PPARγ gene transfer sustains apoptosis, inhibits vascular smooth muscle cell proliferation, and reduces neointima formation after balloon injury in rats

Objective-There is still debate as to whether antiatherosclerotic effect of PPAR gamma ligands is dependant on PPAR gamma gene itself or some other pathway. Methods and Results-To investigate the effect of PPAR gamma gene modulation on neointima formation after balloon injury, we delivered adenoviral vectors expressing the wild-type (WT) dominant negative (DN) PPAR gamma, or a control gene (beta-galactosidase [BG]) into carotid artery after balloon injury in rosiglitazone (a PPAR gamma ligand)-treated (R+) ( 3 mg/kg/d) and nontreated (R-) rats. Two weeks after gene delivery, in both R+ and R- animals, the PPAR gamma-WT gene transfer showed a significantly lower intima-media ratio (IMR) than control group. Moreover, the delivery of a PPAR gamma-DN form showed the highest IMR (in R+WT, 0.51 +/- 0.15; R + BG, 0.89 +/- 0.14; R + DN, 1.20 +/- 0.18, P < 0.05 and in R - WT, 0.91 +/- 0.21; R - BG, 1.44 +/- 0.23; R - DN, 1.74 +/- 0.29, P < 0.05). Proliferation and migration showed same result pattern as IMR. In addition, apoptotic indices were significantly higher in the PPAR gamma-WT gene transferred group than in the PPAR gamma-DN group. Conclusions-In vivo transfer of the PPAR gamma-WT gene was found to inhibit smooth muscle proliferation, sustain apoptosis, and reduce neointima formation after balloon injury irrespective of rosiglitazone treatment. These results indicate that PPAR gamma overexpression itself has a protective role against restenosis after balloon injury.