Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to
vascular injury such as
angioplasty .
Protein kinase G (PKG) has an important
role in the process of VSMC
phenotype switching. In this study, we examined whether
rosiglitazone , a
peroxisome proliferator-activated receptor (
PPAR )-gamma agonist, could modulate VSMC
phenotype through the PKG pathway to reduce neointimal
hyperplasia after
angioplasty .
In vitro experiments showed that
rosiglitazone inhibited the
phenotype change of VSMCs from a contractile to a synthetic form. The
platelet-derived growth factor (PDGF)-induced reduction of PKG level was reversed by
rosiglitazone treatment , resulting in increased PKG activity. This increased activity of PKG resulted in
phosphorylation of
vasodilator -stimulated
phosphoprotein at
serine 239, leading to inhibited proliferation of VSMCs. Interestingly,
rosiglitazone did not change the level of
nitric oxide (NO) or cyclic
guanosine monophosphate (cGMP), which are
upstream of PKG, suggesting that
rosiglitazone influences PKG itself.
Chromatin immunoprecipitation assays for the PKG promoter showed that the activation of PKG by
rosiglitazone was mediated by the increased binding of Sp1 on the
promoter region of PKG. In vivo experiments showed that
rosiglitazone significantly inhibited neointimal formation after balloon
injury .
Immunohistochemistry staining for
calponin and
thrombospondin showed that this effect of
rosiglitazone was mediated by modulating VSMC
phenotype . Our findings demonstrate that
rosiglitazone is a potent modulator of VSMC
phenotype , which is regulated by PKG. This activation of PKG by
rosiglitazone results in reduced neointimal
hyperplasia after
angioplasty . These results provide important mechanistic insight into the cardiovascular-protective effect of
PPARgamma .