Download PDF
Thromb Haemost 2014; 112(02): 243-254
DOI: 10.1160/TH13-06-0517
Review Article
Schattauer GmbH

Human tissue-type plasminogen activator

Egbert K. O. Kruithof
1   Division of Angiology and Hemostasis, Department of Internal Medicine, University Hospital of Geneva and Faculty of Medicine of the University of Geneva, Geneva, Switzerland
,
Sylvie Dunoyer-Geindre
1   Division of Angiology and Hemostasis, Department of Internal Medicine, University Hospital of Geneva and Faculty of Medicine of the University of Geneva, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

Received: 26 June 2013

Accepted after minor revision: 07 March 2014

Publication Date:
04 December 2017 (online)

    Permissions and Reprints

Summary

Tissue-type plasminogen activator (t-PA ) plays an important role in the removal of intravascular fibrin deposits and has several physiological roles and pathological activities in the brain. Its production by many other cell types suggests that t-PA has additional functions outside the vascular and central nervous system. Activity of t-PA is regulated at the level of its gene transcription, its mRNA stability and translation, its storage and regulated release, its interaction with cofactors that enhance its activity, its inhibition by inhibitors such as plasminogen activator inhibitor type 1 or neuroserpin, and its removal by clearance receptors. Gene transcription of t-PA is modulated by a large number of hormones, growth factors, cytokines or drugs and t-PA gene responses may be tissue-specific. The aim of this review is to summarise current knowledge on t-PA function and regulation of its pericellular activity, with an emphasis on regulation of its gene expression.

Keywords

Plasminogen activators - gene regulation - endothelial cells - nervous system

 

  • References

  • 1 Collen D, Lijnen HR. The tissue-type plasminogen activator story. Arterioscler Thromb Vasc Biol 2009; 29: 1151-1155.
    CrossrefPubMedGoogle Scholar
  • 2 Medcalf RL, Davis SM. Plasminogen activation and thrombolysis for ischemic stroke. Int J Stroke 2012; 07: 419-425.
    CrossrefPubMedGoogle Scholar
  • 3 Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 2009; 07: 4-13.
    CrossrefPubMedGoogle Scholar
  • 4 Carmeliet P, Schoonjans L, Kieckens L. et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994; 368: 419-424.
    CrossrefPubMedGoogle Scholar
  • 5 Lijnen HR, Moons L, Beelen V. et al. Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. Thromb Haemost 1995; 74: 1126-1131.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Giles AR, Nesheim ME, Herring SW. et al. The fibrinolytic potential of the normal primate following the generation of thrombin in vivo. Thromb Haemost 1990; 63: 476-481.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Kruithof EK, Mestries JC, Gascon MP. et al. The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation--effect of interleukin 6. Thromb Haemost 1997; 77: 905-910.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Pepper MS, Rosnoblet C, Di Sanza C. et al. Synergistic induction of t-PA by vascular endothelial growth factor and basic fibroblast growth factor and localization of t-PA to Weibel-Palade bodies in bovine microvascular endothelial cells. Thromb Haemost 2001; 86: 702-709.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Pepper MS. Extracellular proteolysis and angiogenesis. Thromb Haemost 2001; 86: 346-355.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Diaz VM, Planaguma J, Thomson TM. et al. Tissue plasminogen activator is required for the growth, invasion, and angiogenesis of pancreatic tumor cells. Gastroenterology 2002; 122: 806-819.
    CrossrefPubMedGoogle Scholar
  • 11 Pawlak R, Strickland S. Tissue plasminogen activator and seizures: a clot-buster’s secret life. J Clin Invest 2002; 109: 1529-1531.
    CrossrefPubMedGoogle Scholar
  • 12 Melchor JP, Strickland S. Tissue plasminogen activator in central nervous system physiology and pathology. Thromb Haemost 2005; 93: 655-660.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Samson AL, Medcalf RL. Tissue-type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity. Neuron 2006; 50: 673-678.
    CrossrefPubMedGoogle Scholar
  • 14 Benarroch EE. Tissue plasminogen activator: beyond thrombolysis. Neurology 2007; 69: 799-802.
    CrossrefPubMedGoogle Scholar
  • 15 Yepes M, Roussel BD, Ali C. et al. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci 2009; 32: 48-55.
    CrossrefPubMedGoogle Scholar
  • 16 Vivien D, Gauberti M, Montagne A. et al. Impact of tissue plasminogen activator on the neurovascular unit: from clinical data to experimental evidence. J Cereb Blood Flow Metab 2011; 31: 2119-2134.
