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Gene Review

Serpine1  -  serpin peptidase inhibitor, clade E (nexin...

Rattus norvegicus

Synonyms: Endothelial plasminogen activator inhibitor, PAI, PAI-1, PAI1A, Pai1, ...
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Disease relevance of Serpine1

  • It was shown that the induction of PAI-1 mRNA and protein expression by insulin and mild hypoxia could be repressed by the PI3K inhibitor wortmannin [1].
  • To determine the molecular mechanisms involved in the basal expression of the rat PAI-1 gene, we have analyzed the cis-acting sequences and the trans-acting factors involved in the transcription of this gene in the HTC rat hepatoma cell line [2].
  • Different doses of 33H1F7 were infused to rats for 30 min and the dose which inactivates rapidly and totally active rat PAI-1 (300 microg/kg/min) was selected to be tested on the thrombosis model [3].
  • Transforming growth factor beta (TGF beta) treatment of rat osteoblast-rich calvarial cells or of the clonal osteogenic sarcoma cells, UMR 106-01, resulted in dose-dependent inhibition of plasminogen activator (PA) activity, and increased production of 3.2 kb mRNA and protein for PA inhibitor -1 (PAI-1) [4].
  • Hepatic stellate cells are an important source of PAI-1 during liver fibrosis [5].

Psychiatry related information on Serpine1


High impact information on Serpine1

  • In fibrotic renal disease, elevated TGF-beta and angiotensin II lead to increased plasminogen activator inhibitor type 1 (PAI-1) [7].
  • Further characterization of vasoactive peptide effects on PAI expression revealed that AII stimulated a 44.8 +/- 25.2-fold and a 12.4 +/- 3.2-fold increase in PAI-2 mRNA in RME cells and rat aortic smooth muscle cells (RASMC), respectively [8].
  • METHODS: PAI-1 synthesis of liver cells at different time points of primary culture was studied by immunoprecipitation of endogenously labeled proteins followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by Northern blotting [9].
  • Transforming growth factor beta 1, tissue plasminogen activator, and dexamethasone increased PAI-1 production in HSCs [9].
  • RESULTS: Among the various types of liver cells, PAI-1 protein and specific transcripts were present in HSCs and endothelial cells, and no major PAI-1 synthesis was detected in Kupffer cells and hepatocytes [9].

Chemical compound and disease context of Serpine1


Biological context of Serpine1


Anatomical context of Serpine1


Associations of Serpine1 with chemical compounds

  • To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress [15].
  • Incubation with lovastatin (5 microM) of proximal tubules isolated from untreated rats induced an increase in tPA and uPA and a decrease in plasminogen activator inhibitor-1 (PAI-1) activities [17].
  • C3 exoenzyme, an inhibitor of the geranylgeranylated-activated Rho protein, reproduced the effect of lovastatin on tPA and PAI- activity and blocked its reversion by GGPP [17].
  • Plasminogen activator inhibitor-1 (PAI-1) expression is directly regulated by clock genes, while angiotensin II modulates both PAI-1 and clock gene expression [19].
  • Candesartan treatment decreased cardiac PAI-1 expression only in the dark in WKY rats but throughout the day in SHR [19].

Physical interactions of Serpine1

  • In addition to the free pool of tPA, a large portion of tPA is complexed to PAI-1 and is therefore functionally inactive [20].
  • Electrophoretic mobility shift assays with radiolabeled oligonucleotides containing the two putative Sp1-binding sites from PAI-1 promoter and nuclear extracts from RASM cells revealed that glucose treatment markedly changed the mobility pattern of the major protein-DNA complexes [21].

Regulatory relationships of Serpine1

  • Pharmacologic inhibition of keratinocyte MEK signaling effectively ablated scrape-induced PAI-1 mRNA expression but failed to attenuate wound-associated increases in cellular PAI-1 protein levels soon after monolayer injury [18].
  • Moreover, purified TGF beta-1 produces a Schwann cell morphology alteration and decreases the secretion of tissue-type plasminogen activator (tPA) and enhances the secretion of plasminogen activator inhibitor (PAI) by Schwann cells [22].
  • In conclusion, G-protein-coupled receptor agonist-induced PAI-1 expression is partially mediated through JNK activation [23].
  • A reverse fibrin zymogram indicated that PAI activity was greatly enhanced in TGF beta-treated CM [24].
  • This stimulation is specifically mediated by TxA2 (thromboxane prostanoid, TP) receptors, since U-46619 also stimulates PAI-1 expression in cells that are transfected with TP receptors, and this stimulation of PAI-1 production is completely blocked by the TxA2 receptor antagonist, SQ-29,548 [25].

Other interactions of Serpine1

  • Systolic blood pressure (SBP) was measured monthly up to 8 months of age, when the animals were killed; then, CG and AG were excised and processed for light microscopy and immunohistochemistry (TGF-beta 1, PAI-1 and protein S100) [26].
  • Western analysis was performed to detect protein expression of PAI-1, uPA and uPAR [5].
  • Egr-1 and PAI-1 were specifically induced during the first few hours in the hyper-perfused lobes following PBL and PH [27].
  • Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1 [28].
  • Northern analysis confirmed upregulation of three of these genes, PAI-1, P2X4, and P15INK4B [29].

