Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia

Kiyoshi Tsuji, Toshiaki Aoki, Emiri Tejima, Ken Arai, Sun Ryung Lee, Dmitriy N. Atochin, Paul L. Huang, Xiaoying Wang, Joan Montaner, Eng H. Lo

Результат исследований: Материалы для журналаСтатья

182 Цитирования (Scopus)

Выдержка

Background and Purpose - Thrombolytic therapy with tissue plasminogen activator (tPA) in ischemic stroke is limited by increased risks of cerebral hemorrhage and brain injury. In part, these phenomena may be related to neurovascular proteolysis mediated by matrix metalloproteinases (MMPs). Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo. Methods - In the first experiment, spontaneously hypertensive rats were subjected to 3 hours of transient focal cerebral ischemia. The effects of tPA (10 mg/kg IV) on ischemic brain MMP-9 levels were assessed by zymography. In the second experiment, wild-type (WT) and tPA knockout mice were subjected to 2 hours of transient focal cerebral ischemia, and MMP-9 levels and brain edema during reperfusion were assessed. Phenotype rescue was performed by administering tPA to the tPA knockout mice. Results - In the first experiment, exogenous tPA did not change infarct size but amplified MMP-9 levels in ischemic rat brain at 24 hours. Coinfusion of the plasmin inhibitor tranexamic acid (300 mg/kg) did not ameliorate this effect, suggesting that it was independent of plasmin. In the second experiment, ischemic MMP-9 levels, infarct size, and brain edema in tPA knockouts were significantly lower than WT mice. Administration of exogenous tPA (10 mg/kg IV) did not alter infarction but reinstated the ischemic MMP-9 response back up to WT levels and correspondingly worsened edema. Conclusions - These data demonstrate that tPA upregulates brain MMP-9 levels in stroke in vivo, and suggest that combination therapies targeting MMPs may improve tPA therapy.

Язык оригиналаАнглийский
Страницы (с-по)1954-1959
Число страниц6
ЖурналStroke
Том36
Номер выпуска9
DOI
СостояниеОпубликовано - сен 2005
Опубликовано для внешнего пользованияДа

Отпечаток

Matrix Metalloproteinase 9
Tissue Plasminogen Activator
Brain Ischemia
Up-Regulation
Stroke
Transient Ischemic Attack
Brain Edema
Matrix Metalloproteinases
Knockout Mice
Brain
Tranexamic Acid
Antifibrinolytic Agents
Fibrinolysin
Thrombolytic Therapy
Cerebral Hemorrhage
Inbred SHR Rats
Brain Injuries
Infarction
Proteolysis
Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Цитировать

Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. / Tsuji, Kiyoshi; Aoki, Toshiaki; Tejima, Emiri; Arai, Ken; Lee, Sun Ryung; Atochin, Dmitriy N.; Huang, Paul L.; Wang, Xiaoying; Montaner, Joan; Lo, Eng H.

В: Stroke, Том 36, № 9, 09.2005, стр. 1954-1959.

Результат исследований: Материалы для журналаСтатья

Tsuji, K, Aoki, T, Tejima, E, Arai, K, Lee, SR, Atochin, DN, Huang, PL, Wang, X, Montaner, J & Lo, EH 2005, 'Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia', Stroke, том. 36, № 9, стр. 1954-1959. https://doi.org/10.1161/01.STR.0000177517.01203.eb
Tsuji, Kiyoshi ; Aoki, Toshiaki ; Tejima, Emiri ; Arai, Ken ; Lee, Sun Ryung ; Atochin, Dmitriy N. ; Huang, Paul L. ; Wang, Xiaoying ; Montaner, Joan ; Lo, Eng H. / Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. В: Stroke. 2005 ; Том 36, № 9. стр. 1954-1959.
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abstract = "Background and Purpose - Thrombolytic therapy with tissue plasminogen activator (tPA) in ischemic stroke is limited by increased risks of cerebral hemorrhage and brain injury. In part, these phenomena may be related to neurovascular proteolysis mediated by matrix metalloproteinases (MMPs). Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo. Methods - In the first experiment, spontaneously hypertensive rats were subjected to 3 hours of transient focal cerebral ischemia. The effects of tPA (10 mg/kg IV) on ischemic brain MMP-9 levels were assessed by zymography. In the second experiment, wild-type (WT) and tPA knockout mice were subjected to 2 hours of transient focal cerebral ischemia, and MMP-9 levels and brain edema during reperfusion were assessed. Phenotype rescue was performed by administering tPA to the tPA knockout mice. Results - In the first experiment, exogenous tPA did not change infarct size but amplified MMP-9 levels in ischemic rat brain at 24 hours. Coinfusion of the plasmin inhibitor tranexamic acid (300 mg/kg) did not ameliorate this effect, suggesting that it was independent of plasmin. In the second experiment, ischemic MMP-9 levels, infarct size, and brain edema in tPA knockouts were significantly lower than WT mice. Administration of exogenous tPA (10 mg/kg IV) did not alter infarction but reinstated the ischemic MMP-9 response back up to WT levels and correspondingly worsened edema. Conclusions - These data demonstrate that tPA upregulates brain MMP-9 levels in stroke in vivo, and suggest that combination therapies targeting MMPs may improve tPA therapy.",
keywords = "Blood-brain barrier, Brain edema, Metalloproteinases, Mice, Tissue plasminogen activator",
author = "Kiyoshi Tsuji and Toshiaki Aoki and Emiri Tejima and Ken Arai and Lee, {Sun Ryung} and Atochin, {Dmitriy N.} and Huang, {Paul L.} and Xiaoying Wang and Joan Montaner and Lo, {Eng H.}",
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T1 - Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia

