Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis

Objective: The ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma) is a key factor in adipogenesis, insulin sensitivity, and cell cycle regulation. Activated PPAR gamma might also have anti-inflammatory and antiatherogenic properties. We tested whether lobeglitazone, a new PPAR gamma 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 < 0.01). Consistent with this, in ApoE(-/-) 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 (TNF alpha)-induced monocyte-endothelial cell adhesion was decreased by downregulating the levels of adhesion molecules. TNF alpha-induced nuclear factor kappa-B (NF-kappa B) 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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.