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-3beta, without change of Akt. The antiproliferative effect of rosiglitazone was reversed by GSK-3beta inactivation. The migration of VSMCs was also suppressed by rosiglitazone that inhibited the expression and activity MMP-9 through GSK-3beta 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-kappaB DNA binding activity, which was also dependent on GSK-3beta. In rat carotid artery, balloon injury significantly inactivated GSK-3beta 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-3beta with adenoviral transfer of catalytically-inactive GSK-KM gene.

CONCLUSIONS Rosiglitazone activates GSK-3beta, which inhibits not only proliferation of VSMCs but also migration of VSMCs through blocking NF-kappaB-dependent MMP-9 activation.