AU - Tsuji, Kiyoshi

AU - Aoki, Toshiaki

AU - Tejima, Emiri

AU - Arai, Ken

AU - Lee, Sun Ryung

AU - Atochin, Dmitriy N.

AU - Huang, Paul L.

AU - Wang, Xiaoying

AU - Montaner, Joan

AU - Lo, Eng H.

PY - 2005/9

Y1 - 2005/9

N2 - Background and Purpose - Thrombolytic therapy with tissue plasminogen activator (tPA) in ischemic stroke is limited by increased risks of cerebral hemorrhage and brain injury. In part, these phenomena may be related to neurovascular proteolysis mediated by matrix metalloproteinases (MMPs). Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo. Methods - In the first experiment, spontaneously hypertensive rats were subjected to 3 hours of transient focal cerebral ischemia. The effects of tPA (10 mg/kg IV) on ischemic brain MMP-9 levels were assessed by zymography. In the second experiment, wild-type (WT) and tPA knockout mice were subjected to 2 hours of transient focal cerebral ischemia, and MMP-9 levels and brain edema during reperfusion were assessed. Phenotype rescue was performed by administering tPA to the tPA knockout mice. Results - In the first experiment, exogenous tPA did not change infarct size but amplified MMP-9 levels in ischemic rat brain at 24 hours. Coinfusion of the plasmin inhibitor tranexamic acid (300 mg/kg) did not ameliorate this effect, suggesting that it was independent of plasmin. In the second experiment, ischemic MMP-9 levels, infarct size, and brain edema in tPA knockouts were significantly lower than WT mice. Administration of exogenous tPA (10 mg/kg IV) did not alter infarction but reinstated the ischemic MMP-9 response back up to WT levels and correspondingly worsened edema. Conclusions - These data demonstrate that tPA upregulates brain MMP-9 levels in stroke in vivo, and suggest that combination therapies targeting MMPs may improve tPA therapy.

AB - Background and Purpose - Thrombolytic therapy with tissue plasminogen activator (tPA) in ischemic stroke is limited by increased risks of cerebral hemorrhage and brain injury. In part, these phenomena may be related to neurovascular proteolysis mediated by matrix metalloproteinases (MMPs). Here, we used a combination of pharmacological and genetic approaches to show that tPA promotes MMP-9 levels in stroke in vivo. Methods - In the first experiment, spontaneously hypertensive rats were subjected to 3 hours of transient focal cerebral ischemia. The effects of tPA (10 mg/kg IV) on ischemic brain MMP-9 levels were assessed by zymography. In the second experiment, wild-type (WT) and tPA knockout mice were subjected to 2 hours of transient focal cerebral ischemia, and MMP-9 levels and brain edema during reperfusion were assessed. Phenotype rescue was performed by administering tPA to the tPA knockout mice. Results - In the first experiment, exogenous tPA did not change infarct size but amplified MMP-9 levels in ischemic rat brain at 24 hours. Coinfusion of the plasmin inhibitor tranexamic acid (300 mg/kg) did not ameliorate this effect, suggesting that it was independent of plasmin. In the second experiment, ischemic MMP-9 levels, infarct size, and brain edema in tPA knockouts were significantly lower than WT mice. Administration of exogenous tPA (10 mg/kg IV) did not alter infarction but reinstated the ischemic MMP-9 response back up to WT levels and correspondingly worsened edema. Conclusions - These data demonstrate that tPA upregulates brain MMP-9 levels in stroke in vivo, and suggest that combination therapies targeting MMPs may improve tPA therapy.

KW - Blood-brain barrier

KW - Brain edema

KW - Metalloproteinases

KW - Mice

KW - Tissue plasminogen activator

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U2 - 10.1161/01.STR.0000177517.01203.eb

DO - 10.1161/01.STR.0000177517.01203.eb

M3 - Article

C2 - 16051896

AN - SCOPUS:24644519846

VL - 36

SP - 1954

EP - 1959

JO - Stroke

JF - Stroke

SN - 0039-2499

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