Tissue Plasminogen Activator Promotes Matrix Metalloproteinase-9 Upregulation After Focal Cerebral Ischemia
- 1 September 2005
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Stroke
- Vol. 36 (9), 1954-1959
- https://doi.org/10.1161/01.str.0000177517.01203.eb
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
This publication has 31 references indexed in Scilit:
- Evidence of Reperfusion Injury, Exacerbated by Thrombolytic Therapy, in Human Focal Brain Ischemia Using a Novel Imaging Marker of Early Blood–Brain Barrier DisruptionStroke, 2004
- Mechanisms of Hemorrhagic Transformation After Tissue Plasminogen Activator Reperfusion Therapy for Ischemic StrokeStroke, 2004
- Early blood–brain barrier disruption in human focal brain ischemiaAnnals of Neurology, 2004
- Equivocal roles of tissue-type plasminogen activator in stroke-induced injuryTrends in Neurosciences, 2004
- In vitro and in vivo effects of tPA and PAI-1 on blood vessel toneBlood, 2004
- Profiles of Matrix Metalloproteinases, Their Inhibitors, and Laminin in Stroke PatientsStroke, 2003
- Cerebral Microvessel Responses to Focal IschemiaJournal of Cerebral Blood Flow & Metabolism, 2003
- Thrombolytic Therapy With Recombinant Tissue Plasminogen Activator for Acute Ischemic StrokeStroke, 2003
- Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9 Expression During Reperfusion InjuryStroke, 2002
- Matrix metalloproteinases in neuroinflammationGlia, 2002