Analytical, diagnostic and therapeutic context of Serpine1

  • S-phase-specific mRNA-levels of H2B-histone protein (H2B), as well as expression analysis of Egr-1, PAI-1 and PRL-1 were examined by Northern blot experiments [27].
  • We examined the expression of PAI-1, uPA, and uPAR mRNAs through the use of in situ hybridization and that of type IV collagen by means of immunohistochemical methods [30].
  • Western blots showed increased PAI-1 in grafts from the LPSN group compared with LXSN and NO groups [31].
  • METHODS AND RESULTS: Guinea pig-to-rat aortic xenografts were seeded with syngeneic Fischer 344 rat smooth muscle cells retrovirally transduced with the rat PAI-1 gene (LPSN group) or the vector alone (LXSN group) [31].
  • PAI-1 mRNA expression was noted at 6 h, peaking at 1 day, and although falling thereafter, remained higher than that of the control group through Day 17 [32].


  1. Hypoxia-inducible factor-1 and hypoxia response elements mediate the induction of plasminogen activator inhibitor-1 gene expression by insulin in primary rat hepatocytes. Kietzmann, T., Samoylenko, A., Roth, U., Jungermann, K. Blood (2003) [Pubmed]
  2. Regulatory sequences and protein-binding sites involved in the expression of the rat plasminogen activator inhibitor-1 gene. Johnson, M.R., Bruzdzinski, C.J., Winograd, S.S., Gelehrter, T.D. J. Biol. Chem. (1992) [Pubmed]
  3. Inactivation of plasminogen activator inhibitor-1 accelerates thrombolysis of a platelet-rich thrombus in rat mesenteric arterioles. Rupin, A., Martin, F., Vallez, M.O., Bonhomme, E., Verbeuren, T.J. Thromb. Haemost. (2001) [Pubmed]
  4. Transforming growth factor beta inhibits plasminogen activator (PA) activity and stimulates production of urokinase-type PA, PA inhibitor-1 mRNA, and protein in rat osteoblast-like cells. Allan, E.H., Zeheb, R., Gelehrter, T.D., Heaton, J.H., Fukumoto, S., Yee, J.A., Martin, T.J. J. Cell. Physiol. (1991) [Pubmed]
  5. Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells. Zhang, L.P., Takahara, T., Yata, Y., Furui, K., Jin, B., Kawada, N., Watanabe, A. J. Hepatol. (1999) [Pubmed]
  6. Gonadotropin-releasing hormone agonist (GnRH-a) therapy alters activity of plasminogen activators, matrix metalloproteinases, and their inhibitors in rat models for adhesion formation and endometriosis: potential GnRH-a-regulated mechanisms reducing adhesion formation. Sharpe-Timms, K.L., Zimmer, R.L., Jolliff, W.J., Wright, J.A., Nothnick, W.B., Curry, T.E. Fertil. Steril. (1998) [Pubmed]
  7. A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis. Huang, Y., Haraguchi, M., Lawrence, D.A., Border, W.A., Yu, L., Noble, N.A. J. Clin. Invest. (2003) [Pubmed]
  8. Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. Feener, E.P., Northrup, J.M., Aiello, L.P., King, G.L. J. Clin. Invest. (1995) [Pubmed]
  9. Gene expression and regulation of plasminogen activator inhibitor type I in hepatic stellate cells of rat liver. Knittel, T., Fellmer, P., Ramadori, G. Gastroenterology (1996) [Pubmed]
  10. Dexamethasone inhibition of tissue-type plasminogen activator (tPA) activity: paradoxical induction of both tPA antigen and plasminogen activator inhibitor. Gelehrter, T.D., Sznycer-Laszuk, R., Zeheb, R., Cwikel, B.J. Mol. Endocrinol. (1987) [Pubmed]
  11. Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats. Ma, L.J., Marcantoni, C., Linton, M.F., Fazio, S., Fogo, A.B. Kidney Int. (2001) [Pubmed]
  12. Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 up-regulation in mesangial cells and in diabetic kidney. Lee, E.A., Seo, J.Y., Jiang, Z., Yu, M.R., Kwon, M.K., Ha, H., Lee, H.B. Kidney Int. (2005) [Pubmed]
  13. Platelet inhibition limits TGF-beta overexpression and matrix expansion after induction of anti-thy1 glomerulonephritis. Peters, H., Eisenberg, R., Daig, U., Liefeldt, L., Westenfeld, R., Gaedeke, J., Krämer, S., Neumayer, H.H. Kidney Int. (2004) [Pubmed]
  14. Experimental hypothyroidism increases plasminogen activator inhibitor activity in rat plasma. Padró, T., van den Hoogen, C.M., Emeis, J.J. Blood Coagul. Fibrinolysis (1993) [Pubmed]
