title: Improvement of peripheral endothelial dysfunction by protein tyrosine phosphatase inhibitors in heart failure.
abstract: BACKGROUND
  Chronic heart failure (CHF) induces endothelial dysfunction characterized by a decrease in nitric oxide (NO) production in response to flow (flow-mediated dilatation [FMD]). Because activation of endothelial NO synthase (eNOS) by flow requires tyrosine phosphorylation, we tested whether endothelial dysfunction could be corrected by increasing phosphotyrosine levels using protein tyrosine phosphatase (PTP) inhibitors and especially inhibitors of PTP1B.
  
  
  RESULTS
  CHF was induced by coronary ligation in mice, and FMD was assessed in isolated and cannulated mesenteric artery segments (2 mm in length and <300 microm in diameter). CHF almost abolished FMD but only moderately affected the response to acetylcholine. In mice with CHF, the PTP1B inhibitors AS279, AS098, and AS713 restored FMD to levels similar to those of normal mice. This restoration was reduced by inhibitors of eNOS and phosphatidylinositol-3 kinase. Polymerase chain reaction and Western blot showed that arteries express PTP1B, and this expression was not affected by CHF. Immunolocalization revealed the presence of PTP1B in the endothelium and the adventitia. Flow induced a transient eNOS phosphorylation that was absent in CHF. PTP1B inhibition stimulated early eNOS phosphorylation and increased phosphorylation of Akt.
  
  
  CONCLUSIONS
  Our results demonstrate for the first time that PTP1B inhibitors may be potent treatments for endothelial dysfunction.
authors.affiliation: INSERM U644, Federate Institute for Multidisciplinary Research on Peptides, Rouen University Medical School, Rouen, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Vercauteren
authors.forename: Elise
authors.initials: E
authors.lastname: Remy
authors.forename: Corinne
authors.initials: C
authors.lastname: Devaux
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dautreaux
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Henry
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bauer
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.forename: Rob
authors.initials: R
authors.lastname: Hooft van Huijsduijnen
authors.forename: Agnès
authors.initials: A
authors.lastname: Bombrun
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002303:Cardiac Output, Low / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000109:Acetylcholine; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D014665:Vasodilator Agents; C516609:Ptpn1 protein, mouse; C516610:Ptpn1 protein, rat