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New Mechanism of Rosiglitazone to Reduce Neointimal Hyperplasia Activation of Glycogen Synthase Kinase-3 beta Followed by Inhibition of MMP-9

Cited 43 time in Web of Science Cited 46 time in Scopus
Authors
Lee, Choon-Soo; Kwon, Yoo-Wook; Yang, Han-Mo; Kim, Sung-Hwan; Hur, Jin; Cho, Hyun-Jai; Park, Young-Bae; Kim, Hyo-Soo; Kang, Hyun-Jae; Park, Kyung-Woo; Kim, Tae-Youn
Issue Date
2009-04
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Citation
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY; Vol.29 4; 472-479
Keywords
restenosisrosiglitazoneVSMCsMMP-9GSK-3 beta
Abstract
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-gamma (PPAR-gamma) 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 beta, without change of Akt. The antiproliferative effect of rosiglitazone was reversed by GSK-3 beta inactivation. The migration of VSMCs was also suppressed by rosiglitazone that inhibited the expression and activity MMP-9 through GSK-3 beta 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-kappa B DNA binding activity, which was also dependent on GSK-3 beta. In rat carotid artery, balloon injury significantly inactivated GSK-3 beta 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 beta with adenoviral transfer of catalytically-inactive GSK-KM gene. Conclusions-Rosiglitazone activates GSK-3 beta, which inhibits not only proliferation of VSMCs but also migration of VSMCs through blocking NF-kappa B-dependent MMP-9 activation. (Arterioscler Thromb Vasc Biol. 2009; 29: 472-479.)
ISSN
1079-5642
Language
English
URI
http://hdl.handle.net/10371/77411
DOI
https://doi.org/10.1161/ATVBAHA.108.176230
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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