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 microg/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 micromol/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 micromol/L).
Conclusions:
Statins reduce tPA-induced MMP-9 dysregulation by inhibiting the Rho signaling pathway. Statins may ameliorate tPA-associated MMP imbalances in stroke.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology
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Animals
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Astrocytes / drug effects*
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Astrocytes / enzymology
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Cells, Cultured / drug effects
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Cells, Cultured / enzymology
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Cerebral Hemorrhage / etiology
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Drug Evaluation, Preclinical
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Enzyme Induction / drug effects
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Intracellular Signaling Peptides and Proteins
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Matrix Metalloproteinase 2 / biosynthesis
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 9 / biosynthesis*
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Matrix Metalloproteinase 9 / genetics
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Neuroprotective Agents / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Pyridines / pharmacology
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Rats
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects*
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Simvastatin / pharmacology*
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Stroke / complications
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Stroke / enzymology
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rho-Associated Kinases
Substances
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Amides
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Intracellular Signaling Peptides and Proteins
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Neuroprotective Agents
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Pyridines
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Recombinant Proteins
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Y 27632
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Simvastatin
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9