The inhibitory effect of dexamethasone on platelet-derived growth factor-induced vascular smooth muscle cell migration through up-regulating PGC-1alpha expression.

Authors: Xu, W  Guo, T  Zhang, Y  Jiang, X  Zhang, Y  Zen, K  Yu, B  Zhang, CY 
Citation: Xu W, etal., Exp Cell Res. 2011 May 1;317(8):1083-92. doi: 10.1016/j.yexcr.2010.10.006. Epub 2010 Oct 15.
Pubmed: (View Article at PubMed) PMID:20955697
DOI: Full-text: DOI:10.1016/j.yexcr.2010.10.006

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 (PPARgamma) coactivator-1 alpha (PGC-1alpha) can inhibit VSMC migration and proliferation. Here, we investigated the role of PGC-1alpha in dexamethasone-reduced VSMC migration and explored the possible mechanism. We first examined PGC-1alpha expression in cultured rat aortic VSMCs. The results revealed that incubation of VSMCs with dexamethasone could significantly elevate PGC-1alpha mRNA expression. In contrast, platelet-derived growth factor (PDGF) decreased PGC-1alpha expression while stimulating VSMC migration. Mechanistic study showed that suppression of PGC-1alpha by small interfering RNA strongly abrogated the inhibitory effect of dexamethasone on VSMC migration, whereas overexpression of PGC-1alpha had the opposite effect. Furthermore, an analysis of MAPK signal pathways showed that dexamethasone inhibited ERK and p38 MAPK phosphorylation in VSMCs. Overexpression of PGC-1alpha decreased both basal and PDGF-induced p38 MAPK phosphorylation, but it had no effect on ERK phosphorylation. Finally, inhibition of PPARgamma activation by a PPARgamma antagonist GW9662 abolished the suppressive effects of PGC-1alpha on p38 MAPK phosphorylation and VSMC migration. These effects of PGC-1alpha were enhanced by a PPARgamma 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-1alpha expression. PGC-1alpha suppresses PDGF-induced VSMC migration through PPARgamma coactivation and, consequently, p38 MAPK inhibition.


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CRRD ID: 8693683
Created: 2014-07-17
Species: All species
Last Modified: 2014-07-17
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.