Peroxisome Proliferator-Activated Receptor-γ–Mediated Effects in the Vasculature

Abstract

Abstract-Peroxisome proliferator-activated receptor (PPAR)-␥ is a nuclear receptor and transcription factor in the steroidsuperfamily. PPAR-␥ agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-␥ also plays critical roles in the vasculature. In vascular endothelial cells, PPAR-␥ activation inhibits endothelial inflammation by suppressing inflammatory gene expression and therefore improves endothelial dysfunction. In vascular smooth muscle cells, PPAR-␥ activation inhibits proliferation and migration and promotes apoptosis. In macrophages, PPAR-␥ activation suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. A recurring theme in many cell types is the modulation of the innate immunity system particularly through altering the activity of the nuclear factor B. This system is likely to be even more prominent in modulating disease in vascular cells V ascular complications such as atherosclerosis and hypertension are primary causes to mortality associated with diabetes and obesity. With the increasing prevalence of diabetes and obesity, 1,2 vascular protection is critical to decreasing this mortality and improving public health as a whole. To accomplish this protection, one member in the nuclear receptor superfamily, peroxisome proliferator-activated receptor (PPAR)-␥, has emerged as an important player. PPAR-␥ ligands, thiazolidinediones (TZDs), are clinically used for type 2 diabetes. It is clear that improving glucose and lipid homeostasis by treating diabetes or insulin resistance has beneficial effects on cardiovascular diseases.

Cyclic phosphatidic acid inhibits the secretion of vascular endothelial growth factor from diabetic human coronary artery endothelial cells through peroxisome proliferator-activated receptor gamma

“…PPARγ plays a critical role in the cardiovascular system, and it is expressed in all cell types of the vessel wall, as well as in monocytes and macrophages [37]. PPARγ agonists promote adipocytic differentiation and stimulate the uptake of low-density lipoprotein by macrophages, leading to foam-cell formation in the arterial wall [38].…”

Treatment with the PPARγ agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome

“…TZDs are selective and potent agonists for the peroxisome proliferatoractivated receptor (PPAR)g, and influence the transcription of genes that regulate lipid and glucose metabolism (8). Recent data suggest that PPARg agonists also may modulate other biological processes that are involved in atherosclerosis, including inflammation (9,10). For example, the PPARg agonist rosiglitazone reduced serum concentrations of CRP in patients with type 2 diabetes and in patients with coronary artery disease (CAD) without diabetes (11).…”

Thiazolidinedione-Induced Fluid Retention Is Independent of Collecting Duct αENaC Activity

“…2 PPAR-␥ is also expressed in other tissues, such as the vasculature, where TZDs affect the inflammatory response and cholesterol homeostasis. [3][4][5] An important clinical limitation for this class of drugs is fluid retention and edema formation, which occurs in up to 5% of patients who have diabetes and are treated with TZDs; as a consequence, these agents are contraindicated in patients with New York Heart Association classes III and IV congestive heart failure. 6,7 Investigators have proposed that TZD-induced edema formation relates to increases in vascular permeability [7][8][9][10] and vasodilation.…”