Prostacyclin synthase gene transfer inhibits neointimal formation by suppressing PPARδ expression

Objective Prostacyclin (PGI2) is a potent ligand of peroxisome proliferator-activated receptor δ (PPARδ) that regulates cell growth and differentiation. The aim of this study was to elucidate how endogenous PGI2 overexpression affects the expressions of PPARδ and mitogen-activated protein kinases (MAPKs) in the development of neointimal formation in experimental angioplasty with adenovirus-mediated PGI2 synthase (Ad-PGIS) gene transfer. Methods and results In human aortic smooth muscle cells, protein blotting analysis showed that PGI2 overproduction decreased the levels of phosphorylated p38 MAPK (P-p38 MAPK) (2.0-fold versus 0.83-fold relative to control). Immunohistochemical analysis in balloon-injured arteries revealed diffuse expression of PPARδ in the neointima of control vessels, with no expression in uninjured vessels. The level of PPARδ expression was lower in Ad-PGIS-treated arteries than in control vessels, with the PPARδ localized in the neointima adjacent to endothelium. Staining of P-p38 MAPK showed a similar pattern to PPARδ among the three groups. Morphometric analysis at day 14 revealed that Ad-PGIS reduced the intima-to-media ratio by up to 59%. Conclusions Ad-PGIS gene transfer reduced PPARδ expression and inhibited neointimal formation after balloon injury in accordance with the reduction in the phosphorylation of p38 MAPK.