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

Bart Staels (), Wolfgang Koenig, Aïda Habib, Régine Merval, Marilyne Lebret, Inés Pineda Torra, Philippe Delerive, Abdessamad Fadel, Giulia Chinetti, Jean-Charles Fruchart, Jamila Najib, Jacques Maclouf and Alain Tedgui
Additional contact information
Bart Staels: U325 INSERM, Institut Pasteur
Wolfgang Koenig: University of Ulm
Aïda Habib: U348 INSERM and IFR ‘Circulation Lariboisière’
Régine Merval: U141 INSERM and IFR ‘Circulation Lariboisiàre’
Marilyne Lebret: U348 INSERM and IFR ‘Circulation Lariboisière’
Inés Pineda Torra: U325 INSERM, Institut Pasteur
Philippe Delerive: U325 INSERM, Institut Pasteur
Abdessamad Fadel: U325 INSERM, Institut Pasteur
Giulia Chinetti: U325 INSERM, Institut Pasteur
Jean-Charles Fruchart: U325 INSERM, Institut Pasteur
Jamila Najib: U325 INSERM, Institut Pasteur
Jacques Maclouf: U348 INSERM and IFR ‘Circulation Lariboisière’
Alain Tedgui: U141 INSERM and IFR ‘Circulation Lariboisiàre’

Nature, 1998, vol. 393, issue 6687, 790-793

Abstract: Abstract 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 diabetes1. Whereas PPARγ promotes lipid storage by regulating adipocyte differentiation, PPARα stimulates the β-oxidative degradation of fatty acids. PPARα-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARα is also a modulator of inflammation2. Hypolipidaemic fibrate drugs are PPARα ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes3, even in the absence of their atherogenic lipoprotein-lowering effect4,5. Here we show that PPARα is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis3. In these smooth-muscle cells, we find that PPARα ligands, and not PPARγ 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 PPARα repression of NF-κB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARα inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARα in the vascular wall may influence the process of atherosclerosis and re-stenosis.

Date: 1998
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DOI: 10.1038/31701

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