Peroxisome proliferator-activated receptors (PPARs): nuclear receptors with functions in the vascular wall

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARα is highly expressed in liver, muscle, kidney and heart, where it stimulates the β:-oxidative degradation of fatty acids. PPARγ is predominantly expressed in intestine and adipose tissue when it triggers adipocyte differentiation and promotes lipid storage. Recently, the expression of PPARα and PPARγ was also reported in cells of the vascular wall, such as monocyte/macrophages, endothelial and smooth muscle cells. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARα and PPARγ respectively. Furthermore, fatty acid-derivatives and eicosanoids are natural PPAR ligands: PPARα is activated by leukotriene B4, whereas prostaglandin J2 is a PPARγ ligand, as well as some components of oxidized LDL, such as 9- and 13-HODE. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control and, by consequence, in related diseases such as atherosclerosis. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFα and metalloproteases) by negatively interfering with the NF-κB, STAT and AP-1 signalling pathways in cells of the vascular wall. Furthermore, PPARs may also control lipid metabolism in the cells of the atherosclerotic plaque. In addition, different clinical trials (such as the LOCAT, BECAIT and VA-HIT) as well as animal studies indicate that PPAR activators may have anti-atherogenic properties by reducing the progression of atherosclerotic lesions. In this review, we summarize the evidence indicating that PPARα and PPARγ directly modulate vessel wall functions, and its consequences in the control of cardiovascular disease.