Peroxisome Proliferator-Activated Receptors and Atherogenesis

Abstract

A large body of data gathered over the past couple of years has identified the peroxisome proliferator-activated receptors (PPAR) α, γ, and β/δ as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARα, γ, and β/δ subtypes are ≈60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARα is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARα controls expression of genes implicated in lipid metabolism. PPARγ, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARγ include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyΔ 12,14 -prostaglandin J 2 , and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARβ/δ are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARβ/δ stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARα and PPARγ activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARβ/δ agonists on atherogenesis. Given the widespread use of PPARα and PPARγ agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications.