PDF herunterladen
Thromb Haemost 2007; 98(05): 963-969
DOI: 10.1160/TH07-03-0194
Theme Issue Article
Schattauer GmbH

Matrix metalloproteinase (MMP) induction and inhibition at different doses of recombinant tissue plasminogen activator following experimental stroke

Dorothe Burggraf
1   Department of Neurology, Ludwig-Maximilians University, Klinikum Großhadern, Munich, Germany
,
Helge K. Martens
2   Technical University of Munich, Department of Oral and Cranio-maxillofacial Surgery, Munich, Germany
,
Martin Dichgans
1   Department of Neurology, Ludwig-Maximilians University, Klinikum Großhadern, Munich, Germany
,
Gerhard F. Hamann
3   Department of Neurology, HSK Dr. Horst-Schmidt-Klinik, Wiesbaden, Germany
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 15. März 2007

Accepted after resubmission 08. Oktober 2007

Publikationsdatum:
30. November 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

Although recombinant tissue plasminogen activator (rt-PA) is successfully used for thrombolysis in human stroke, it may increase the risk of haemorrhagic complications. It was shown that the matrix metalloproteinase (MMP) system is critically involved in basal lamina degradation after middle cerebral artery occlusion and reperfusion following rt-PA administration. We describe the effects of different doses of rt-PA (saline, 0.9, 9, or 18 mg rt-PA/kg body weight) on the MMPs, their specific inhibitors (TIMPs), and also their inducer protein EMMPRIN following experimental cerebral ischemia (3 hours [h], 24 h reperfusion, suture model) in rats. The amount of MMP-2 and -9 was measured by gelatine zymography, TIMP-1 and -2 by reverse gelatine zymography, and the content of EMMPRIN and the basal lamina component collagen type IV by Western blotting. The amount of both MMPs steadily rose with increasing doses of rt- PA (p<0.05). In contrast, their endogenous inhibitors TIMPs decreased (p<0.001). A balance between the proteases and their inhibitors was achieved at the low dose of 0.9 mg/kg rt-PA in the rats, which significantly coincided with the demonstrated protection of collagen type IV degradation at this dose. The inducer protein EMMPRIN increased in parallel to its substrate MMP-2. Exogenous rt-PA leads to an increase of the MMP-inducing system by EMMPRIN, and a rise of the degrading MMPs follows. However, at low to moderate doses of rt-PA the microvascular basal lamina was protected, probably due to inhibition of MMP-2 and MMP-9 by the upregulation of their inhibitors. This strongly supports use of the lowest effective dosage of rt-PA available.