    CrossrefPubMedGoogle Scholar
  • 17 Lemarchant S, Docagne F, Emery E. et al. tPA in the injured central nervous system: different scenarios starring the same actor?. Neuropharmacology 2012; 62: 749-756.
    CrossrefPubMedGoogle Scholar
  • 18 Ortolano S, Spuch C. tPA in the central nervous system: relations between tPA and cell surface LRPs. Recent Pat Endocr Metab Immune Drug Discov 2013; 07: 65-76.
    CrossrefPubMedGoogle Scholar
  • 19 Akassoglou K, Kombrinck KW, Degen JL. et al. Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 2000; 149: 1157-1166.
    CrossrefPubMedGoogle Scholar
  • 20 Wang Y, Jiang X, Hand AR. et al. Additional evidence that the sympathetic nervous system regulates the vessel wall release of tissue plasminogen activator. Blood Coagul Fibrinolysis 2002; 13: 471-481.
    CrossrefPubMedGoogle Scholar
  • 21 Jiang X, Wang Y, Hand AR. et al. Storage and release of tissue plasminogen activator by sympathetic axons in resistance vessel walls. Microvasc Res 2002; 64: 438-447.
    CrossrefPubMedGoogle Scholar
  • 22 Schaefer U, Machida T, Vorlova S. et al. The plasminogen activator system modulates sympathetic nerve function. J Exp Med 2006; 203: 2191-2200.
    CrossrefPubMedGoogle Scholar
  • 23 Schaefer U, Vorlova S, Machida T. et al. Modulation of sympathetic activity by tissue plasminogen activator is independent of plasminogen and urokinase. J Pharmacol Exp Ther 2007; 322: 265-273.
    CrossrefPubMedGoogle Scholar
  • 24 Sitter T, Toet K, Fricke H. et al. Modulation of procoagulant and fibrinolytic system components of mesothelial cells by inflammatory mediators. Am J Physiol 1996; 271: R1256-1263.
    CrossrefPubMedGoogle Scholar
  • 25 Haslinger B, Goedde MF, Toet KH. et al. Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. Kidney Int 2002; 62: 1611-1619.
    CrossrefPubMedGoogle Scholar
  • 26 Aarons CB, Cohen PA, Gower A. et al. Statins (HMG-CoA reductase inhibitors) decrease postoperative adhesions by increasing peritoneal fibrinolytic activity. Ann Surg 2007; 245: 176-184.
    CrossrefPubMedGoogle Scholar
  • 27 Mellor H, Parker PJ. The extended protein kinase C superfamily. Biochem J 1998; 332: 281-292.
    CrossrefPubMedGoogle Scholar
  • 28 Kooistra T, Bosma PJ, Toet K. et al. Role of protein kinase C and cyclic adeno-sine monophosphate in the regulation of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and platelet-derived growth factor mRNA levels in human endothelial cells. Possible involvement of proto-oncogenes c-jun and c-fos. Arterioscler Thromb 1991; 11: 1042-1052.
    PubMedGoogle Scholar
  • 29 Schuermann M, Jager R, Salge U. et al. Control of proteinase expression by phorbol-ester- and Fos-dependent pathways in human non-small-cell lung-cancer cells. Int J Cancer 1997; 71: 275-283.
    CrossrefPubMedGoogle Scholar
  • 30 Levin EG, Marotti KR, Santell L. Protein kinase C and the stimulation of tissue plasminogen activator release from human endothelial cells. Dependence on the elevation of messenger RNA. J Biol Chem 1989; 264: 16030-16036.
    PubMedGoogle Scholar
  • 31 Costa M, Shen Y, Medcalf RL. Overexpression of a dominant negative CREB protein in HT-1080 cells selectively disrupts plasminogen activator inhibitor type 2 but not tissue-type plasminogen activator gene expression. FEBS Lett 2000; 482: 75-80.
    CrossrefPubMedGoogle Scholar
  • 32 Medcalf RL, Kruithof EK, Schleuning WD. Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes. J Exp Med 1988; 168: 751-759.
    CrossrefPubMedGoogle Scholar
  • 33 Ulfhammer E, Larsson P, Karlsson L. et al. TNF-alpha mediated suppression of tissue type plasminogen activator expression in vascular endothelial cells is NF-kappaB- and p38 MAPK-dependent. J Thromb Haemost 2006; 04: 1781-1789.
    CrossrefPubMedGoogle Scholar
  • 34 Bergh N, Larsson P, Ulfhammer E. et al. Effect of shear stress, statins and TNF-alpha on hemostatic genes in human endothelial cells. Biochem Biophys Res Commun 2012; 420: 166-171.