  15. Cellular carbonyl stress enhances the expression of plasminogen activator inhibitor-1 in rat white adipocytes via reactive oxygen species-dependent pathway. Uchida, Y., Ohba, K., Yoshioka, T., Irie, K., Muraki, T., Maru, Y. J. Biol. Chem. (2004) [Pubmed]
  16. Isolation and characterization of the rat plasminogen activator inhibitor-1 gene. Bruzdzinski, C.J., Riordan-Johnson, M., Nordby, E.C., Suter, S.M., Gelehrter, T.D. J. Biol. Chem. (1990) [Pubmed]
  17. Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells: role of geranylgeranylation and Rho proteins. Essig, M., Vrtovsnik, F., Nguyen, G., Sraer, J.D., Friedlander, G. J. Am. Soc. Nephrol. (1998) [Pubmed]
  18. PAI-1 expression is required for epithelial cell migration in two distinct phases of in vitro wound repair. Providence, K.M., Higgins, P.J. J. Cell. Physiol. (2004) [Pubmed]
  19. Circadian gene expression of clock genes and plasminogen activator inhibitor-1 in heart and aorta of spontaneously hypertensive and Wistar-Kyoto rats. Naito, Y., Tsujino, T., Kawasaki, D., Okumura, T., Morimoto, S., Masai, M., Sakoda, T., Fujioka, Y., Ohyanagi, M., Iwasaki, T. J. Hypertens. (2003) [Pubmed]
  20. Immunohistochemical localization of tissue plasminogen activator in vascular endothelium of stroke-prone regions of the rat brain. Schreiber, S.S., Tan, Z., Sun, N., Wang, L., Zlokovic, B.V. Neurosurgery (1998) [Pubmed]
  21. Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells. Chen, Y.Q., Su, M., Walia, R.R., Hao, Q., Covington, J.W., Vaughan, D.E. J. Biol. Chem. (1998) [Pubmed]
  22. Transforming growth factor beta as a neuronoglial signal during peripheral nervous system response to injury. Rogister, B., Delrée, P., Leprince, P., Martin, D., Sadzot, C., Malgrange, B., Munaut, C., Rigo, J.M., Lefebvre, P.P., Octave, J.N. J. Neurosci. Res. (1993) [Pubmed]
  23. Role of c-Jun NH2-terminal kinase in G-protein-coupled receptor agonist-induced cardiac plasminogen activator inhibitor-1 expression. Omura, T., Yoshiyama, M., Matsumoto, R., Kusuyama, T., Enomoto, S., Nishiya, D., Izumi, Y., Kim, S., Ichijo, H., Motojima, M., Akioka, K., Iwao, H., Takeuchi, K., Yoshikawa, J. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  24. Regulation of plasminogen activator and plasminogen activator inhibitor production by growth factors and cytokines in rat calvarial cells. Cheng, S.L., Shen, V., Peck, W.A. Calcif. Tissue Int. (1991) [Pubmed]
  25. Thromboxane A2 modulates the fibrinolytic system in glomerular mesangial cells. Coffman, T.M., Spurney, R.F., Mannon, R.B., Levenson, R. Am. J. Physiol. (1998) [Pubmed]
  26. Plasminogen activator inhibitor-1 and transforming growth factor-beta 1 in carotid glomus and autonomic ganglia from spontaneously hypertensive rats. Milei, J., Cao, G., Grana, D.R., Toblli, J.E. J. Hypertens. (2004) [Pubmed]
  27. The induction of the immediate-early-genes Egr-1, PAI-1 and PRL-1 during liver regeneration in surgical models is related to increased portal flow. Mueller, L., Broering, D.C., Meyer, J., Vashist, Y., Goettsche, J., Wilms, C., Rogiers, X. J. Hepatol. (2002) [Pubmed]
  28. Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1. Görlach, A., Berchner-Pfannschmidt, U., Wotzlaw, C., Cool, R.H., Fandrey, J., Acker, H., Jungermann, K., Kietzmann, T. Thromb. Haemost. (2003) [Pubmed]
  29. Identification of three genes of known function expressed by alveolar epithelial type I cells. Qiao, R., Zhou, B., Liebler, J.M., Li, X., Crandall, E.D., Borok, Z. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  30. Renal synthesis of urokinase type-plasminogen activator, its receptor, and plasminogen activator inhibitor-1 in diabetic nephropathy in rats: modulation by angiotensin-converting-enzyme inhibitor. Kenichi, M., Masanobu, M., Takehiko, K., Shoko, T., Akira, F., Katsushige, A., Takashi, H., Yoshiyuki, O., Shigeru, K. J. Lab. Clin. Med. (2004) [Pubmed]
  31. Prevention of aneurysm development and rupture by local overexpression of plasminogen activator inhibitor-1. Allaire, E., Hasenstab, D., Kenagy, R.D., Starcher, B., Clowes, M.M., Clowes, A.W. Circulation (1998) [Pubmed]
  32. Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis. Feng, L., Tang, W.W., Loskutoff, D.J., Wilson, C.B. J. Am. Soc. Nephrol. (1993) [Pubmed]
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