title: Protein tyrosine phosphatase SHP2 mediates chronic insulin-induced endothelial inflammation.
abstract: OBJECTIVE
  Insulin promotes adhesion of leukocytes to the endothelium through increased expression of surface adhesion molecules. We determined whether src-homology domain-2-containing protein tyrosine phosphatase 2 (SHP2), a downstream effecter of insulin signaling, is involved in insulin-induced endothelial inflammation.
  
  
  RESULTS
  In human umbilical vein-derived endothelial cells, treatment with insulin (100 nmol/L) increased Tyr(542) phosphorylation, activity, and subsequently expression of SHP2. Increase in SHP2 accompanied a parallel decrease in the availability of the anti-inflammatory molecule, NO. This consequently enhanced the expression of cell adhesion molecules. Decrease in NO index was caused by endothelial NO synthase (eNOS) uncoupling and increased arginase activity. Among the 2 isoforms, insulin treatment induced the expression of arginase II. Inactivation of endogenous SHP2 via NSC87877 [8-hydroxy-7-(6-sulfonapthalen-2-yl)-diazenyl-quinoline-5-sulfonic acid] and its knockdown by small interfering RNA decreased arginase activity by blocking arginase II expression; however, it failed to restore eNOS coupling. Inactivation of SHP2 also abrogated insulin-mediated leukocyte adhesion by blocking the expression of adhesion molecules. Finally, downregulation of endogenous arginase II blocked insulin-mediated endothelial inflammation.
  
  
  CONCLUSIONS
  SHP2 mediates chronic insulin-induced endothelial inflammation by limiting the production of NO in an eNOS-independent and arginase-II-dependent manner.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai-600 036, India.
authors.forename: Hemant
authors.initials: H
authors.lastname: Giri
authors.forename: Ilayaraja
authors.initials: I
authors.lastname: Muthuramu
authors.forename: Monalisa
authors.initials: M
authors.lastname: Dhar
authors.forename: K
authors.initials: K
authors.lastname: Rathnakumar
authors.forename: Uma
authors.initials: U
authors.lastname: Ram
authors.forename: Madhulika
authors.initials: M
authors.lastname: Dixit
mesh_terms: D001119:Arginase / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007328:Insulin / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D007328:Insulin; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C477631:ARG2 protein, human; D001119:Arginase