Peroxisome Proliferator-Activated Receptor γ Down-Regulates Receptor for Advanced Glycation End Products and Inhibits Smooth Muscle Cell Proliferation in a Diabetic and Nondiabetic Rat Carotid Artery Injury Model
- 1 April 2006
- journal article
- Published by Elsevier in The Journal of Pharmacology and Experimental Therapeutics
- Vol. 317 (1) , 37-43
- https://doi.org/10.1124/jpet.105.095125
Abstract
Diabetes is associated with an increase in circulating advanced glycosylation end products (AGEs) and the increased expression of the receptor for AGEs (RAGE). Inhibition of AGE/RAGE binding through the administration of soluble RAGE (sRAGE) has been shown to decrease neointimal hyperplasia. Peroxisome proliferator-activated receptor γ (PPARγ), which inhibits neointimal hyperplasia, has been shown to decrease RAGE expression in cultured endothelial cells. We hypothesized that PPARγ agonists inhibit neointimal hyperplasia via down-regulation of RAGE in vivo. Pretreatment of rat aortic smooth muscle cells (SMCs) with PPARγ agonist rosiglitazone significantly down-regulated RAGE expression and inhibited SMC proliferation in response to the RAGE agonist S100/calgranulins. In vivo studies showed that rosiglitazone decreased RAGE expression and SMC proliferation at 7 days following carotid arterial injury in both diabetic and nondiabetic rats. At 21 days following injury, neointimal formation was significantly decreased in both diabetic and nondiabetic animals that received rosiglitazone. To determine whether inhibition of neointimal formation by PPARγ activation could fully be accounted for by its down-regulation of RAGE, we compared the results obtained in animals treated with sRAGE, PPARγ activator, and sRAGE + PPARγ activator. Consistent with PPARγ working through its effects on RAGE, we found that the addition of PPARγ activator to sRAGE did not result in any further decrease in neointimal formation. These data demonstrate for the first time that PPARγ agonists inhibit RAGE expression at sites of arterial injury and suggest that down-regulation of RAGE by the PPARγ activation inhibits neointimal formation in response to arterial injury.Keywords
This publication has 41 references indexed in Scilit:
- Activation of Peroxisome Proliferator-activated Receptor γ Inhibits Interleukin-1β-induced Membrane-associated Prostaglandin E2 Synthase-1 Expression in Human Synovial Fibroblasts by Interfering with Egr-1Published by Elsevier ,2004
- Regulation of the Growth Arrest and DNA Damage-Inducible Gene 45 (GADD45) by Peroxisome Proliferator-Activated Receptor γ in Vascular Smooth Muscle CellsCirculation Research, 2003
- RAGE Blockade Stabilizes Established Atherosclerosis in Diabetic Apolipoprotein E–Null MiceCirculation, 2002
- Pioglitazone Enhances Cytokine-Induced Apoptosis in Vascular Smooth Muscle Cells and Reduces Intimal HyperplasiaCirculation, 2001
- Human vascular smooth muscle cells of diabetic origin exhibit increased proliferation, adhesion, and migrationJournal of Vascular Surgery, 2001
- Long-term effects of troglitazone: open-label extension studies in type 2 diabetic patients.Diabetes Care, 2000
- Peroxisome Proliferator-Activated Receptor Activators Inhibit Thrombin-Induced Endothelin-1 Production in Human Vascular Endothelial Cells by Inhibiting the Activator Protein-1 Signaling PathwayCirculation Research, 1999
- PPARγ-Ligands Inhibit Migration Mediated by Multiple Chemoattractants in Vascular Smooth Muscle CellsJournal of Cardiovascular Pharmacology, 1999
- Anti–Monocyte Chemoattractant Protein-1/Monocyte Chemotactic and Activating Factor Antibody Inhibits Neointimal Hyperplasia in Injured Rat Carotid ArteriesCirculation Research, 1999
- Effects of Troglitazone and Pioglitazone on Cytokine-Mediated Endothelial Cell Proliferation In VitroJournal of Cardiovascular Pharmacology, 1998