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Gene Review

Serpine1  -  serine (or cysteine) peptidase inhibitor,...

Mus musculus

Synonyms: Endothelial plasminogen activator inhibitor, Mr1, PAI, PAI-1, PAI1, ...
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Disease relevance of Serpine1

  • Our results suggest that short days trigger expression of Hif1alpha, Serpine1, and Tgfbetar3 to inhibit angiogenesis or promote apoptosis during testicular regression, and also trigger expression of Tnf to promote angiogenesis during testicular recrudescence [1].
  • Although elevated plasma plasminogen activator inhibitor 1 (PAI-1) is associated with obesity, very little is known about its tissue or cellular origin, or about the events that lead to increased PAI-1 levels under obese conditions [2].
  • The two u-PA and PAI-1 producing cell lines showed the highest frequency to form spontaneous lung metastases after subcutaneous inoculation, whereas five of the six cell lines formed lung colonies after intravenous inoculation [3].
  • Obesity is associated with a cluster of abnormalities, including hypertension, insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor beta (TGF-beta) [4].
  • The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice [5].
  • Diabetic Pai-1 transgenic mice did not develop increased albuminuria or glomerular injury, but the tubulointerstitial area was modestly enhanced [6].

Psychiatry related information on Serpine1

  • In two different mouse models of Alzheimer's disease, chronically elevated Abeta peptide in the brain correlates with the upregulation of plasminogen activator inhibitor-1 (PAI-1) and inhibition of the tPA-plasmin system [7].

High impact information on Serpine1

  • CO drove ischemic protection by activating soluble guanylate cyclase and thereby suppressed hypoxic induction of the gene encoding plasminogen activator inhibitor-1 (PAI-1) in mononuclear phagocytes, which reduced accrual of microvascular fibrin [8].
  • We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes [9].
  • Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity [10].
  • These data suggest that an enhanced expression of the PAI-1 gene in visceral fat may increase plasma levels and may have a role in the development of vascular disease in visceral obesity [10].
  • Plasma PAI-1 levels were closely correlated with visceral fat area but not with subcutaneous fat area in human subjects [10].

Chemical compound and disease context of Serpine1


Biological context of Serpine1


Anatomical context of Serpine1


Associations of Serpine1 with chemical compounds


Regulatory relationships of Serpine1

  • These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors [23].
  • Injection of plasminogen induced a variable increase (on average 7- to 10-fold) of PAI-1, but no correlation with the extent of spontaneous clot lysis was observed [24].
  • However, in lean mice, TNF-alpha-induced PAI-1 expression is mediated primarily by the p55 TNFR [25].
  • Insulin-induced HUVEC migration and angiotube formation was also enhanced in the presence of VN and this enhancement is inhibited by PAI-1 [26].
  • CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression [27].

Other interactions of Serpine1

  • The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies [23].
  • Tumors in UPA-/- and PAI-1-/- mice displayed lower proliferative and higher apoptotic indices and displayed a different neovascular morphology, as compared with WT mice [17].
  • This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL [28].
  • Induction of expression of tPA and PAI-1 transcripts was detected in activated astrocytes in the white matter [29].
  • These observations suggest that the p75 TNFR may play a role in attenuating TNF-alpha-induced PAI-1 mRNA expression in acute inflammatory conditions [25].

