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

Toshiaki Hitomi, Toshiyuki Habu, Hatasu Kobayashi, Hiroko Okuda, Kouji H. Harada, Kenji Osafune, Daisuke Taura, Masakatsu Sone, Isao Asaka, Tomonaga Ameku, Akira Watanabe, Tomoko Kasahara, Tomomi Sudo, Fumihiko Shiota, Hirokuni Hashikata, Yasushi Takagi, Daisuke Morito, Susumu Miyamoto, Kazuwa Nakao, Akio Koizumi

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13-19
Number of pages7
JournalBiochemical and biophysical research communications
Volume438
Issue number1
DOIs
Publication statusPublished - 2013 Aug 16
Externally publishedYes

Keywords

  • Angiogenesis
  • Endothelium
  • IPS cells
  • Moyamoya disease
  • RNF213
  • Securin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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