Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells

Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.

[1]  Raymond Sawaya,et al.  The role of autophagy in cancer development and response to therapy , 2005, Nature Reviews Cancer.

[2]  H. Shepard,et al.  Macrophage-induced angiogenesis is mediated by tumour necrosis factor-α , 1987, Nature.

[3]  M. Fukui,et al.  Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. , 1999, American journal of human genetics.

[4]  Jing Zhao,et al.  An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E-/- mice , 2014, Scientific Reports.

[5]  K. Wang,et al.  Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[6]  Valerio Embrione,et al.  A Gene Network Regulating Lysosomal Biogenesis and Function , 2009, Science.

[7]  M. Lotze,et al.  Interleukin-17 augments tumor necrosis factor-alpha-induced elaboration of proangiogenic factors from fibroblasts. , 2004, Immunology letters.

[8]  T. Pawlik,et al.  Regulation of herpes simplex virus γ134.5 expression and oncolysis of diffuse liver metastases by Myb34.5 , 2002 .

[9]  T. Tominaga,et al.  Increased expression of serum Matrix Metalloproteinase-9 in patients with moyamoya disease. , 2009, Surgical neurology.

[10]  T. Tominaga,et al.  Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: A susceptibility gene for moyamoya disease , 2014, Brain Research.

[11]  Qiang Li,et al.  Serum miRNA Signature in Moyamoya Disease , 2014, PloS one.

[12]  A Takaku,et al.  Cerebrovascular "moyamoya" disease. Disease showing abnormal net-like vessels in base of brain. , 1969, Archives of neurology.

[13]  T. Tominaga,et al.  Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease , 2015, Brain Research.

[14]  A. Maity,et al.  Molecular Neuroscience Review Article , 2011 .

[15]  D. Tregouet,et al.  A rare Asian founder polymorphism of Raptor may explain the high prevalence of Moyamoya disease among East Asians and its low prevalence among Caucasians , 2010, Environmental health and preventive medicine.

[16]  K. Nakao,et al.  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. , 2013, Biochemical and biophysical research communications.

[17]  H. Hara,et al.  Inhibitor of double stranded RNA-dependent protein kinase protects against cell damage induced by ER stress , 2006, Neuroscience Letters.

[18]  J. Hiscott,et al.  Molecular mechanisms regulating induction of interleukin‐6 gene transcription by interferon‐γ , 1997, European journal of immunology.

[19]  J. Hoseki,et al.  Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state , 2014, Scientific Reports.

[20]  M. Fukui,et al.  Linkage Analysis of Moyamoya Disease on Chromosome 6 , 2000, Journal of child neurology.

[21]  Xi-qing Sun,et al.  Effects of Simulated Microgravity on Human Umbilical Vein Endothelial Cell Angiogenesis and Role of the PI3K-Akt-eNOS Signal Pathway , 2012, PloS one.

[22]  K. Bala,et al.  Effect of different mitogens and serum concentration on HUVEC morphology and characteristics: implication on use of higher passage cells. , 2011, Tissue & cell.

[23]  H. Tolley,et al.  Phosphatidylinositol 3-Kinase Inhibition by LY294002 Radiosensitizes Human Cervical Cancer Cell Lines , 2006, Clinical Cancer Research.

[24]  Susumu Goto,et al.  Data, information, knowledge and principle: back to metabolism in KEGG , 2013, Nucleic Acids Res..

[25]  N. Sakai,et al.  Studies on cytomegalovirus and Epstein-Barr virus infection in Moyamoya disease , 1997, Clinical Neurology and Neurosurgery.

[26]  Toshihiro Tanaka,et al.  Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. , 2000, Stroke.

[27]  T. Hara,et al.  Nod1 Ligands Induce Site-Specific Vascular Inflammation , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[28]  A. Fujiyama,et al.  Identification of RNF213 as a Susceptibility Gene for Moyamoya Disease and Its Possible Role in Vascular Development , 2011, PloS one.

[29]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Fukui,et al.  A novel susceptibility locus for moyamoya disease on chromosome 8q23 , 2004, Journal of Human Genetics.

[31]  S. Roman,et al.  Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia. , 2014, American journal of human genetics.

[32]  K. Nakao,et al.  The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality. , 2013, Biochemical and biophysical research communications.

[33]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[34]  V. Fuster,et al.  Epithelial-to-Mesenchymal and Endothelial-to-Mesenchymal Transition: From Cardiovascular Development to Disease , 2012, Circulation.

[35]  T. Tominaga,et al.  Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene , 2014, Neuroreport.

[36]  O. Ohara,et al.  Unique activation status of peripheral blood mononuclear cells at acute phase of Kawasaki disease , 2009, Clinical and experimental immunology.

[37]  B. Bendok,et al.  Moyamoya disease: a review of histopathology, biochemistry, and genetics. , 2011, Neurosurgical focus.

[38]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[39]  A. Ballabio,et al.  Identification of microRNA-regulated gene networks by expression analysis of target genes , 2012, Genome research.

[40]  Hedi Peterson,et al.  g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments , 2007, Nucleic Acids Res..

[41]  A. Ballabio,et al.  MicroRNA target prediction by expression analysis of host genes. , 2009, Genome research.

[42]  D. Tirschwell,et al.  Moyamoya disease in Washington State and California , 2005, Neurology.

[43]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[44]  Eric C. Griffith,et al.  Cell cycle inhibition by the anti-angiogenic agent TNP-470 is mediated by p53 and p21WAF1/CIP1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Z. Werb,et al.  Matrix Metalloproteinases: Regulators of the Tumor Microenvironment , 2010, Cell.

[46]  H. Seno,et al.  Anti-viral protein APOBEC3G is induced by interferon-α stimulation in human hepatocytes , 2006 .

[47]  A. Hata,et al.  A genome-wide association study identifies RNF213 as the first Moyamoya disease gene , 2011, Journal of Human Genetics.

[48]  T. Koeda,et al.  Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection , 2002, Brain and Development.

[49]  T. Pawlik,et al.  Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5. , 2002, The Journal of clinical investigation.