    CrossrefPubMedGoogle Scholar
  • 35 Chang YC, Yang SF, Huang FM. et al. Induction of tissue plasminogen activator gene expression by proinflammatory cytokines in human pulp and gingival fibroblasts. J Endod 2003; 29: 114-117.
    CrossrefPubMedGoogle Scholar
  • 36 Chang YC, Ho YC, Chou LS. et al. Signal transduction pathways involved in the stimulation of tissue type plasminogen activator by interleukin-1alpha and Porphyromonas gingivalis in human osteosarcoma cells. J Periodontal Res 2006; 41: 374-380.
    CrossrefPubMedGoogle Scholar
  • 37 Wilson HM, Haites NE, Reid FJ. et al. Interleukin-1 beta up-regulates the plas-minogen activator/plasmin system in human mesangial cells. Kidney Int 1996; 49: 1097-1104.
    CrossrefPubMedGoogle Scholar
  • 38 Huang FM, Tsai CH, Chen YJ. et al. Examination of the signal transduction pathways leading to upregulation of tissue type plasminogen activator by interleukin-1alpha in human pulp cells. J Endod 2006; 32: 30-33.
    CrossrefPubMedGoogle Scholar
  • 39 Larsson P, Ulfhammer E, Karlsson L. et al. Effects of IL-1beta and IL-6 on tissue-type plasminogen activator expression in vascular endothelial cells. Thromb Res 2008; 123: 342-351.
    CrossrefPubMedGoogle Scholar
  • 40 Mestries JC, Kruithof EK, Gascon MP. et al. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw 1994; 05: 275-281.
    PubMedGoogle Scholar
  • 41 Hosoya S, Ohbayashi E, Matsushima K. et al. Stimulatory effect of interleukin-6 on plasminogen activator activity from human dental pulp cells. J Endod 1998; 24: 331-334.
    CrossrefPubMedGoogle Scholar
  • 42 Xiao Y, Bunn CL, Bartold PM. Effect of lipopolysaccharide from periodontal pathogens on the production of tissue plasminogen activator and plasminogen activator inhibitor 2 by human gingival fibroblasts. J Periodontal Res 2001; 36: 25-31.
    CrossrefPubMedGoogle Scholar
  • 43 Wang WY, Xu GZ, Tian J. et al. Inhibitory effect on LPS-induced retinal microglial activation of downregulation of t-PA expression by siRNA interference. Curr Eye Res 2009; 34: 476-484.
    CrossrefPubMedGoogle Scholar
  • 44 van Deventer SJ, Buller HR, ten Cate JW. et al. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520-2526.
    CrossrefPubMedGoogle Scholar
  • 45 Chia S, Qadan M, Newton R. et al. Intra-arterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans. Arterioscler Thromb Vasc Biol 2003; 23: 695-701.
    CrossrefPubMedGoogle Scholar
  • 46 Kruithof EK. Regulation of plasminogen activator inhibitor type 1 gene expression by inflammatory mediators and statins. Thromb Haemost 2008; 100: 969-975.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Lansink M, Kooistra T. Stimulation of tissue-type plasminogen activator expression by retinoic acid in human endothelial cells requires retinoic acid receptor beta 2 induction. Blood 1996; 88: 531-541.
    CrossrefPubMedGoogle Scholar
  • 48 Kooistra T, Opdenberg JP, Toet K. et al. Stimulation of tissue-type plasminogen activator synthesis by retinoids in cultured human endothelial cells and rat tissues in vivo. Thromb Haemost 1991; 65: 565-572.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Bulens F, Ibanez-Tallon I, Van Acker P. et al. Retinoic acid induction of human tissue-type plasminogen activator gene expression via a direct repeat element (DR5) located at –7 kilobases. J Biol Chem 1995; 270: 7167-7175.
    CrossrefPubMedGoogle Scholar
  • 50 Hultman K, Tjarnlund-Wolf A, Fish RJ. et al. Retinoids and activation of PKC induce tissue-type plasminogen activator expression and storage in human astrocytes. J Thromb Haemost 2008; 06: 1796-1803.
    CrossrefPubMedGoogle Scholar
  • 51 Medh RD, Santell L, Levin EG. Stimulation of tissue plasminogen activator production by retinoic acid: synergistic effect on protein kinase C-mediated activation. Blood 1992; 80: 981-987.
