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

Abstract

Peroxisome proliferator-activated receptor gamma(PPAR gamma) 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 PPAR gamma activity. In the present study, we investigated the effect of sumoylation on the antiatherogenic property of PPAR gamma. PPAR gamma-K107R sumoylation mutant, PPAR gamma-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 PPAR gamma-K107R, PPAR gamma-WT or control gene were delivered into the carotid arteries of rats after balloon injury. The PPAR gamma-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. PPAR gamma-K107R or WT gene transfer inhibited VSMCs proliferation and migration to a greater extent than the control. The PPAR gamma-K107R had more potent activity than PPAR gamma-WT in this regard. PPAR gamma-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 PPAR gamma-K107R decreased IMR further compared to PPAR gamma-WT. In addition, the PPAR gamma-K107R transfer showed a lower proliferation index and a higher apoptotic index than PPAR gamma-WT. In conclusion, the PPAR gamma 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 PPAR gamma might play an important role against atherosclerosis. (C) 2009 Elsevier Ireland Ltd. All rights reserved.