title: The endothelial tyrosine phosphatase SHP-1 plays an important role for vascular haemostasis in TNFα -induced inflammation in vivo.
abstract: BACKGROUND
  Inflammation and endothelium-derived superoxides are important pathomechanisms in atherothrombotic diseases. We could previously show that the tyrosine phosphatase SHP-1 acts as a negative regulator in endothelial superoxide production. In this study we investigated the influence of SHP-1 on platelet-endothelium interaction and arterial thrombosis in TNFα -induced endothelial inflammation in vivo.
  
  
  METHODS
  Arteriolar thrombosis and platelet rolling in vivo were investigated in C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model.
  
  
  RESULTS
  Inhibition of SHP-1 by the specific pharmacological inhibitor sodium stibogluconate did not significantly enhance platelet-endothelium interaction in vivo under physiological conditions but led to an augmented fraction of rolling platelets in TNFα -induced systemic inflammation. Accordingly, ferric-chloride-induced arteriolar thrombus formation, which was already increased by SHP-1 inhibition, was further enhanced in the setting of TNFα -induced inflammation. Platelet aggregation in vitro as well as ex vivo was not influenced by SHP-1-inhibition. In cultured endothelial cells, sodium stibogluconate increased TNFα -induced surface expression of p-selectin and von Willebrand factor. Additionally, TNFα increased SHP-1 activity and protein expression.
  
  
  CONCLUSIONS
  The endothelial tyrosine phosphatase SHP-1 plays an important role for vascular hemostasis in vivo, which is crucial in TNF α -induced endothelial inflammation where it may serve as an autoinhibitory molecule to prevent excess inflammatory response and thrombus formation.
authors.affiliation: Medizinische Klinik und Poliklinik IV, Innenstadt, Ludwig Maximilians Universität München, Ziemssenstr 1, 80336 Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Koch
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.forename: Thomas
authors.initials: T
authors.lastname: Czermak
authors.forename: Erik
authors.initials: E
authors.lastname: Gaitzsch
authors.forename: Stefan
authors.initials: S
authors.lastname: Alig
authors.forename: Hanna
authors.initials: H
authors.lastname: Mannell
authors.forename: Markus
authors.initials: M
authors.lastname: Niemeyer
authors.forename: Florian
authors.initials: F
authors.lastname: Krötz
authors.forename: Markus
authors.initials: M
authors.lastname: Wörnle
mesh_terms: D000818:Animals; D000967:Antimony Sodium Gluconate / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D004727:Endothelium / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D000967:Antimony Sodium Gluconate