    CrossrefPubMedGoogle Scholar
  • 52 Antonopoulos AS, Margaritis M, Shirodaria C. et al. Translating the effects of statins: from redox regulation to suppression of vascular wall inflammation. Thromb Haemost 2012; 108: 840-848.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Essig M, Nguyen G, Prie D. et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ Res 1998; 83: 683-690.
    PubMedGoogle Scholar
  • 54 Dunoyer-Geindre S, Fish RJ, Kruithof EK. Regulation of the endothelial plasminogen activator system by fluvastatin. Role of Rho family proteins, actin polymerisation and p38 MAP kinase. Thromb Haemost 2011; 105: 461-472.
    PubMedGoogle Scholar
  • 55 Bruni F, Pasqui AL, Pastorelli M. et al. Effect of atorvastatin on different fibri-nolyis mechanisms in hypercholesterolemic subjects. Int J Cardiol 2004; 95: 269-274.
    CrossrefPubMedGoogle Scholar
  • 56 Ludwig S, Dharmalingam S, Erickson-Nesmith S. et al. Impact of simvastatin on hemostatic and fibrinolytic regulators in Type 2 diabetes mellitus. Diabetes Res Clin Pract 2005; 70: 110-118.
    CrossrefPubMedGoogle Scholar
  • 57 Qu HY, Xiao YW, Jiang GH. et al. Effect of atorvastatin versus rosuvastatin on levels of serum lipids, inflammatory markers and adiponectin in patients with hypercholesterolemia. Pharm Res 2009; 26: 958-964.
    CrossrefPubMedGoogle Scholar
  • 58 Goicoechea M, de Vinuesa SG, Lahera V. et al. Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease. J Am Soc Nephrol 2006; 17: S231-235.
    CrossrefPubMedGoogle Scholar
  • 59 Kooistra T, van den Berg J, Tons A. et al. Butyrate stimulates tissue-type plasminogen-activator synthesis in cultured human endothelial cells. Biochem J 1987; 247: 605-612.
    CrossrefPubMedGoogle Scholar
  • 60 Arts J, Lansink M, Grimbergen J. et al. Stimulation of tissue-type plasminogen activator gene expression by sodium butyrate and trichostatin A in human endothelial cells involves histone acetylation. Biochem J 1995; 310: 171-176.
    CrossrefPubMedGoogle Scholar
  • 61 Huber D, Cramer EM, Kaufmann JE. et al. Tissue-type plasminogen activator (t-PA) is stored in Weibel-Palade bodies in human endothelial cells both in vitro and in vivo. Blood 2002; 99: 3637-3645.
    CrossrefPubMedGoogle Scholar
  • 62 Dunoyer-Geindre S, Kruithof EK. Epigenetic control of tissue-type plasminogen activator synthesis in human endothelial cells. Cardiovasc Res 2011; 90: 457-463.
    CrossrefPubMedGoogle Scholar
  • 63 Larsson P, Ulfhammer E, Magnusson M. et al. Role of histone acetylation in the stimulatory effect of valproic acid on vascular endothelial tissue-type plasmi-nogen activator expression. PLoS One 2012; 07: e31573.
    CrossrefPubMedGoogle Scholar
  • 64 Fisher R, Waller EK, Grossi G. et al. Isolation and characterization of the human tissue-type plasminogen activator structural gene including its 5’ flanking region. J Biol Chem 1985; 260: 11223-11230.
    CrossrefPubMedGoogle Scholar
  • 65 Henderson BR, Sleigh MJ. TATA box-independent transcription of the human tissue plasminogen activator gene initiates within a sequence conserved in related genes. FEBS Lett 1992; 309: 130-134.
    CrossrefPubMedGoogle Scholar
  • 66 Costa M, Shen Y, Maurer F. et al. Transcriptional regulation of the tissue-type plasminogen-activator gene in human endothelial cells: identification of nuclear factors that recognise functional elements in the tissue-type plasminogen-acti-vator gene promoter. Eur J Biochem 1998; 258: 123-131.
    CrossrefPubMedGoogle Scholar
  • 67 Encode-Project-Consortium. Dunham I, Kundaje A. et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 489. 57-74.
    PubMedGoogle Scholar
  • 68 Medcalf RL, Ruegg M, Schleuning WD. A DNA motif related to the cAMP-responsive element and an exon-located activator protein-2 binding site in the human tissue-type plasminogen activator gene promoter cooperate in basal expression and convey activation by phorbol ester and cAMP. J Biol Chem 1990; 265: 14618-14626.
