenesis without\n IFN<\/jats:styled-content>\n \u2010\u03b2, but\n RNF<\/jats:styled-content>\n 213 R4810K overexpression could. To correlate biochemical function as\n ATP<\/jats:styled-content>\n ase and the role of\n RNF<\/jats:styled-content>\n 213 oligomer formation with antiangiogenic activity, we investigated the effects of mutations in the\n AAA<\/jats:styled-content>\n +<\/jats:sup>\n module. A mutation of the Walker B motif (\n WEQ<\/jats:styled-content>\n ), which stabilizes oligomerization, inhibited angiogenesis, but\n AAA<\/jats:styled-content>\n +<\/jats:sup>\n module deletion, which cannot initiate oligomerization, did not. Intriguingly, R4810K, similar to\n WEQ<\/jats:styled-content>\n , decreased\n ATP<\/jats:styled-content>\n ase activity, suggesting its antiangiogenic activity through stabilizing oligomers. To confirm the antiangiogenic effect of\n RNF<\/jats:styled-content>\n 213 upregulation in\u00a0vivo, vascular\n EC<\/jats:styled-content>\n \u2010 or smooth muscle cell\u2010specific Rnf213 R4757K (R4810K ortholog) or\n WT<\/jats:styled-content>\n transgenic (Tg) mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in EC\u2010specific Rnf213 R4757K Tg mice, whereas it was not suppressed in other mice.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This study suggests the importance of inflammatory signals as environmental factors and R4810K carriers for susceptibility to cerebral hypoxia. A specific inhibitor of\n ATP<\/jats:styled-content>\n binding to the first\n AAA<\/jats:styled-content>\n +<\/jats:sup>\n could be a promising therapeutic candidate for\n MMD<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.115.002146","type":"journal-article","created":{"date-parts":[[2018,9,14]],"date-time":"2018-09-14T19:04:02Z","timestamp":1536951842000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":138,"title":["Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo"],"prefix":"10.1161","volume":"4","author":[{"given":"Hatasu","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiaki","family":"Hitomi","sequence":"additional","affiliation":[{"name":"Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan"},{"name":"Department of Preventive Medicine, St Marianna University School of Medicine, Kawasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Okuda","sequence":"additional","affiliation":[{"name":"Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotomo","family":"Shioi","sequence":"additional","affiliation":[{"name":"Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohiko","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakatsu","family":"Sone","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Taura","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouji H.","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Habu","sequence":"additional","affiliation":[{"name":"Radiation Biology Center, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Takagi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","first-page":"37","article-title":"Hypoplasia of bilateral internal carotid arteries","volume":"9","author":"Takeuchi K","year":"1957","unstructured":"Takeuchi K, Shimizu K. 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