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• W2012531466 abstract "Plasminogen activator (PA) inhibitor type 2 (PAI‐2; SERPINB2) is an atypical and enigmatic member of the Ov‐serpin family of serine protease inhibitors (SERPINS) 1.Medcalf R.L. Stasinopoulos S.J. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2.FEBS J. 2005; 272: 4858-67Crossref PubMed Scopus (108) Google Scholar, 2.Lee J.A. Cochran B.J. Lobov S. Ranson M. Forty years later and the role of plasminogen activator inhibitor type 2/SERPINB2 is still an enigma.Semin Thromb Hemost. 2011; 37: 395-407Crossref PubMed Scopus (34) Google Scholar. PAI‐2 was originally identified as an inhibitor of urokinase PA (u‐PA) 3.Kawano T. Morimoto K. Uemura Y. Partial purification and properties of urokinase inhibitor from human placenta.J Biochem. 1970; 67: 333-42Crossref PubMed Scopus (106) Google Scholar, but it also inhibits soluble 4.Thorsen S. Philips M. Selmer J. Lecander I. Astedt B. Kinetics of inhibition of tissue‐type and urokinase‐type plasminogen activator by plasminogen‐activator inhibitor type 1 and type 2.FEBS J. 1988; 175: 33-9Google Scholar and cell surface‐bound tissue‐type PA (t‐PA) 5.Lee J.A. Croucher D.R. Ranson M. Differential endocytosis of tissue plasminogen activator by serpins PAI‐1 and PAI‐2 on human peripheral blood monocytes.Thromb Haemost. 2010; 104: 1133-42Crossref PubMed Scopus (7) Google Scholar. However, from the outset, questions were raised about its real biological role and significance, given that the vast majority of PAI‐2 is located in the intracellular compartment of leukocytes and a restricted number of other cells. Although a secreted and glycosylated form can be produced 6.Ye R.D. Wun T.C. Sadler J.E. Mammalian protein secretion without signal peptide removal. Biosynthesis of plasminogen activator inhibitor‐2 in U‐937 cells.J Biol Chem. 1988; 263: 4869-75Abstract Full Text PDF PubMed Google Scholar, its intracellular predominance certainly challenged the idea that PAI‐2 functioned as a PA inhibitor, given that both u‐PA and t‐PA, its only known protease targets, are exclusively extracellular. Circulating plasma levels of PAI‐2 are barely detectable, except during late pregnancy and in some monocytic leukemias. Furthermore, it is also not clear why a second PA inhibitor is needed, as PAI‐1, the most prominent PA inhibitor in vivo, is a fully secreted SERPIN, and is also a more efficient inhibitor of both u‐PA and t‐PA than PAI‐2 4.Thorsen S. Philips M. Selmer J. Lecander I. Astedt B. Kinetics of inhibition of tissue‐type and urokinase‐type plasminogen activator by plasminogen‐activator inhibitor type 1 and type 2.FEBS J. 1988; 175: 33-9Google Scholar. PAI‐2 may have no protease inhibitory role in vivo, a possibility that is not without precedence among Ov‐SERPINs (e.g. Maspin 7.Bass R. Fernandez A.M. Ellis V. Maspin inhibits cell migration in the absence of protease inhibitory activity.J Biol Chem. 2002; 277: 46845-8Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar) with documented biological activity but no known protease target. Nonetheless, PAI‐2 has continued to tantalize and torment the field. Even the magnitude of its expression profile 8.Medcalf R.L. Plasminogen activator inhibitor type 2: still an enigmatic serpin but a model for gene regulation.Methods Enzymol. 2011; 499: 105-34Crossref PubMed Scopus (23) Google Scholar was baffling, as PAI‐2 mRNA expression could be increased > 1000‐fold in U937 monocytes 9.Medcalf R.L. Cell‐ and gene‐specific interactions between signal transduction pathways revealed by okadaic acid. Studies on the plasminogen activating system.J Biol Chem. 1992; 267: 12220-6Abstract Full Text PDF PubMed Google Scholar, fibrosarcoma cells 10.Maurer F. Medcalf R.L. Plasminogen activator inhibitor type 2 gene induction by tumor necrosis factor and phorbol ester involves transcriptional and post‐transcriptional events. Identification of a functional nonameric AU‐rich motif in the 3′‐untranslated region.J Biol Chem. 1996; 271: 26074-80Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar and neurons 11.Zhang S.J. Zou M. Lu L. Lau D. Ditzel D.A. Delucinge‐Vivier C. Aso Y. Descombes P. Bading H. Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity.PLoS Genet. 2009; 5: e1000604Crossref PubMed Scopus (228) Google Scholar following various inducements. In stimulated fibrosarcoma cells, the PAI‐2 protein content increased to such an extent that it constituted nearly 0.3% of total intracellular protein 10.Maurer F. Medcalf R.L. Plasminogen activator inhibitor type 2 gene induction by tumor necrosis factor and phorbol ester involves transcriptional and post‐transcriptional events. Identification of a functional nonameric AU‐rich motif in the 3′‐untranslated region.J Biol Chem. 1996; 271: 26074-80Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar. So why have cells evolved to produce so much of this protein? These levels of PAI‐2 are orders of magnitude greater than what is needed to inhibit any protease, let alone u‐PA or t‐PA. While the PAI‐2 aficionados have continued their debate since the initial discovery of PAI‐2 in 1970, more and more in vivo data have accumulated to implicate PAI‐2 in many intracellular settings, essentially all unrelated to PA inhibition, including attenuation of apoptosis 12.Park J.M. Greten F.R. Wong A. Westrick R.J. Arthur J.S. Otsu K. Hoffmann A. Montminy M. Karin M. Signaling pathways and genes that inhibit pathogen‐induced macrophage apoptosis – CREB and NF‐kappaB as key regulators.Immunity. 2005; 23: 319-29Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, promotion of autophagy 13.Chuang S.Y. Yang C.H. Chou C.C. Chiang Y.P. Chuang T.H. Hsu L.C. TLR‐induced PAI‐2 expression suppresses IL‐1beta processing via increasing autophagy and NLRP3 degradation.Proc Natl Acad Sci USA. 2013; 110: 16079-84Crossref PubMed Scopus (119) Google Scholar, modulation of monocyte differentiation 14.Yu H. Maurer F. Medcalf R.L. Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation.Blood. 2002; 99: 2810-18Crossref PubMed Scopus (56) Google Scholar, and even neuroprotection 11.Zhang S.J. Zou M. Lu L. Lau D. Ditzel D.A. Delucinge‐Vivier C. Aso Y. Descombes P. Bading H. Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity.PLoS Genet. 2009; 5: e1000604Crossref PubMed Scopus (228) Google Scholar. On the other hand, a more recent study has linked tumor‐derived PAI‐2 to abetting tumor cell invasion of brain tissue by interfering with plasmin‐mediated cleavage of Fas ligand on astrocytes 15.Valiente M. Obenauf A.C. Jin X. Chen Q. Zhang X.H. Lee D.J. Chaft J.E. Kris M.G. Huse J.T. Brogi E. Massague J. Serpins promote cancer cell survival and vascular co‐option in brain metastasis.Cell. 2014; 156: 1002-16Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, providing evidence, albeit circumstantial, that PAI‐2 was interfering with u‐PA or t‐PA in vivo. PAI‐2‐deficient mice reported in 1999 carried no obvious phenotype and certainly nothing related to hemostasis 16.Dougherty K.M. Pearson J.M. Yang A.Y. Westrick R.J. Baker M.S. Ginsburg D. The plasminogen activator inhibitor‐2 gene is not required for normal murine development or survival.Proc Natl Acad Sci USA. 1999; 96: 686-91Crossref PubMed Scopus (99) Google Scholar. However, other studies have linked murine PAI‐2 deficiency with adaptive immunity 17.Schroder W.A. Le T.T. Major L. Street S. Gardner J. Lambley E. Markey K. MacDonald K.P. Fish R.J. Thomas R. Suhrbier A. A physiological function of inflammation‐associated SerpinB2 is regulation of adaptive immunity.J Immunol. 2010; 184: 2663-70Crossref PubMed Scopus (82) Google Scholar, an impaired response to infection 18.Zhao A. Yang Z. Sun R. Grinchuk V. Netzel‐Arnett S. Anglin I.E. Driesbaugh K.H. Notari L. Bohl J.A. Madden K.B. Urban Jr, J.F. Antalis T.M. Shea‐Donohue T. SerpinB2 is critical to Th2 immunity against enteric nematode infection.J Immunol. 2013; 190: 5779-87Crossref PubMed Scopus (27) Google Scholar, and with nutritionally induced adipose tissue development 19.Lijnen H.R. Frederix L. Scroyen I. Deficiency of plasminogen activator inhibitor‐2 impairs nutritionally induced murine adipose tissue development.J Thromb Haemost. 