Pleiotropic effects of peroxisome proliferator-activated receptor γ and δ in vascular diseases

Abstract

Peroxisome proliferator-activated receptors gamma (PPARγ) and delta (PPARδ) are nuclear receptors that have significant physiological effects on glucose and lipid metabolism. Experimental studies in animal models of metabolic disease have demonstrated their effects on improving lipid profile, insulin sensitivity, and reducing inflammatory responses. PPARγ and -δ are also expressed in the vasculature and their beneficial effects have been examined in various cardiovascular disease models such as atherosclerosis, hypertension, diabetic vascular complications, etc. using pharmacological ligands or genetic tools including viral vectors and transgenic mice. These studies suggest that PPARγ and δ are antiinflammatory, antiatherogenic, antioxidant, and antifibrotic against vascular diseases. Several signaling pathways, effector molecules, as well as coactivators/repressors have been identified as responsible for the protective effects of PPARγ and -δ in the vasculature. We discuss the pleiotropic effect of PPARγ and δ in vascular dysfunction, including atherosclerosis, hypertension, vascular remodeling, vascular injury, and diabetic vasculopathy, in various animal models, and the major underlying mechanisms. We also compare the phenotypes of several endothelial cell/vascular smooth muscle-specific PPARγ and -δ knockout and overexpressing transgenic mice in various disease models, and the implications underlying the functional importance of vascular PPARγ and δ in regulating whole-body homeostasis.