    CrossrefPubMedGoogle Scholar
  • 69 Arts J, Herr I, Lansink M. et al. Cell-type specific DNA-protein interactions at the tissue-type plasminogen activator promoter in human endothelial and HeLa cells in vivo and in vitro. Nucleic Acids Res 1997; 25: 311-317.
    CrossrefPubMedGoogle Scholar
  • 70 Costa M, Medcalf RL. Ectopic expression of the cAMP-responsive element binding protein inhibits phorbol ester-mediated induction of tissue-type plasminogen activator gene expression. Eur J Biochem 2001; 268: 987-996.
    CrossrefPubMedGoogle Scholar
  • 71 Merchiers P, Bulens F, De Vriese A. et al. Involvement of Sp1 in basal and retinoic acid induced transcription of the human tissue-type plasminogen activator gene. FEBS Lett 1999; 456: 149-154.
    CrossrefPubMedGoogle Scholar
  • 72 Pan W, Chang MJ, Booyse FM. et al. Quercetin induced tissue-type plasminogen activator expression is mediated through Sp1 and p38 mitogen-activated protein kinase in human endothelial cells. J Thromb Haemost 2008; 06: 976-985.
    CrossrefPubMedGoogle Scholar
  • 73 Pham NL, Franzen A, Levin EG. NF1 regulatory element functions as a repressor of tissue plasminogen activator expression. Arterioscler Thromb Vasc Biol 2004; 24: 982-987.
    CrossrefPubMedGoogle Scholar
  • 74 Wu W, Pew T, Zou M. et al. Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival. J Biol Chem 2005; 280: 4117-4124.
    CrossrefPubMedGoogle Scholar
  • 75 Fujiwara J, Kimura T, Ayusawa D. et al. A novel regulatory sequence affecting the constitutive expression of tissue plasminogen activator (tPA) gene in human melanoma (Bowes) cells. J Biol Chem 1994; 269: 18558-18562.
    CrossrefPubMedGoogle Scholar
  • 76 Lux W, Klobeck HG, Daniel PB. et al. In vivo and in vitro analysis of the human tissue-type plasminogen activator gene promoter in neuroblastomal cell lines: evidence for a functional upstream kappaB element. J Thromb Haemost 2005; 03: 1009-1017.
    CrossrefPubMedGoogle Scholar
  • 77 Bulens F, Merchiers P, Ibanez-Tallon I. et al. Identification of a multihormone responsive enhancer far upstream from the human tissue-type plasminogen activator gene. J Biol Chem 1997; 272: 663-671.
    CrossrefPubMedGoogle Scholar
  • 78 Jern C, Ladenvall P, Wall U. et al. Gene Polymorphism of t-PA is Associated With Forearm Vascular Release Rate of t-PA. Arterioscl, Thromb Vasc Biol 1999; 19: 454-459.
    CrossrefPubMedGoogle Scholar
  • 79 Tjarnlund-Wolf A, Medcalf RL, Jern C. The t-PA –7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid. Blood 2005; 105: 1060-1067.
    CrossrefPubMedGoogle Scholar
  • 80 Borel V, Marceau G, Gallot D. et al. Retinoids regulate human amniotic tissue-type plasminogen activator gene by a two-step mechanism. J Cell Mol Med 2010; 14: 1793-1805.
    CrossrefPubMedGoogle Scholar
  • 81 Yu H, Schleuning WD, Michl M. et al. Control elements between –9.5 and –3.0 kb in the human tissue-type plasminogen activator gene promoter direct spatial and inducible expression to the murine brain. Eur J Neurosci 2001; 14: 799-808.
    CrossrefPubMedGoogle Scholar
  • 82 Ouyang Y, Huang P, Huang C. Inhibitory effect of 3’-untranslated region (3’-UTR) of human tissue-plasminogen activator (ht-PA) mRNA on its expression. Sci China B 1995; 38: 1253-1260.
    PubMedGoogle Scholar
  • 83 Huarte J, Stutz A, O’Connell ML. et al. Transient translational silencing by reversible mRNA deadenylation. Cell 1992; 69: 1021-1030.
    CrossrefPubMedGoogle Scholar
  • 84 Dubois-Dauphin M, Eder-Colli L, Vallet P. et al. Induction of enhanced green fluorescent protein expression in response to lesions in the nervous system. J Comp Neurol 2004; 474: 108-122.
    CrossrefPubMedGoogle Scholar
  • 85 Shin CY, Kundel M, Wells DG. Rapid, activity-induced increase in tissue plasminogen activator is mediated by metabotropic glutamate receptor-dependent mRNA translation. J Neurosci 2004; 24: 9425-9433.
