Effect of a peroxisome proliferator-activated receptor γ sumoylation mutant on neointimal formation after balloon injury in rats

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor regulating inflammation, atherosclerosis, insulin sensitivity and adipogenesis. Recently, it has been discovered that modification by the small ubiquitin-like modifier (SUMO) plays an important role in PPARγ activity. In the present study, we investigated the effect of sumoylation on the antiatherogenic property of PPARγ. PPARγ-K107R sumoylation mutant, PPARγ-wild type (WT) and control genes were transfected on vascular smooth muscle cells (VSMCs) to compare their effect on the proliferation and migration. Adenoviral vectors expressing the PPARγ-K107R, PPARγ-WT or control gene were delivered into the carotid arteries of rats after balloon injury. The PPARγ-K107R increased the transcriptional activity of peroxisome proliferator response element (PPRE) and had a more potent transcriptional repression activity on the inducible nitric oxide synthase (iNOS) promoter as compared to the other sumoylation mutants or WT. PPARγ-K107R or WT gene transfer inhibited VSMCs proliferation and migration to a greater extent than the control. The PPARγ-K107R had more potent activity than PPARγ-WT in this regard. PPARγ-K107R or WT transfer showed a significantly lower intima-media ratio (IMR) than the control after balloon injury in rats. Again, the delivery of the PPARγ-K107R decreased IMR further compared to PPARγ-WT. In addition, the PPARγ-K107R transfer showed a lower proliferation index and a higher apoptotic index than PPARγ-WT. In conclusion, the PPARγ sumoylation mutant K107R strongly inhibited VSMCs proliferation and migration, sustained apoptosis, and reduced neointimal formation after balloon injury. These results indicate that desumoylation at K107 in PPARγ might play an important role against atherosclerosis.