title: Endothelial protease nexin-1 is a novel regulator of A disintegrin and metalloproteinase 17 maturation and endothelial protein C receptor shedding via furin inhibition.
abstract: OBJECTIVE
  Human protein C is a plasma serine protease that plays a key role in hemostasis, and activated protein C (aPC) is known to elicit protective responses in vascular endothelial cells. This cytoprotective activity requires the interaction of the protease with its cell membrane receptor, endothelial protein C receptor. However, the mechanisms regulating the beneficial cellular effects of aPC are not well known. We aimed to determine whether a serine protease inhibitor called protease nexin-1 (PN-1) or serpinE2, expressed by vascular cells, can modulate the effect of aPC on endothelial cells.
  
  
  RESULTS
  We found that vascular barrier protective and antiapoptotic activities of aPC were reduced both in endothelial cells underexpressing PN-1 and in endothelial cells whose PN-1 function was blocked by a neutralizing antibody. Our in vitro data were further confirmed in vivo. Indeed, we found that vascular endothelial growth factor-mediated hyperpermeability in the skin of mice was markedly reduced by local intradermal injection of aPC in wild-type mice but not in PN-1-deficient mice. Furthermore, we demonstrated a previously unknown protective role of endothelial PN-1 on endothelial protein C receptor shedding. We provided evidence that PN-1 inhibits furin, a serine protease that activates a disintegrin and metalloproteinase 17 involved in the shedding of endothelial protein C receptor. We indeed evidenced a direct interaction between PN-1 and furin in endothelial cells.
  
  
  CONCLUSIONS
  Our results thus demonstrate an original role of PN-1 as a furin convertase inhibitor, providing new insights for understanding the regulation of endothelial protein C receptor-dependent aPC endothelial protective effects.
authors: INSERM, U698, Paris, France.
authors: Yacine
authors: Y
authors: Boulaftali
authors: Déborah
authors: D
authors: François
authors: Laurence
authors: L
authors: Venisse
authors: Martine
authors: M
authors: Jandrot-Perrus
authors: Véronique
authors: V
authors: Arocas
authors: Marie-Christine
authors: MC
authors: Bouton
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071096:ADAMTS Proteins; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002199:Capillary Permeability; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D000074283:Endothelial Protein C Receptor; D045683:Furin / Q000378:metabolism*; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D058258:Serpin E2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply*; D014162:Transfection
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; C478370:PROCR protein, human; C080248:Procr protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C545486:SERPINE2 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C468731:FURIN protein, human; D045683:Furin; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C579149:ADAMTS17 protein, human
keywords: endothelial cell protein C receptor; furin; protease nexin I; protein C; serpinE2