Keywords

MMP-2/-9 - TIMP-1/-2 - cerebral ischemia - basal lamina - EMMPRIN
 

  • References

  • 1 Tissue plasminogen activator for acute ischemic stroke.. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333: 1581-1587.
    CrossrefPubMedSuche in Google Scholar
  • 2 Hamann GF, Okada Y, del Zoppo GJ. Haemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J Cereb Blood Flow Metab 1996; 16: 1373-1378.
    CrossrefPubMedSuche in Google Scholar
  • 3 Jian Liu K, Rosenberg GA. Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med 2005; 39: 71-80.
    CrossrefPubMedSuche in Google Scholar
  • 4 del Zoppo GJ, von Kummer R, Hamann GF. Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke. J Neurol Neurosurg Psychiatry 1998; 65: 1-9.
    CrossrefPubMedSuche in Google Scholar
  • 5 Tan HK, Heywood D, Ralph GS. et al. Tissue inhibitor of metalloproteinase 1 inhibits excitotoxic cell death in neurons. Mol Cell Neurosci 2003; 22: 98-106.
    CrossrefPubMedSuche in Google Scholar
  • 6 Rosenberg GA, Estrada EY, Dencoff JE. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 1998; 29: 2189-2195.
    CrossrefPubMedSuche in Google Scholar
  • 7 Wang X, Lo EH. Triggers and mediators of haemorrhagic transformation in cerebral ischemia. Mol Neurobiol 2003; 28: 229-244.
    CrossrefPubMedSuche in Google Scholar
  • 8 Hamann GF, Liebetrau M, Martens H. et al. Microvascular basal lamina injury after experimental focal cerebral ischemia and reperfusion in the rat. J Cereb Blood Flow Metab 2002; 22: 526-533.
    CrossrefPubMedSuche in Google Scholar
  • 9 Burggraf D, Martens HK, Jager G. et al. Recombinant human tissue plasminogen activator protects the basal lamina in experimental focal cerebral ischemia. Thromb Haemost 2003; 89: 1072-1080.
    Thieme ConnectPubMedSuche in Google Scholar
  • 10 Kelly MA, Shuaib A, Todd KG. Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis. Exp Neurol 2006; 200: 38-49.
    CrossrefPubMedSuche in Google Scholar
  • 11 Fukuda S, Fini CA, Mabuchi T. et al. Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke 2004; 35: 998-1004.
    CrossrefPubMedSuche in Google Scholar
  • 12 Biswas C, Zhang Y, DeCastro R. et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 1995; 55: 434-439.
    PubMedSuche in Google Scholar
  • 13 Caudroy S, Polette M, Tournier JM. et al. Expression of the extracellular matrix metalloproteinase inducer (EMMPRIN) and the matrix metalloproteinase- 2 in bronchopulmonary and breast lesions. J Histochem Cytochem 1999; 47: 1575-1580.
    CrossrefPubMedSuche in Google Scholar
  • 14 Burggraf D, Martens HK, Liebetrau M. et al. A new approach to reduce the number of animals used in experimental focal cerebral ischemia models. Neurosci Lett 2005; 386: 88-93.
    CrossrefPubMedSuche in Google Scholar
  • 15 Karges HE, Funk KA, Ronneberger H. Activity of coagulation and fibrinolysis parameters in animals. Arzneimittelforschung 1994; 44: 793-797.
    PubMedSuche in Google Scholar
  • 16 Longa EZ, Weinstein PR, Carlson S. et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989; 20: 84-91.
    CrossrefPubMedSuche in Google Scholar
  • 17 Paxinos G, Watson C. The rat brain. Academic press; 4th ed. San Diego, London, Boston: 1998
    Suche in Google Scholar
  • 18 Gasche Y, Fujimura M, Morita-Fujimura Y. et al. Early appearance of activated matrix metalloproteinase- 9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J Cereb Blood Flow Metab 1999; 19: 1020-1028.
    CrossrefPubMedSuche in Google Scholar
  • 19 Oliver GW, Leferson JD, Stetler-Stevenson WG. et al. Quantitative reverse zymography: analysis of picogram amounts of metalloproteinase inhibitors using gelatinase A and B reverse zymograms. Anal Biochem 1997; 244: 161-166.
    CrossrefPubMedSuche in Google Scholar
  • 20 Miyazawa T, Bonnekoh P, Widmann R. et al. Heating of the brain to maintain normothermia during ischemia aggravates brain injury in the rat. Acta Neuropathol 1993; 85: 488-494.
    PubMedSuche in Google Scholar
  • 21 Dawson DA, Hallenbeck JM. Acute focal ischemia- induced alterations in MAP2 immunostaining: description of temporal changes and utilization as a marker for volumetric assessment of acute brain injury. J Cereb Blood Flow Metab 1996; 16: 170-174.
    CrossrefPubMedSuche in Google Scholar
  • 22 Kloss CU, Thomassen N, Fesl G. et al. Tissue-saving infarct volumetry using histochemistry validated by MRI in rat focal ischemia. Neurol Res 2002; 24: 713-718.
    CrossrefPubMedSuche in Google Scholar
  • 23 Heo JH, Lucero J, Abumiya T. et al. Matrix Metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 1999; 19: 624-633.
    CrossrefPubMedSuche in Google Scholar
  • 24 Lee SR, Tsuji K, Lee SR. et al. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci 2004; 24: 671-678.
    CrossrefPubMedSuche in Google Scholar
