title: Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice.
abstract: BACKGROUND
  The resolution of deep vein thrombosis requires an inflammatory response and mobilization of proteases, such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), to degrade the thrombus and remodel the injured vein wall. Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor (serpin) with unique immunosuppressive and cell survival properties that was originally identified as an inhibitor of uPA.
  
  
  OBJECTIVE
  To investigate the role of PAI-2 in venous thrombus formation and resolution.
  
  
  METHODS
  Venous thrombus resolution was compared in wild-type C57BL/6, PAI-2(-/-) , and PAI-1(-/-) mice using the stasis model of deep vein thrombosis. Formed thrombi were harvested, thrombus weights were recorded, and tissue was analyzed for uPA and MMP activities, PAI-1 expression, and the nature of inflammatory cell infiltration.
  
  
  RESULTS
  We found that the absence of PAI-2 enhanced venous thrombus resolution, while thrombus formation was unaffected. Enhanced venous thrombus resolution in PAI-2(-/-) mice was associated with increased uPA activity and reduced levels of PAI-1, with no significant effect on MMP-2 and -9 activities. PAI-1 deficiency resulted in an increase in thrombus resolution similar to PAI-2 deficiency, but additionally reduced venous thrombus formation and altered MMP activity. PAI-2-deficient thrombi had increased levels of the neutrophil chemoattractant CXCL2, which was associated with early enhanced neutrophil recruitment.
  
  
  CONCLUSIONS
  These data identify PAI-2 as a novel regulator of venous thrombus resolution, which modulates several pathways involving both inflammatory and uPA activity mechanisms, distinct from PAI-1. Further examination of these pathways may lead to potential therapeutic prospects in accelerating thrombus resolution.
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Siefert
authors.forename: C
authors.initials: C
authors.lastname: Chabasse
authors.forename: S
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: M H
authors.initials: MH
authors.lastname: Hoofnagle
authors.forename: D K
authors.initials: DK
authors.lastname: Strickland
authors.forename: R
authors.initials: R
authors.lastname: Sarkar
authors.forename: T M
authors.initials: TM
authors.lastname: Antalis
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D007150:Immunohistochemistry; D007249:Inflammation; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics* / Q000502:physiology; D013927:Thrombosis / Q000378:metabolism; D020246:Venous Thrombosis / Q000235:genetics* / Q000628:therapy
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: plasminogen activator inhibitor 1; plasminogen activator inhibitor 2; serine protease inhibitors; serine proteases; urokinase-type plasminogen activator; venous thrombosis