Tissue Plasminogen Activator Promotes Matrix Metalloproteinase-9 Upregulation After Focal Cerebral Ischemia

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.

Involvement of Matrix Metalloproteinase in Neuroblast Cell Migration from the Subventricular Zone after Stroke

“…MMPs are rapidly upregulated after brain injury after trauma, ischemia, and hemorrhage (Mun-Bryce and Rosenberg, 1998;Gasche et al, 1999;Heo et al, 1999;Wang et al, 2000;Power et al, 2003). Degradation of neurovascular substrates lead to blood-brain barrier leakage, edema, and hemorrhage (Asahi et al, , 2001Lo et al, 2004;Tsuji et al, 2005). Furthermore, interruption of cell-matrix signaling may also trigger anoikis-like processes of brain cell death (Gu et al, 2002;Lee and Lo, 2004).…”

Measuring Elevated Microvascular Permeability and Predicting Hemorrhagic Transformation in Acute Ischemic Stroke Using First-Pass Dynamic Perfusion CT Imaging

“…36 LRP can also upregulate matrix metalloproteinase-9, a mediator of extracellular proteolysis of the neurovascular matrix. 37,38 In comparison to the observations by Kassner et al, 24 we examined a larger study population consisting of both patients with and without rtPA treatment. Moreover, this study examined the use of PCT, which has several advantages over perfusion-weighted MR imaging (PWI) in stroke evaluation.…”

Efficacy of recombinant annexin 2 for fibrinolytic therapy in a rat embolic stroke model: A magnetic resonance imaging study

“…The exact mechanisms of t-PA-induced blood-brain barrier damage following cerebral ischemia remain poorly understood. Some authors speculate t-PA upregulates brain matrix metallopro-teinase-9 (MMP-9) levels in stroke Wang et al, 2003;Tsuji et al, 2005), resulting in increased vascular permeability. To the contrary, others found that a plasminogen and MMP-9 had an independent mechanism of blood-brain barrier damage through t-PA (Yepes et al, 2003).…”