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Enhanced venous thrombus resolution in plasminogen activator inhibitor type‐2 deficient mice
Author(s) -
Siefert S. A.,
Chabasse C.,
Mukhopadhyay S.,
Hoofnagle M. H.,
Strickland D. K.,
Sarkar R.,
Antalis T. M.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12657
Subject(s) - thrombus , plasminogen activator , plasminogen activator inhibitor 1 , venous thrombosis , thrombosis , medicine
Summary 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.