1. Effect of a new PPAR-gamma agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis
- Author
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Ho Seon Park, Kyong Soo Park, Sung Hee Choi, Kyoung Min Kim, Kuy Sook Lee, Young-Bum Kim, Jie Eun Lee, Hak Chul Jang, Jae Hoon Moon, and Soo Lim
- Subjects
Male ,Apolipoprotein E ,medicine.medical_specialty ,Endothelium ,Lobeglitazone ,Peroxisome proliferator-activated receptor ,Biology ,Diet, High-Fat ,PPAR agonist ,Rats, Sprague-Dawley ,Mice ,Apolipoproteins E ,Risk Factors ,Neointima ,Internal medicine ,Cell Adhesion ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Receptor ,Aorta ,Chemokine CCL2 ,Cell Proliferation ,Cell Nucleus ,Mice, Knockout ,chemistry.chemical_classification ,Adiponectin ,Tumor Necrosis Factor-alpha ,Transcription Factor RelA ,Atherosclerosis ,Immunohistochemistry ,Plaque, Atherosclerotic ,Rats ,PPAR gamma ,C-Reactive Protein ,Carotid Arteries ,Cholesterol ,Pyrimidines ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Thiazolidinediones ,Tumor necrosis factor alpha ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
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.
- Published
- 2015