Abstract 287: Rosiglitazone Regulates Glycogen Synthase Kinase-3β via a PPAR-γ Independent mechanism, and Reduces Neointimal Hyperplasia after Vascular Injury
Introduction: PPAR-γ agonists have emerged as candidate drugs to prevent restenosis after coronary angioplasty. However, the mechanism of how PPAR-γ agonists reduce neointimal hyperplasia is still unclear. In this study, we investigated whether modulation of key signals can inhibit neointima growth.
Methods and Results: In vitro, rosiglitazone did not suppress the activity of Akt, but attenuated the level of GSK-3β and ERK phosphorylation in rat VSMCs. This led to a reduction in viable cell number, which was mediated by induction of apoptosis and inhibition of proliferation. These effects were not reversed by PPAR-γ antagonists, suggesting a PPAR-γ independent effect. Rosiglitazone significantly suppressed MMP-9 in western blot and zymography, leading to the inhibition of VSMC migration. EMSA and immunocytochemistry demonstrated that rosiglitazone inhibited AP-1 & NF-κ B binding to MMP-9 gene promoter, which was reversed by dominant-negative GSK-3β. In vivo, rosiglitazone significantly decreased intima to media ratio at 2 weeks (control versus rosiglitazone 1.26±0.49 versus 0.63±0.11, p<0.05. see figure⇓). Conversely, dominant-negative GSK-3β gene transfer reversed the inhibition of intimal hyperplasia by rosiglitazone.
Conclusions: We show for the first time that rosiglitazone modulates GSK-3β activity via a PPAR-γ independent mechanism, which leads to decreased VSMC viability and neointimal formation. Furthermore, rosiglitazone inhibits VSMCs migration by the suppression of MMP-9 through AP-1 and NF-κB. Our data give mechanistic insight into previously observed antiproliferative effects of rosiglitazone.