Effects of Pparγ Ligands on Atherosclerosis and Cardiovascular Disease

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors regulating the expression of genes that control lipid and glucose homeostasis, modulating thus the major metabolic disorders predisposing to atherosclerosis and subsequent cardiovascular diseases [1]. Moreover, PPARs exert additional anti-inflammatory and lipid-modulating effects in the arterial wall, being therefore interesting molecular targets for the treatment of atherosclerosis [2]. Finally, PPARs regulate genes that control thrombogenicity which occurs after the rupture of atherosclerotic plaques [3,4]. Three different PPARs have been identified (PPARα, PPARβ/δ, PPARγ) each displaying distinct tissue distribution patterns [5]. PPARs are activated by natural ligands (such as fatty acids and eiconasoids) and by pharmacological agonists. Whereas ligands for PPARβ/δ are still in the experimental stage, PPARα and PPARγ are the targets of two classes of drugs currently used in clinical practice: fibrates and thiazolidinediones (TZDs) respectively. Pioglitazone and rosiglitazone are TZDs currently used for the treatment of type 2 diabetes as insulin sensitizing agents. These drugs have not only significant hypoglycemic effects, but also potential positive effects on lipid metabolism, the endothelium, oxidative stress, and vascular inflammation [6]. These additive actions of TZDs might reduce the development of atherosclerosis. Preclinical development of PPAR ligands that would act on metabolic factors which enhance atherosclerosis includes the analysis of their effects in suitable murine models. However, the development of a reliable experimental animal model is not easy because ideally the regulatory pathways in these models need to be similar to those in humans [7].