    CrossrefPubMedGoogle Scholar
  • 86 Tranquille N, Emeis JJ. The simultaneous acute release of tissue-type plasminogen activator and von Willebrand factor in the perfused rat hindleg region. Thromb Haemost 1990; 63: 454-458.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 87 Tranquille N, Emeis JJ. On the role of calcium in the acute release of tissue-type plasminogen activator and von Willebrand factor from the rat perfused hindleg region. Thromb Haemost 1991; 66: 479-483.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Tranquille N, Emeis JJ. The role of cyclic nucleotides in the release of tissue-type plasminogen activator and von Willebrand factor. Thromb Haemost 1993; 69: 259-261.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 89 Chandler WL, Levy WC, Stratton JR. The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine. Circulation 1995; 92: 2984-2994.
    CrossrefPubMedGoogle Scholar
  • 90 Wall U, Jern S, Tengborn L. et al. Evidence of a local mechanism for desmopressin-induced tissue-type plasminogen activator release in human forearm. Blood 1998; 91: 529-537.
    CrossrefPubMedGoogle Scholar
  • 91 Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 01: 682-689.
    CrossrefPubMedGoogle Scholar
  • 92 Hrafnkelsdottir T, Gudnason T, Wall U. et al. Regulation of local availability of active tissue-type plasminogen activator in vivo in man. J Thromb Haemost 2004; 02: 1960-1968.
    CrossrefPubMedGoogle Scholar
  • 93 Datta YH, Youssoufian H, Marks PW. et al. Targeting of a heterologous protein to a regulated secretion pathway in cultured endothelial cells. Blood 1999; 94: 2696-2703.
    CrossrefPubMedGoogle Scholar
  • 94 Rosnoblet C, Vischer UM, Gerard RD. et al. Storage of tissue-type plasminogen activator in Weibel-Palade bodies of human endothelial cells. Arterioscler Thromb Vasc Biol 1999; 19: 1796-1803.
    CrossrefPubMedGoogle Scholar
  • 95 Emeis JJ, van den Eijnden-Schrauwen Y, van den Hoogen CM. et al. An endothelial storage granule for tissue-type plasminogen activator. J Cell Biol 1997; 139: 245-256.
    CrossrefPubMedGoogle Scholar
  • 96 Knipe L, Meli A, Hewlett L. et al. A revised model for the secretion of tPA and cytokines from cultured endothelial cells. Blood 2010; 116: 2183-2191.
    CrossrefPubMedGoogle Scholar
  • 97 Knop M, Aareskjold E, Bode G. et al. Rab3D and annexin A2 play a role in regulated secretion of vWF, but not tPA, from endothelial cells. EMBO J 2004; 23: 2982-2992.
    CrossrefPubMedGoogle Scholar
  • 98 Hegeman RJ, van den Eijnden-Schrauwen Y, Emeis JJ. Adenosine 3’:5’-cyclic monophosphate induces regulated secretion of tissue-type plasminogen activator and von Willebrand factor from cultured human endothelial cells. Thromb Haemost 1998; 79: 853-858.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 99 Lochner JE, Honigman LS, Grant WF. et al. Activity-dependent release of tissue plasminogen activator from the dendritic spines of hippocampal neurons revealed by live-cell imaging. J Neurobiol 2006; 66: 564-577.
    CrossrefPubMedGoogle Scholar
  • 100 Rijken DC, Hoylaerts M, Collen D. Fibrinolytic properties of one-chain and two-chain human extrinsic (tissue-type) plasminogen activator. J Biol Chem 1982; 257: 2920-2925.
    CrossrefPubMedGoogle Scholar
  • 101 Silverstein RL, Nachman RL, Leung LL. et al. Activation of immobilized plasminogen by tissue activator. Multimolecular complex formation. J Biol Chem 1985; 260: 10346-10352.
    PubMedGoogle Scholar
  • 102 Cesarman GM, Guevara CA, Hajjar KA. An endothelial cell receptor for plasminogen/tissue plasminogen activator (t-PA). II. Annexin II-mediated enhancement of t-PA-dependent plasminogen activation. J Biol Chem 1994; 269: 21198-21203.
    PubMedGoogle Scholar
  • 103 Kingston IB, Castro MJ, Anderson S. In vitro stimulation of tissue-type plasminogen activator by Alzheimer amyloid beta-peptide analogues. Nat Med 1995; 01: 138-142.
    CrossrefPubMedGoogle Scholar
  • 104 Gebbink MF. Tissue-type plasminogen activator-mediated plasminogen activation and contact activation, implications in and beyond haemostasis. J Thromb Haemost 2011; 09 (Suppl. 01) 174-181.
