Enhanced Venous Thrombus Resolution in Plasminogen Activator Inhibitor Type-2 Deficient Mice
| Autor: | Dudley K. Strickland, Mark H. Hoofnagle, Toni M. Antalis, Christine Chabasse, Suzanne A Siefert, Rajabrata Sarkar, Subhradip Mukhopadhyay |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Proteases
Pathology medicine.medical_specialty Neutrophils Mice Transgenic Matrix metalloproteinase Article chemistry.chemical_compound Mice Plasminogen Activator Inhibitor 1 medicine Plasminogen Activator Inhibitor 2 Animals cardiovascular diseases Thrombus Crosses Genetic Oligonucleotide Array Sequence Analysis Inflammation Venous Thrombosis Macrophages Thrombosis Hematology medicine.disease Immunohistochemistry Mice Inbred C57BL Venous thrombosis chemistry Matrix Metalloproteinase 9 Plasminogen activator inhibitor-1 Immunology Plasminogen activator inhibitor-2 cardiovascular system Matrix Metalloproteinase 2 Plasminogen activator |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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