on February 5, 2009
Published online before print February 5, 2009, doi: 10.1161/ATVBAHA.108.176230
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Submitted on August 20, 2008
Accepted on January 22, 2009
New Mechanism of Rosiglitazone to Reduce Neointimal Hyperplasia. Activation of Glycogen Synthase Kinase-3
Followed by Inhibition of MMP-9
Choon-Soo Lee ;
From the Innovative Research Institute for Cell Therapy (IRICT), Seoul National University Hospital; and the National Research Laboratory for Cardiovascular Stem Cell, Seoul National University College of Medicine, Seoul, Korea.
* To whom correspondence should be addressed. E-mail: hyosoo{at}snu.ac.kr.
Objective—Mechanism of neointimal hyperplasia after vascular injury includes activation of signaling pathways and matrix metalloproteinases (MMPs) that are involved in cell proliferation and migration. Rosiglitazone, a synthetic peroxisome proliferator-activated receptor-
(PPAR-) agonist, was reported to inhibit neointimal hyperplasia in diabetic animals and humans. But the underlying mechanism has not been clarified. In this study, we examined how rosiglitazone inhibited neointimal hyperplasia.
Methods and Results—The proliferation and survival of cultured rat VSMCs were reduced by rosiglitazone, which was mediated by inhibition of ERK and activation GSK-3
, without change of Akt. The antiproliferative effect of rosiglitazone was reversed by GSK-3 inactivation. The migration of VSMCs was also suppressed by rosiglitazone that inhibited the expression and activity MMP-9 through GSK-3 activation. Thus migration of MMP-9(-/-) VSMCs from MMP-9 knockout mice was not affected by rosiglitazone. The underlying mechanism of MMP-9 suppression by rosiglitazone was that it inhibited NF-
B DNA binding activity, which was also dependent on GSK-3. In rat carotid artery, balloon injury significantly inactivated GSK-3 with induction of MMP-9, which was effectively prevented by rosiglitazone. Thus, rosiglitazone significantly decreased the ratio of intima to media by reducing proliferation and inducing apoptosis of VSMCs at neointima, which was reversed by inactivation of GSK-3 with adenoviral transfer of catalytically-inactive GSK-KM gene.
Conclusions—Rosiglitazone activates GSK-3, which inhibits not only proliferation of VSMCs but also migration of VSMCs through blocking NF-B–dependent MMP-9 activation.