    CrossrefPubMedGoogle Scholar
  • 105 Kruithof EK, Tran-Thang C, Ransijn A. et al. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood 1984; 64: 907-913.
    CrossrefPubMedGoogle Scholar
  • 106 Erickson LA, Hekman CM, Loskutoff DJ. The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related. Proc Natl Acad Sci USA 1985; 82: 8710-8714.
    CrossrefPubMedGoogle Scholar
  • 107 Thorsen S, Philips M, Selmer J. et al. Kinetics of inhibition of tissue-type and urokinase-type plasminogen activator by plasminogen-activator inhibitor type 1 and type 2. Eur J Biochem 1988; 175: 33-39.
    CrossrefPubMedGoogle Scholar
  • 108 Nagamine Y. Transcriptional regulation of the plasminogen activator inhibitor type 1--with an emphasis on negative regulation. Thromb Haemost 2008; 100: 1007-1013.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 109 Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008; 99: 995-1000.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 110 Semeraro N, Ammollo CT, Semeraro F. et al. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012; 129: 290-295.
    CrossrefPubMedGoogle Scholar
  • 111 Iwaki T, Urano T, Umemura K. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol 2012; 157: 291-298.
    CrossrefPubMedGoogle Scholar
  • 112 Declerck PJ, Gils A. Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin. Semin Thromb Hemost 2013; 39: 356-364.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 113 Hastings GA, Coleman TA, Haudenschild CC. et al. Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. Implications for the regulation of motor learning and neuronal survival. J Biol Chem 1997; 272: 33062-33067.
    PubMedGoogle Scholar
  • 114 Vivien D, Buisson A. Serine protease inhibitors: novel therapeutic targets for stroke?. J Cereb Blood Flow Metab 2000; 20: 755-764.
    CrossrefPubMedGoogle Scholar
  • 115 Miranda E, Lomas DA. Neuroserpin: a serpin to think about. Cell Mol Life Sci 2006; 63: 709-722.
    CrossrefPubMedGoogle Scholar
  • 116 Galliciotti G, Sonderegger P. Neuroserpin. Front Biosci 2006; 11: 33-45.
    CrossrefPubMedGoogle Scholar
  • 117 Rodriguez-Gonzalez R, Sobrino T, Rodriguez-Yanez M. et al. Association between neuroserpin and molecular markers of brain damage in patients with acute ischemic stroke. J Transl Med 2011; 09: 58.
    CrossrefPubMedGoogle Scholar
  • 118 Bu G, Williams S, Strickland DK. et al. Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci USA 1992; 89: 7427-7431.
    CrossrefPubMedGoogle Scholar
  • 119 Orth K, Willnow T, Herz J. et al. Low density lipoprotein receptor-related protein is necessary for the internalization of both tissue-type plasminogen activator-inhibitor complexes and free tissue-type plasminogen activator. J Biol Chem 1994; 269: 21117-21122.
    CrossrefPubMedGoogle Scholar
  • 120 Noorman F, Braat EA, Rijken DC. Degradation of tissue-type plasminogen activator by human monocyte-derived macrophages is mediated by the mannose receptor and by the low-density lipoprotein receptor-related protein. Blood 1995; 86: 3421-3427.
    CrossrefPubMedGoogle Scholar
  • 121 Suzuki Y, Nagai N, Yamakawa K. et al. Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein. Blood 2009; 114: 3352-3358.
    CrossrefPubMedGoogle Scholar
  • 122 Sashindranath M, Sales E, Daglas M. et al. The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans. Brain 2012; 135: 3251-3264.
    CrossrefPubMedGoogle Scholar
  • 123 Cohen MC, Rohtla KM, Lavery CE. et al. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol 1997; 79: 1512-1516.
    CrossrefPubMedGoogle Scholar
  • 124 Grimaudo V, Hauert J, Bachmann F. et al. Diurnal variation of the fibrinolytic system. Thromb Haemost 1988; 59: 495-499.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 125 Angleton P, Chandler WL, Schmer G. Diurnal variation of tissue-type plasmi-nogen activator and its rapid inhibitor (PAI-1). Circulation 1989; 79: 101-106.
    CrossrefPubMedGoogle Scholar
  • 126 Rudnicka AR, Rumley A, Lowe GD. et al. Diurnal, seasonal, and blood-processing patterns in levels of circulating fibrinogen, fibrin D-dimer, C-reactive protein, tissue plasminogen activator, and von Willebrand factor in a 45-year-old population. Circulation 2007; 115: 996-1003.
