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

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 < 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 G0/G1 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.

• Authors: Soo Lim, Kuy-Sook Lee, Jie Eun Lee, Ho Seon Park, Kyoung Min Kim, Jae Hoon Moon, Sung Hee Choi, Kyong Soo Park, Young Bum Kim, Hak Chul Jang
• Journal: Atherosclerosis (Atherosclerosis) Vol. 243 Issue 1 Pg. 107-19 (Nov 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 26363808 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apolipoproteins E
• Ccl2 protein, mouse
• Ccl2 protein, rat
• Chemokine CCL2
• PPAR gamma
• Pyrimidines
• Rela protein, mouse
• Rela protein, rat
• Thiazolidinediones
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• C-Reactive Protein
• Cholesterol
• lobeglitazone

Topics

• Animals
• Aorta (pathology)
• Apolipoproteins E (genetics)
• Atherosclerosis (prevention & control)
• C-Reactive Protein (metabolism)
• Carotid Arteries (pathology)
• Cell Adhesion
• Cell Nucleus (metabolism)
• Cell Proliferation
• Chemokine CCL2 (metabolism)
• Cholesterol (metabolism)
• Diet, High-Fat
• Human Umbilical Vein Endothelial Cells
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout
• Neointima (drug therapy)
• PPAR gamma (agonists)
• Plaque, Atherosclerotic (genetics)
• Pyrimidines (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Risk Factors
• Thiazolidinediones (therapeutic use)
• Transcription Factor RelA (genetics)
• Tumor Necrosis Factor-alpha (metabolism)