Published Online
on June 1, 2006

A more recent version of this article appeared on July 1, 2006

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Submitted on March 2, 2006
Accepted on March 30, 2006

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; and 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.

^* To whom correspondence should be addressed. 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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