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

Journal Article · Fri Aug 16 00:00:00 EDT 2013 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2013.07.004· OSTI ID:22242048

Hitomi, Toshiaki ^[1]; Habu, Toshiyuki ^[2]; Kobayashi, Hatasu; Okuda, Hiroko; Harada, Kouji H. ^[1]; Osafune, Kenji ^[3]; Taura, Daisuke; Sone, Masakatsu ^[4]; Asaka, Isao; Ameku, Tomonaga; Watanabe, Akira; Kasahara, Tomoko; Sudo, Tomomi; Shiota, Fumihiko ^[3]; Hashikata, Hirokuni; Takagi, Yasushi ^[5]; Morito, Daisuke ^[6]; Miyamoto, Susumu ^[5]; Nakao, Kazuwa ^[4]; Koizumi, Akio ^[1]

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1. Department of Health and Environmental Sciences, Kyoto University, Kyoto (Japan)
2. Radiation Biology Center, Kyoto University, Kyoto (Japan)
3. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan)
4. Department of Medicine and Clinical Science, Kyoto University, Kyoto (Japan)
5. Department of Neurosurgery, Kyoto University,Kyoto (Japan)
6. Faculty of Life Sciences, Kyoto Sangyo University, Kyoto (Japan)

Highlights: •Angiogenic activities were reduced in iPSECs from MMD patients. •Many mitosis-regulated genes were downregulated in iPSECs from MMD patients. •RNF213 R4810K downregulated Securin and inhibited angiogenic activity. •Securin suppression by siRNA reduced angiogenic activities of iPSECs and HUVECs. -- 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.

• OSTI ID: 22242048
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 438, Issue 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANGIOGENESIS
CARRIERS
DISEASES
ENDOTHELIUM
FIBROBLASTS
GENES
IN VITRO
INHIBITION
MITOSIS
PATIENTS
RNA
STEM CELLS
VEINS