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Objective The ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is a key factor in adipogenesis, insulin sensitivity, and cell cycle regulation. Activated PPARγ might also have anti-inflammatory and antiatherogenic properties. We tested whether lobeglitazone, a new PPARγ agonist, might protect against atherosclerosis. Methods A rat model of balloon injury to the carotid artery, and high-fat, high-cholesterol diet-fed apolipoprotein E gene knockout (ApoE −/− ) mice were studied. Results After the balloon injury, lobeglitazone treatment (0.3 and 0.9 mg/kg) caused a significant decrease in the intima-media ratio compared with control rats (2.2 ± 0.9, 1.8 ± 0.8, vs. 3.3 ± 1.2, P −/− mice fed a high-fat diet, lobeglitazone treatment (1, 3, and 10 mg/kg) for 8 weeks reduced atherosclerotic lesion sizes in the aorta compared with the control mice in a dose-dependent manner. Treatment of vascular smooth muscle cells with lobeglitazone inhibited proliferation and migration and blocked the cell cycle G 0 /G 1 to S phase progression dose-dependently. In response to lobeglitazone, tumor necrosis factor alpha (TNFα)-induced monocyte-endothelial cell adhesion was decreased by downregulating the levels of adhesion molecules. TNFα-induced nuclear factor kappa-B (NF-κB) p65 translocation into the nucleus was also blocked in endothelial cells. Insulin resistance was decreased by lobeglitazone treatment. Circulating levels of high sensitivity C-reactive protein and monocyte chemoattractant protein-1 were decreased while adiponectin levels were increased by lobeglitazone in the high-fat diet-fed ApoE −/− mice. Conclusion Lobeglitazone has antiatherosclerotic properties and has potential for treating patients with diabetes and cardiovascular risk.

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