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Enhanced venous thrombus resolution in plasminogen activator inhibitor type‐2 deficient mice

https://doi.org/10.1111/jth.12657Get rights and content
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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.

Keywords

plasminogen activator inhibitor 1
plasminogen activator inhibitor 2
serine protease inhibitors
serine proteases
urokinase‐type plasminogen activator
venous thrombosis

Cited by (0)

See also Gardiner EE, Medcalf RL. Is plasminogen activator inhibitor type 2 really a plasminogen activator inhibitor after all? This issue, pp 1703–5.

Manuscript handled by: R. Medcalf

Final decision: P. H. Reitsma, 30 June 2014