Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice

Zhao, Bing; Ikeda, Yasuhiko; Ihara, Hayato; Urano, Tetsumei; Fan, Wen Ying; Mikawa, Sumiko; Suzuki, Yasuhiro; Kondo, Kazunao; Sato, Kohji; Nagai, Nobuo; Umemura, Kazuo

doi:10.1182/blood-2003-03-0835

Cited by 75 publications

(63 citation statements)

References 35 publications

(46 reference statements)

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“…Although Lo and colleagues (Asahi et al, 2001) could not unambiguously demonstrate degradation of laminin in the ischemic brain, they could not rule out this possibility. Our results support a model in which production of proMMP-9, and subsequent activation by NO (Gu et al, 2002) or tPA (Zhao et al, 2004), leads to laminin cleavage and resulting neuronal cell death. In fact, the effect of MMP-9 is functionally similar to that of tPA, which is also known to contribute to laminin degradation (Chen and Strickland, 1997;Wang et al, 1998;Indyk et al, 2003).…”

Section: Discussionsupporting

confidence: 85%

A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia

Z¹,

Cui²,

Brown³

et al. 2005

J. Neurosci.

387

326

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. We determined that MMP-9 degrades the extracellular matrix protein laminin and that this degradation induces neuronal apoptosis in a transient focal cerebral ischemia model in mice. We also determined that the highly specific thiirane gelatinase inhibitor SB-3CT blocks MMP-9 activity, including MMP-9-mediated laminin cleavage, thus rescuing neurons from apoptosis. We conclude that MMP-9 is a highly promising drug target and that SB-3CT derivatives have significant therapeutic potential in stroke patients.

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Section: Discussionsupporting

confidence: 85%

A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia

Z¹,

Cui²,

Brown³

et al. 2005

J. Neurosci.

387

326

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“…2). In a mouse photothrombotic MCA occlusion model, delayed administration of heparin (3 hours after insult) failed to cause cerebral hemorrhage in tPA KO mice but significantly increased hemorrhage in WT (Zhao et al, 2004). Activity and mRNA levels of tPA were increased in microglial cells in the ischemic border of WT mice after heparin administration.…”

Section: Tpa Knockoutsmentioning

confidence: 94%

The Neurotoxicity of Tissue Plasminogen Activator?

Kaur

Zhao

Klein

et al. 2004

J Cereb Blood Flow Metab

240

185

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Abstract:Tissue plasminogen activator (tPA), a fibrin specific activator for the conversion of plasminogen to plasmin, stimulates thrombolysis and rescues ischemic brain by restoring blood flow. However, emerging data suggests that under some conditions, both tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. Animal models suggest that in severe ischemia with injury to the blood brain barrier (BBB) there is injury attributed to the protease effects of this exogenous tPA. Besides clot lysis per se, tPA may have pleiotropic actions in the brain, including direct vasoactivity, cleaveage of the N-methyl-Daspartate (NMDA) NR1 subunit, amplification of intracellular Ca ++ conductance, and activation of other extracellular proteases from the matrix metalloproteinase (MMP) family, e.g. MMP-9. These effects may increase excitotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage. If tPA is effective and reverses ischemia promptly, the BBB remains intact and exogenous tPA remains within the vascular space. If tPA is ineffective and ischemia is prolonged, there is the risk that exogenous tPA will injure both the neurovascular unit and the brain. Methods of neuroprotection, which prevent tPA toxicity or additional mechanical means to open cerebral vessels, are now needed.

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“…4,7,17 Male C57Bl/6 mice weighing 20 to 30 g were used. At 4 hours after MCA occlusion, 10 mg/kg of recombinant t-PA or the same volume of solvent was administered as a bolus in the tail or penile vein.…”

Section: Thrombotic Ischemic Stroke and Icbmentioning

confidence: 99%

Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor–related protein

Suzuki

Nagai

Yamakawa

et al. 2009

Blood

Self Cite

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Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it increases the risk of intracranial bleeding (ICB). Previously, we have shown in a mouse stroke model that stromelysin-1 (matrix metalloproteinase-3 [MMP-3]) induced in endothelial cells was critical for ICB induced by t-PA. In the present study, using bEnd.3 cells, a mouse brain-derived endothelial cell line, we showed that MMP-3 was induced by both ischemic stress and t-PA treatment. This induction by t-PA was prevented by inhibition either of low-density lipoprotein receptor-related protein (LRP) or of nuclear factor-B activation. LRP was upregulated by ischemic stress, both in bEnd. IntroductionTissue-type plasminogen activator (t-PA) is a thrombolytic agent that degrades fibrin clots through activation of plasminogen to plasmin. 1 Although t-PA given within 3 hours from onset of ischemic stroke improves the clinical outcome in patients, it induces a 10-fold increase of symptomatic intracranial bleeding (ICB). 2 Furthermore, delayed t-PA treatment beyond 3 hours is associated with an increased risk of hemorrhagic transformation and with enhanced brain injury. 3 The increase of ICB by delayed treatment with t-PA was also observed in a mouse stroke model. 4 Matrix metalloproteinases (MMPs), a family of zinc endopeptidases, contribute to tissue remodeling through degradation of extracellular matrix proteins. For ICB associated with ischemic stroke, MMPs have a key role in the degradation of the barrier of blood vessels. 5,6 Previously, we have shown that the increase in ICB caused by t-PA treatment was impaired in mice with gene deficiency of MMP-3 (stromelysin-1) and that a broad-spectrum MMP inhibitor suppressed ICB in wild-type but not in MMP-3-deficient mice. 7 MMP-3 can be activated by plasmin 8 and has a broad-spectrum substrate specificity. 9 Furthermore, t-PA treatment induced MMP-3 selectively in endothelial cells at the ischemic damaged area in a mouse stroke model, 7 suggesting that MMP-3 may be involved in degradation of the barrier of blood vessels and contribute to ICB. However, the mechanism underlying MMP-3 induction by t-PA remained unknown and is the subject of the present study.Low-density lipoprotein receptor-related protein (LRP), a member of the lipoprotein receptor family, is a scavenger receptor that binds a variety of biologic ligands and is thought to be primarily involved in lipoprotein metabolism 10 and in clearance of proteaseinhibitor complexes in the adult brain. 11 Recent reports have shown that t-PA induces MMP-9 in brain endothelial cells 12 and increases the blood-brain barrier permeability via LPR activation, 13 suggesting a role for LRP as a t-PA receptor. It has also been reported that LRP activation by t-PA stimulates the nuclear factor kappa-B (NF-B) pathway. 14 In this study, we have evaluated whether the LRP/NF-B pathway plays a role in MMP-3 induction by t-PA treatment. Therefore, we used bEnd.3 cells, a transformed endothelial cell line derived from mouse brain, as w...

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Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice

Cited by 75 publications

References 35 publications

A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia

A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia

The Neurotoxicity of Tissue Plasminogen Activator?

Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor–related protein

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