  • 25 Wang X, Jung J, Asahi M. et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 2000; 20: 7037-7042.
    CrossrefPubMedSuche in Google Scholar
  • 26 Lorenzl S, De Pasquale G, Segal AZ. et al. Dysregulation of the levels of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in the early phase of cerebral ischemia. Stroke 2003; 34: 37-38.
    CrossrefPubMedSuche in Google Scholar
  • 27 Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated haemorrhagic transformation after embolic focal ischemia in rats. Stroke 2002; 33: 831-836.
    CrossrefPubMedSuche in Google Scholar
  • 28 Gasche Y, Soccal PM, Kanemitsu M. et al. Matrix metalloproteinases and diseases of the central nervous system with a special emphasis on ischemic brain. Front Biosci 2006; 11: 1289-1301.
    CrossrefPubMedSuche in Google Scholar
  • 29 Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002; 115: 3719-3727.
    CrossrefPubMedSuche in Google Scholar
  • 30 Lindsey ML. MMP induction and inhibition in myocardial infarction. Heart Fail Rev 2004; 9: 7-19.
    CrossrefPubMedSuche in Google Scholar
  • 31 Crocker SJ, Pagenstecher A, Campbell IL. The TIMPs tango with MMPs and more in the central nervous system. J Neurosci Res 2004; 75: 1-11.
    CrossrefPubMedSuche in Google Scholar
  • 32 Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 2005; 50: 329-339.
    CrossrefPubMedSuche in Google Scholar
  • 33 Yang Y, Estrada EY, Thompson JF. et al. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007; 27: 697-709.
    CrossrefPubMedSuche in Google Scholar
  • 34 Asahi M, Asahi K, Jung JC. et al. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 2000; 20: 1681-1689.
    CrossrefPubMedSuche in Google Scholar
  • 35 Chang DI, Hosomi N, Lucero J. et al. Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J Cereb Blood Flow Metab 2003; 23: 1408-1419.
    CrossrefPubMedSuche in Google Scholar
  • 36 Gasche Y, Copin JC, Sugawara T. et al. Matrix metalloproteinase inhibition prevents oxidative stressassociated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab 2001; 21: 1393-1400.
    CrossrefPubMedSuche in Google Scholar
  • 37 Tanaka H, Takai S, Jin D. et al. Inhibition of matrix metalloproteinase-9 activity by trandolapril after middle cerebral artery occlusion in rats. Hypertens Res 2007; 30: 469-475.
    CrossrefPubMedSuche in Google Scholar
  • 38 Rosell A, Ortega-Aznar A, Alvarez-Sabín J. et al. Increased brain expression of matrix metalloproteinase- 9 after ischemic and haemorrhagic human stroke. Stroke 2006; 37: 1399-1406.
    CrossrefPubMedSuche in Google Scholar
  • 39 Ning M, Furie KL, Koroshetz WJ. et al. Association between tPA therapy and raised early matrix metalloproteinase- 9 in acute stroke. Neurology 2006; 66: 1550-1555.
    CrossrefPubMedSuche in Google Scholar
  • 40 Lorenzl S, De Pasquale G, Segal AZ. et al. Dysregulation of the levels of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in the early phase of cerebral ischemia. Stroke 2003; 34: 37-38.
    CrossrefPubMedSuche in Google Scholar
  • 41 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17: 463-516.
    CrossrefPubMedSuche in Google Scholar
  • 42 Wang Z, Juttermann R, Soloway PD. TIMP-2 is required for efficient activation of proMMP-2 in vivo. J Biol Chem 2000; 275: 26411-26415.
    CrossrefPubMedSuche in Google Scholar
  • 43 Grobholz K, Burggraf D, Martens KH. et al. Recombinant tissue plasminogen activator attenuates basal lamina antigen loss after experimental focal cerebral ischemia. Neurol Res 2005; 27: 212-217.
    CrossrefPubMedSuche in Google Scholar
  • 44 Yang D, Pan HC, Chen CJ. et al. Effects of tissue plasminogen activator on cerebral microvessels of rats during focal cerebral ischemia and reperfusion. Neurol Res 2007; 29: 274-282.
    CrossrefPubMedSuche in Google Scholar
  • 45 Yamaguchi T, Mori E, Minematsu K. et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke 2006; 37: 1810-1815.
    CrossrefPubMedSuche in Google Scholar
  • 46 Guo H, Zucker S, Gordon MK. et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Biol Chem 1997; 272: 24-27.
    CrossrefPubMedSuche in Google Scholar
  • 47 Sameshima T, Nabeshima K, Toole BP. et al. Expression of emmprin (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas. Int J Cancer 2000; 88: 21-27.
    CrossrefPubMedSuche in Google Scholar
  • 48 Egawa N, Koshikawa N, Tomari T. et al. Membrane type 1 matrix metalloproteinase (MT1-MMP/ MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells. J Biol Chem 2006; 281: 37576-37585.
    CrossrefPubMedSuche in Google Scholar
  • 49 Quemener C, Gabison EE, Naimi B. et al. Extracellular matrix metalloproteinase inducer up-regulates the urokinase-type plasminogen activator system promoting tumor cell invasion. Cancer Res 2007; 67: 9-15.
    CrossrefPubMedSuche in Google Scholar