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

• Published in: Biochemical and biophysical research communications Vol. 438; no. 1; pp. 13 - 19
• Main Authors: Hitomi, Toshiaki, Habu, Toshiyuki, Kobayashi, Hatasu, Okuda, Hiroko, Harada, Kouji H., Osafune, Kenji, Taura, Daisuke, Sone, Masakatsu, Asaka, Isao, Ameku, Tomonaga, Watanabe, Akira, Kasahara, Tomoko, Sudo, Tomomi, Shiota, Fumihiko, Hashikata, Hirokuni, Takagi, Yasushi, Morito, Daisuke, Miyamoto, Susumu, Nakao, Kazuwa, Koizumi, Akio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.08.2013
• Subjects: 60 APPLIED LIFE SCIENCES; Adenosine Triphosphatases; alleles; ANGIOGENESIS; CARRIERS; Cells, Cultured; Child; DISEASES; Down-Regulation; endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; ENDOTHELIUM; Female; FIBROBLASTS; gene expression; GENES; Humans; IN VITRO; induced pluripotent stem cells; INHIBITION; iPS cells; Male; Middle Aged; MITOSIS; Moyamoya disease; Moyamoya Disease - metabolism; Moyamoya Disease - pathology; Mutation - genetics; Neoplasm Proteins - metabolism; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - physiopathology; PATIENTS; Pluripotent Stem Cells - metabolism; Pluripotent Stem Cells - pathology; RNA; RNA interference; RNF213; Securin; STEM CELLS; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; VEINS; Angiogenesis; Moyamoya disease; RNF213; Securin; iPS cells; Endothelium
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2013.07.004

•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. 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.