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

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.

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Figure 1: PPARα, but not PPARγ, is expressed in SMC.
Figure 2: PPARα, but not PPARγ, activators inhibit the IL-1 mediated induction of IL-6 and 6-keto-PGF secretion by SMC.
Figure 3: PPARα activators, but not PPARγ activators, inhibit IL-1-mediated induction of COX-2 protein in SMC.
Figure 4: PPARα activators, but not PPARγ activators, inhibit the IL-1-mediated induction of COX-2 mRNA in SMC.
Figure 5: Fibrates inhibit the induction of human COX-2 promoter activity by PMA, p65/RelA and p50 via PPARα.
Figure 6: The PPARα activator fenofibrate reduces the inflammatory response in patients with coronary atheroclerosis.

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Acknowledgements

We acknowledge the technical contribution of O. Vidal, P. Poulain and B. Derudas, and thank C. Haegeman for p50 and p65/RelA, S. Prescott for human COX-2 promoter plasmids, and M. Sund for help with statistical analysis. This work was supported by grants from the Association pour la Recherche sur le Cancer (to J.M.), CNAMTS/INSERM (to A.T.) and the Région Nord-Pas de Calais. B.S. and J.M. are members of the CNRS.

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Staels, B., Koenig, W., Habib, A. et al. Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 393, 790–793 (1998). https://doi.org/10.1038/31701

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