title: Caveolin-1, Ring finger protein 213, and endothelial function in Moyamoya disease.
abstract: Moyamoya disease is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for Moyamoya disease in East Asian countries. However, the pathogenesis of Moyamoya disease remains unclear.
  
  
  
  We prospectively analyzed clinical data for 139 patients with Moyamoya disease (108 bilateral Moyamoya disease, 31 unilateral Moyamoya disease), 61 patients with intracranial atherosclerotic stroke, and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor (VEGF) and receptor (VEGFR2), and antagonizing cytokine (endostatin)) and endothelial dysfunction (asymmetric dimethylarginine (ADMA), and nitric oxide and its metabolites (nitrite and nitrate)) between patients with Moyamoya disease and intracranial atherosclerotic stroke. We then performed path analysis to evaluate whether a certain protein biomarker mediates the association between genes and Moyamoya disease.
  
  
  
  Caveolin-1 level was decreased in patients with Moyamoya disease and markedly decreased in RNF213 variant carriers. Circulating factors such as VEGF and VEGFR2 did not differ among the groups. Markers for endothelial dysfunction were significantly higher in patients with intracranial atherosclerotic stroke but normal in those with Moyamoya disease. Path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 levels that could lead to Moyamoya disease. The level of combined marker of Moyamoya disease (caveolin-1) and intracranial atherosclerotic stroke (ADMA, an endothelial dysfunction marker) predicted Moyamoya disease with good sensitivity and specificity.
  
  
  
  Our results suggest that Moyamoya disease is a caveolae disorder but is not related to endothelial dysfunction or dysregulation of circulating cytokines.
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea ohyoung.bang@samsung.com.|Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Oh Young
authors.initials: OY
authors.lastname: Bang
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.|Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Chung
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Suk Jae
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Oh
authors.affiliation: Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Soo Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Yeon Hee
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Cha
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Je Young
authors.initials: JY
authors.lastname: Yeon
authors.affiliation: Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Keon Ha
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Gyeong-Moon
authors.initials: GM
authors.lastname: Kim
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Chin-Sang
authors.initials: CS
authors.lastname: Chung
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Kwang Ho
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Pyoung
authors.initials: P
authors.lastname: Jeon
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Seung Chyul
authors.initials: SC
authors.lastname: Hong
authors.affiliation: Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.|Medical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Gyeong Joon
authors.initials: GJ
authors.lastname: Moon
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D002537:Intracranial Arteriosclerosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000235:genetics* / Q000378:metabolism*; D011446:Prospective Studies; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051242:Caveolin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: Moyamoya disease; RNF213; caveolin-1; diagnosis; endothelial dysfunction; intracranial stenosis