2007; 5: 2259-65Crossref PubMed Scopus (22) Google Scholar, again seemingly unrelated to u‐PA or t‐PA inhibition. Up until now, there have been scant reports that have directly associated PAI‐2 with thrombosis, hemostasis or fibrinolysis in vivo, despite the fact that PAI‐2 was identified as a PA inhibitor and, according to that definition, should somehow and somewhere block u‐PA‐mediated (and t‐PA‐mediated) plasmin formation. This lack of in vivo data is surprising, given earlier reports supporting a role for monocyte‐derived PAI‐2 in blocking u‐PA‐mediated clot lysis in vitro 20.Ritchie H. Robbie L.A. Kinghorn S. Exley R. Booth N.A. Monocyte plasminogen activator inhibitor 2 (PAI‐2) inhibits u‐PA‐mediated fibrin clot lysis and is cross‐linked to fibrin.Thromb Haemost. 1999; 81: 96-103Crossref PubMed Scopus (63) Google Scholar. In a paper by Siefert et al. 21.Siefert S.A. Chabasse C. Mukhopadhyay S. Hoofnagle M.H. Strickland D.K. Sarkar R. Antalis T.M. Enhanced venous thrombus resolution in plasminogen activator inhibitor type‐2 deficient mice.J Thromb Haemost. 2014; 12: 1706-16Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, published in this issue of JTH, evidence is presented to implicate PAI‐2 as a modulator of venous thrombus resolution in vivo. To set this stage, previous studies using u‐PA–/– or t‐PA–/– mice have reported that optimal stasis‐induced venous thrombus resolution of endogenous clots requires u‐PA, and not t‐PA, and that this curious effect of u‐PA correlated with increased monocyte infiltration into the thrombus 22.Singh I. Burnand K.G. Collins M. Luttun A. Collen D. Boelhouwer B. Smith A. Failure of thrombus to resolve in urokinase‐type plasminogen activator gene‐knockout mice: rescue by normal bone marrow‐derived cells.Circulation. 2003; 107: 869-75Crossref PubMed Scopus (146) Google Scholar. It was suggested that the u‐PA‐mediated lysis occurred indirectly via monocyte‐derived matrix metalloproteinases (MMPs) or via receptor‐mediated lysosomal degradation. As PAI‐2 is expressed at a high level in monocytes, it seemed reasonable to ask whether the u‐PA‐dependent component of spontaneous thrombus resolution would be enhanced in the absence of PAI‐2, allowing u‐PA to more effectively initiate lysis via whatever mechanism is available. The authors observed that thrombus resolution was significantly enhanced in PAI‐2–/– mice, but without any noticeable effect on thrombus formation. Importantly, active u‐PA levels in the thrombi of PAI‐2–/– mice were increased approximately 12‐fold as compared with u‐PA levels in thrombi formed in wild‐type mice (Table 1), consistent with this prediction. On face value, the accelerated thrombus resolution would seem to be a consequence of the elevation in u‐PA activity resulting from the absence of its cognate inhibitor, PAI‐2. Presumably, the unabated u‐PA was initiating conventional plasmin‐mediated fibrinolysis, given that MMP‐dependent gelatinolytic activity was unaltered in PAI‐2–/– mice (Table 1).Table 1Comparison of thrombus‐related parameters observed in 21.Siefert S.A. Chabasse C. Mukhopadhyay S. Hoofnagle M.H. Strickland D.K. Sarkar R. Antalis T.M. Enhanced venous thrombus resolution in plasminogen activator inhibitor type‐2 deficient mice.J Thromb Haemost. 2014; 12: 1706-16Abstract Full Text Full Text PDF PubMed Scopus (31) Google ScholarThrombus parameterMice deficient in:PAI‐1PAI‐2Initial size of venous thrombus↓–Venous thrombus resolution↑↑↑↑Intrathrombus u‐PA protein levels––Intrathrombus u‐PA activity↑↑↑Intrathrombus PAI‐1 levelsNA↓Intrathrombus MMP2 and MMP9 activity↑ and ↓–Neutrophil infiltration–↑Macrophage infiltration↑↓Macrophage CXCL1 and CXCL2 mRNAND↑↑Intrathrombus CXCL2 proteinND↑MMP, matrix metalloproteinase; NA, not applicable; ND, not done; PAI‐1, plasminogen activator inhibitor type 1; PAI‐2, plasminogen activator inhibitor type 2; u‐PA, urokinase plasminogen activator; –, no difference from wild type. Arrows indicate changes from levels observed in wild‐type animals. Open table in a new tab MMP, matrix metalloproteinase; NA, not applicable; ND, not done; PAI‐1, plasminogen activator inhibitor type 1; PAI‐2, plasminogen activator inhibitor type 2; u‐PA, urokinase plasminogen activator; –, no difference from wild type. Arrows indicate changes from levels observed in wild‐type animals. What was unexpected, however, was that the thrombi formed in PAI‐2–/– mice also had a concomitant reduction (~ 80%) in PAI‐1 (Table 1). This was a surprise, as one may have anticipated, if anything, that an increase in PAI‐1 would have occurred to compensate for the PAI‐2 deficiency. Nonetheless, was the increase in active u‐PA seen in the PAI‐2–/– mice actually a consequence of PAI‐1 suppression? Perhaps this was the case, as thrombi formed in PAI‐1–/– mice also resolved faster and to a similar extent as seen in PAI‐2–/– mice. Moreover, thrombi formed in PAI‐1–/– mice also had a four‐fold increase in u‐PA activity, albeit not as profound as that seen in PAI‐2–/– mice (12‐fold). Additional effects seen in PAI‐1–/– mice were that thrombus formation was also impaired (consistent with previous reports 23.Diaz J.A. Ballard‐Lipka N.E. Farris D.M. Hawley A.E. Wrobleski S.K. Myers D.D. Henke P.K. Lawrence D.A. Wakefield T.W. Impaired fibrinolytic system in ApoE gene‐deleted mice with hyperlipidemia augments deep vein thrombosis.J Vasc Surg. 2012; 55: 815-22Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar), and MMP‐2 and MMP‐9 levels were altered, depending on the time frame of analysis (increased early; decreased late). There were also clear differences in the repertoire of inflammatory cells in thrombi formed in PAI‐1–/– vs. PAI‐2–/– mice (Table 1). Whether these differences have any relevance to stasis‐induced thrombus dynamics is not known, although it is plausible, but the point was well made that PAI‐1 and PAI‐2 deficiency have contrasting effects on thrombus formation, and that PAI‐2 deficiency may have both PAI‐1‐dependent and PAI‐1‐independent effects on thrombus resolution. The authors also reported that thioglycollate‐stimulated macrophages from PAI‐2‐deficient mice had increased levels of the neutrophil chemoattractant CXCL2, raising the question that the observed increase in thrombus resolution may also result from some undefined immunomodulatory effect that could be attributable directly to PAI‐2 deficiency or indirectly to the selective increase in neutrophils that was also seen in these thrombi. What is clear from this study is that PAI‐2 deficiency promotes venous thrombus resolution. The pertinent question is how? Although the authors did not formally prove that the increase in u‐PA was the cause of the accelerated thrombus resolution, this does seem likely, even if the liberation of active u‐PA is being helped by PAI‐1 suppression, as u‐PA–/– mice also have impaired thrombus resolution 22.Singh I. Burnand K.G. Collins M. Luttun A. Collen D. Boelhouwer B. Smith A. Failure of thrombus to resolve in urokinase‐type plasminogen activator gene‐knockout mice: rescue by normal bone marrow‐derived cells.Circulation. 2003; 107: 869-75Crossref PubMed Scopus (146) Google Scholar. So will the PAI‐2 aficionados view this as evidence for regulation of u‐PA by PAI‐2 in vivo? The answer to this is probably ‘yes’, and a recent publication showing an anti‐metastatic role for PAI‐2 (most likely via u‐PA blockade) adds further support to this notion 24.Schroder W.A. Major L.D. Le T.T. Gardner J. Sweet M.J. Janciauskiene S. Suhrbier A. Tumor cell‐expressed SerpinB2 is present on microparticles and inhibits metastasis.Cancer Med. 2014; 3: 500-13Crossref PubMed Scopus (29) Google Scholar. However, the surprising downregulation of PAI‐1 in thrombi of PAI‐2–/– mice has added another layer of complexity to the PAI‐2 story. Although further work is needed, what is apparent is that PAI‐2 deficiency produces a phenotype that appears to be the first to be linked to the regulation of u‐PA activity in hemostasis in vivo. PAI‐2 may therefore be a genuine PA inhibitor after all. E. E. Gardiner and R. L. Medcalf contributed intellectually to the manuscript. R. L. Medcalf wrote the first draft of the manuscript. E. E. Gardiner edited and corrected the manuscript. The authors state that they have no conflict of interest. The authors would like to thank R. K. Andrews (Monash University) and M. Ranson (University of Wollongong) for critically reading the manuscript." @default.
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• W2012531466 title "Is plasminogen activator inhibitor type 2 really a plasminogen activator inhibitor after all?" @default.
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