    CrossrefPubMedGoogle Scholar
  • 127 Eriksson E, Risberg B. Measurement of tissue plasminogen activator in plasma. A comparison of 3 methods and description of a new improved technique. Thromb Res 1987; 46: 213-223.
    PubMedGoogle Scholar
  • 128 Oishi K, Ohkura N. Chronic circadian clock disruption induces expression of the cardiovascular risk factor plasminogen activator inhibitor-1 in mice. Blood Coagul Fibrinolysis 2013; 24: 106-108.
    CrossrefPubMedGoogle Scholar
  • 129 Oishi K. Plasminogen activator inhibitor-1 and the circadian clock in metabolic disorders. Clin Exp Hypertens 2009; 31: 208-219.
    CrossrefPubMedGoogle Scholar
  • 130 Chandler WL, Alessi MC, Aillaud MF. et al. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-768.
    CrossrefPubMedGoogle Scholar
  • 131 Smith DT, Hoetzer GL, Greiner JJ. et al. Effects of ageing and regular aerobic exercise on endothelial fibrinolytic capacity in humans. J Physiol 2003; 546: 289-298.
    CrossrefPubMedGoogle Scholar
  • 132 Ladenvall P, Wall U, Jern S. et al. Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus: association with vascular t-PA release in vivo. Thromb Haemost 2000; 84: 150-155.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 133 Tjarnlund-Wolf A, Hultman K, Curtis MA. et al. Allelic imbalance of tissue-type plasminogen activator (t-PA) gene expression in human brain tissue. Thromb Haemost 2011; 105: 945-953.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 134 Ladenvall P, Johansson L, Jansson JH. et al. Tissue-type plasminogen activator –7,351C/T enhancer polymorphism is associated with a first myocardial infarction. Thromb Haemost 2002; 87: 105-109.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 135 Jannes J, Hamilton-Bruce MA, Pilotto L. et al. Tissue plasminogen activator –7351C/T enhancer polymorphism is a risk factor for lacunar stroke. Stroke 2004; 35: 1090-1094.
    CrossrefPubMedGoogle Scholar
  • 136 Babu MS, Prabha TS, Kaul S. et al. Association of genetic variants of fibrinolytic system with stroke and stroke subtypes. Gene 2012; 495: 76-80.
    CrossrefPubMedGoogle Scholar
  • 137 Ridker PM, Baker MT, Hennekens CH. et al. Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator (t-PA) and risks of myocardial infarction among middle-aged men. Arterioscler Thromb Vasc Biol 1997; 17: 1687-1690.
    CrossrefPubMedGoogle Scholar
  • 138 Armstrong CA, Bevan SN, Gormley KT. et al. Tissue plasminogen activator –7351C/T polymorphism and lacunar stroke. Stroke. 2006 37. 329 author reply 330.
    PubMedGoogle Scholar
  • 139 Asselbergs FW, Williams SM, Hebert PR. et al. Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels. Genomics 2007; 89: 362-369.
    CrossrefPubMedGoogle Scholar
  • 140 Penrod NM, Poku KA, Vaughan DE. et al. Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population. PLoS One 2011; 06: e16639.
    CrossrefPubMedGoogle Scholar
  • 141 Lansink M, Jong M, Bijsterbosch M. et al. Increased clearance explains lower plasma levels of tissue-type plasminogen activator by estradiol: evidence for potently enhanced mannose receptor expression in mice. Blood 1999; 94: 1330-1336.
    CrossrefPubMedGoogle Scholar
  • 142 Lowe GD, Danesh J, Lewington S. et al. Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J 2004; 25: 252-259.
    PubMedGoogle Scholar
  • 143 Thompson SG, Kienast J, Pyke SD. et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-641.
    PubMedGoogle Scholar
  • 144 Freynhofer MK, Draxler DF, Gruber SC. et al. Endogenous t-PA-antigen is an independent predictor of adverse cardiovascular events and all-cause death in patients with atrial fibrillation. J Thromb Haemost 2013; 11: 1069-1077.
    CrossrefPubMedGoogle Scholar
  • 145 Yarnell J, McCrum E, Rumley A. et al. Association of European population levels of thrombotic and inflammatory factors with risk of coronary heart disease: the MONICA Optional Haemostasis Study. Eur Heart J 2005; 26: 332-342.
    CrossrefPubMedGoogle Scholar
  • 146 Willeit P, Thompson A, Aspelund T. et al. Hemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses. PLoS One 2013; 08: e55175.
    CrossrefPubMedGoogle Scholar