Analytical, diagnostic and therapeutic context of Serpine1


  1. Photoperiod-induced differential expression of angiogenesis genes in testes of adult Peromyscus leucopus. Pyter, L.M., Hotchkiss, A.K., Nelson, R.J. Reproduction (2005) [Pubmed]
  2. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. Samad, F., Yamamoto, K., Loskutoff, D.J. J. Clin. Invest. (1996) [Pubmed]
  3. Metastatic behavior of human melanoma cell lines in nude mice correlates with urokinase-type plasminogen activator, its type-1 inhibitor, and urokinase-mediated matrix degradation. Quax, P.H., van Muijen, G.N., Weening-Verhoeff, E.J., Lund, L.R., Danø, K., Ruiter, D.J., Verheijen, J.H. J. Cell Biol. (1991) [Pubmed]
  4. Tumor necrosis factor alpha is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1. Samad, F., Uysal, K.T., Wiesbrock, S.M., Pandey, M., Hotamisligil, G.S., Loskutoff, D.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  5. Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice. Kawasaki, T., Dewerchin, M., Lijnen, H.R., Vermylen, J., Hoylaerts, M.F. Blood (2000) [Pubmed]
  6. Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease. Lassila, M., Fukami, K., Jandeleit-Dahm, K., Semple, T., Carmeliet, P., Cooper, M.E., Kitching, A.R. Diabetologia (2007) [Pubmed]
  7. The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. Melchor, J.P., Pawlak, R., Strickland, S. J. Neurosci. (2003) [Pubmed]
  8. Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis. Fujita, T., Toda, K., Karimova, A., Yan, S.F., Naka, Y., Yet, S.F., Pinsky, D.J. Nat. Med. (2001) [Pubmed]
  9. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Bajou, K., Noël, A., Gerard, R.D., Masson, V., Brunner, N., Holst-Hansen, C., Skobe, M., Fusenig, N.E., Carmeliet, P., Collen, D., Foidart, J.M. Nat. Med. (1998) [Pubmed]
  10. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Shimomura, I., Funahashi, T., Takahashi, M., Maeda, K., Kotani, K., Nakamura, T., Yamashita, S., Miura, M., Fukuda, Y., Takemura, K., Tokunaga, K., Matsuzawa, Y. Nat. Med. (1996) [Pubmed]
  11. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Ma, L.J., Mao, S.L., Taylor, K.L., Kanjanabuch, T., Guan, Y., Zhang, Y., Brown, N.J., Swift, L.L., McGuinness, O.P., Wasserman, D.H., Vaughan, D.E., Fogo, A.B. Diabetes (2004) [Pubmed]
  12. Aging accelerates endotoxin-induced thrombosis : increased responses of plasminogen activator inhibitor-1 and lipopolysaccharide signaling with aging. Yamamoto, K., Shimokawa, T., Yi, H., Isobe, K., Kojima, T., Loskutoff, D.J., Saito, H. Am. J. Pathol. (2002) [Pubmed]
  13. Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. Hattori, N., Degen, J.L., Sisson, T.H., Liu, H., Moore, B.B., Pandrangi, R.G., Simon, R.H., Drew, A.F. J. Clin. Invest. (2000) [Pubmed]
  14. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Carmeliet, P., Moons, L., Lijnen, R., Janssens, S., Lupu, F., Collen, D., Gerard, R.D. Circulation (1997) [Pubmed]
  15. Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue. Morange, P.E., Aubert, J., Peiretti, F., Lijnen, H.R., Vague, P., Verdier, M., Négrel, R., Juhan-Vague, I., Alessi, M.C. Diabetes (1999) [Pubmed]
  16. Transforming growth factor beta 1 induces neointima formation through plasminogen activator inhibitor-1-dependent pathways. Otsuka, G., Agah, R., Frutkin, A.D., Wight, T.N., Dichek, D.A. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  17. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Gutierrez, L.S., Schulman, A., Brito-Robinson, T., Noria, F., Ploplis, V.A., Castellino, F.J. Cancer Res. (2000) [Pubmed]
  18. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Eitzman, D.T., Westrick, R.J., Xu, Z., Tyson, J., Ginsburg, D. Blood (2000) [Pubmed]
  19. Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia. Docagne, F., Nicole, O., Marti, H.H., MacKenzie, E.T., Buisson, A., Vivien, D. FASEB J. (1999) [Pubmed]
  20. Induction of plasminogen activator inhibitor 1 gene expression in murine liver by lipopolysaccharide. Cellular localization and role of endogenous tumor necrosis factor-alpha. Fearns, C., Loskutoff, D.J. Am. J. Pathol. (1997) [Pubmed]
  21. Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Nicholas, S.B., Aguiniga, E., Ren, Y., Kim, J., Wong, J., Govindarajan, N., Noda, M., Wang, W., Kawano, Y., Collins, A., Hsueh, W.A. Kidney Int. (2005) [Pubmed]
  22. Cellular degradation of free and inhibitor-bound tissue-type plasminogen activator--requirement for a co-receptor? Camani, C., Gavin, O., Kruithof, E.K. Thromb. Haemost. (2000) [Pubmed]
  23. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. Bajou, K., Masson, V., Gerard, R.D., Schmitt, P.M., Albert, V., Praus, M., Lund, L.R., Frandsen, T.L., Brunner, N., Dano, K., Fusenig, N.E., Weidle, U., Carmeliet, G., Loskutoff, D., Collen, D., Carmeliet, P., Foidart, J.M., Noël, A. J. Cell Biol. (2001) [Pubmed]
  24. Restoration of thrombolytic potential in plasminogen-deficient mice by bolus administration of plasminogen. Lijnen, H.R., Carmeliet, P., Bouché, A., Moons, L., Ploplis, V.A., Plow, E.F., Collen, D. Blood (1996) [Pubmed]
  25. Divergent roles for p55 and p75 TNF-alpha receptors in the induction of plasminogen activator inhibitor-1. Pandey, M., Tuncman, G., Hotamisligil, G.S., Samad, F. Am. J. Pathol. (2003) [Pubmed]
  26. Plasminogen activator inhibitor type-1 inhibits insulin signaling by competing with alphavbeta3 integrin for vitronectin binding. López-Alemany, R., Redondo, J.M., Nagamine, Y., Muñoz-Cánoves, P. Eur. J. Biochem. (2003) [Pubmed]
  27. CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression. Oishi, K., Ohkura, N., Wakabayashi, M., Shirai, H., Sato, K., Matsuda, J., Atsumi, G., Ishida, N. J. Thromb. Haemost. (2006) [Pubmed]
  28. Transcriptional profiling after bile duct ligation identifies PAI-1 as a contributor to cholestatic injury in mice. Wang, H., Vohra, B.P., Zhang, Y., Heuckeroth, R.O. Hepatology (2005) [Pubmed]
  29. Coordinated induction of extracellular proteolysis systems during experimental autoimmune encephalomyelitis in mice. Teesalu, T., Hinkkanen, A.E., Vaheri, A. Am. J. Pathol. (2001) [Pubmed]
  30. Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury. Dai, E., Guan, H., Liu, L., Little, S., McFadden, G., Vaziri, S., Cao, H., Ivanova, I.A., Bocksch, L., Lucas, A. J. Biol. Chem. (2003) [Pubmed]
  31. Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. Lijnen, H.R., Moons, L., Beelen, V., Carmelie, P., Collen, D. Thromb. Haemost. (1995) [Pubmed]
  32. Differential expression of urokinase-type plasminogen activator, its receptor, and inhibitors in mouse skin after exposure to a tumor-promoting phorbol ester. Lund, L.R., Eriksen, J., Ralfkiaer, E., Rømer, J. J. Invest. Dermatol. (1996) [Pubmed]
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