title: Fli1 deficiency contributes to the downregulation of endothelial protein C receptor in systemic sclerosis: a possible role in prothrombotic conditions.
abstract: BACKGROUND
  Endothelial protein C receptor (EPCR), expressed predominantly on endothelial cells, plays a critical role in the regulation of the coagulation system and also mediates various cytoprotective effects by binding and activating protein C. So far, the role of EPCR has not been studied in systemic sclerosis (SSc).
  
  
  OBJECTIVE
  To investigate the potential contribution of EPCR to the development of SSc.
  
  
  METHODS
  EPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining, immunoblotting and/or quantitative reverse-transcription polymerase chain reaction. Fli1, binding to the PROCR promoter, was assessed by chromatin immunoprecipitation. Serum EPCR levels were determined by enzyme-linked immunosorbent assay in 65 patients with SSc and 20 healthy subjects.
  
  
  RESULTS
  EPCR expression was decreased in dermal small vessels of SSc lesional skin compared with those of healthy control skin. Transcription factor Fli1, deficiency of which is implicated in SSc vasculopathy, occupied the PROCR promoter, and EPCR expression was suppressed in Fli1 small interfering RNA-treated endothelial cells and dermal small vessels of Fli1(+/-) mice. In patients with SSc, decreased serum EPCR levels were associated with diffuse skin involvement, interstitial lung disease and digital ulcers. Furthermore, serum EPCR levels inversely correlated with plasma levels of plasmin-α2-plasmin inhibitor complex (PIC). Importantly, bosentan significantly reversed circulating EPCR and PIC levels in patients with SSc, and the expression of Fli1 and EPCR in dermal small vessels was elevated in patients treated with bosentan compared with untreated patients.
  
  
  CONCLUSIONS
  Endothelial EPCR downregulation due to Fli1 deficiency may contribute to hypercoagulation status leading to tissue fibrosis and impaired peripheral circulation in SSc.
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Saigusa
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Toyama
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshizaki
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyagaki
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sugaya
authors.affiliation: Department of Dermatology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sato
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001761:Bleomycin / Q000494:pharmacology; D000077300:Bosentan; D016022:Case-Control Studies; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism; D000074283:Endothelial Protein C Receptor; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005341:Fibrinolysin / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D055806:Microvessels / Q000378:metabolism; D008875:Middle Aged; D051789:Proto-Oncogene Protein c-fli-1 / Q000172:deficiency*; D011956:Receptors, Cell Surface / Q000502:physiology*; D012595:Scleroderma, Systemic / Q000097:blood / Q000209:etiology*; D013449:Sulfonamides / Q000494:pharmacology; D019851:Thrombophilia / Q000209:etiology; D000979:alpha-2-Antiplasmin / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D065128:Endothelin Receptor Antagonists; C478370:PROCR protein, human; D051789:Proto-Oncogene Protein c-fli-1; D011956:Receptors, Cell Surface; D013449:Sulfonamides; D000979:alpha-2-Antiplasmin; C037742:plasmin-plasmin inhibitor complex; D001761:Bleomycin; D005341:Fibrinolysin; D000077300:Bosentan