ACTIVATION OF HUMAN AORTIC SMOOTH-MUSCLE CELLS IS INHIBITED BY PPAR-ALPHA BUT NOT BY PPAR-GAMMA ACTIVATORS

Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorder s 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 ligand s that inhibit the progressive formation of atherosclerotic lesions, w hich involves chronic inflammatory processes: even in the absence of t heir atherogenic lipoprotein-lowering effect(4,5). Here we show that P PAR alpha is expressed in human aortic smooth-muscle cells, which part icipate in plaque formation and post-angioplasty re-stenosis(3). In th ese smooth-muscle cells, we find that PPAR alpha ligands, and not PPAR gamma ligands, inhibit interleukin-1-induced production of interleuki n-6 and prostaglandin and expression of cyclooxygenase-2. This inhibit ion 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 o f interleukin-6, fibrinogen and C-reactive protein. We conclude that a ctivators of PPAR alpha inhibit the inflammatory response of aortic sm ooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPAR alpha in the vascular wall may influen ce the process of atherosclerosis and re-stenosis.