The Inhibitory Effect Of Dexamethasone On Platelet-derived Growth Factor-induced Vascular Smooth Muscle Cell Migration Through Up-regulating PGC-1 α Expression

Dexamethasone has been shown to inhibit vascular smooth muscle cell (VSMC) migration, which is required for preventing restenosis. However, the mechanism underlying effect of dexamethasone remains unknown.We have previously demonstrated that peroxisome proliferator-activated receptor gamma (PPARy) coactivator-1 alpha (PGC-1α) can inhibit VSMC migration and proliferation. Here, we investigated the role of PGC-la in dexamethasone-reduced VSMC migration and explored the possible mechanism. We first examined PGC-la expression in cultured rat aortic VSMCs. The results revealed that incubation of VSMCs with dexamethasone could significantly elevate PGC-1αmRNA expression. In contrast, platelet-derived growth factor (PDGF) decreased PGC-1αexpression while stimulating VSMC migration. Mechanistic study showed that suppression of PGC-1αby small interfering RNA strongly abrogated the inhibitory effect of dexamethasone on VSMC migration, whereas overexpression of PGC-1αhad the opposite effect.Furthermore, an analysis of MAPK signal pathways showed that dexamethasone inhibited ERK and p38 MAPK phosphorylation in VSMCs. Overexpression of PGC-la decreased both basal and PDGF-induced p38 MAPK phosphorylation, but it had no effect on ERK phosphorylation. Finally, inhibition of PPARy activation by a PPARy antagonist GW9662 abolished the suppressive effects of PGC-1αon p38 MAPK phosphorylation and VSMC migration. These effects of PGC-1αwere enhanced by a PPARy agonist troglitazone.Collectively, our data indicated for the first time that one of the anti-migrated mechanisms of dexamethasone is due to the induction of PGC-la expression. PGC-la suppresses PDGF-induced VSMC migration through PPARy coactivation and, consequently, p38 MAPK inhibition.