Reduction of Tissue Plasminogen Activator-Induced Matrix Metalloproteinase-9 by Simvastatin in Astrocytes

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Abstract
Background and Purpose— Hemorrhagic conversion after tissue plasminogen activator (tPA) stroke therapy has been linked with elevations in matrix metalloproteinase-9 (MMP-9) at the neurovascular interface. Here, we test the idea that statins may directly ameliorate tPA-induced MMP-9 dysregulation. Methods— Recombinant human tPA (5 μg/mL) was added to primary rat cortical astrocytes. Zymography was used to quantify MMP-9 levels in conditioned media. Effects of simvastatin or the Rho kinase inhibitor Y-27632 were assessed by pretreating cells before tPA exposure. Results— Simvastatin (1 to 10 μmol/L) significantly reduced tPA-induced MMP-9 in cortical astrocytes. This effect may be mediated via the Rho kinase pathway because tPA-induced activation of Rho signaling was suppressed by simvastatin, and tPA-induced MMP-9 levels were similarly reduced by the Rho kinase inhibitor Y-27632 (1 to 10 μmol/L). Conclusions— Statins reduce tPA-induced MMP-9 dysregulation by inhibiting the Rho signaling pathway. Statins may ameliorate tPA-associated MMP imbalances in stroke.