Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators

Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes(1). Whereas PPAR gamma promotes Lipid storage by regulating adipocyte differentiation, PPAR alpha stimulates the beta-oxidative degradation of fatty acids. PPAR alpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPAR alpha is also a modulator of inflammation(2). Hypolipidaemic fibrate drugs are PPAR alpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes: even in the absence of their atherogenic lipoprotein-lowering effect(4,5). Here we show that PPAR alpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis(3). In these smooth-muscle cells, we find that PPAR alpha ligands, and not PPAR gamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPAR alpha repression of NF-kappa B signalling, In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPAR alpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPAR alpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.