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(Stroke. 2006;37:1910.)
© 2006 American Heart Association, Inc.

Research Reports

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

Sophia Wang, BA; Sun-Ryung Lee, PhD; Shu-Zhen Guo, PhD; Woo Jean Kim, PhD; Joan Montaner, MD; Xiaoying Wang, PhD Eng H. Lo, PhD

From the Neuroprotection Research Laboratory (S.W., S.R.L., S.Z.G., W.J.K., X.W., E.H.L.), Departments of Radiology and Neurology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Mass; Department of Life Science (S.R.L.), Cheju National University, Korea; Mount Sinai School of Medicine (S.W.), New York, NY; and Vall de’Hebron Hospital (J.M.), Barcelona, Spain.

Correspondence to Eng H. Lo, Neuroprotection Research Laboratory, MGH East 149-2401, Charlestown, MA 02129. E-mail Lo{at}helix.mgh harvard.edu

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.

Key Words: hemorrhage • stroke

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