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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schoonjans, K., Martin, G., Staels, B. & Auwerx, J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr. Opin. Lipidol. 8, 159–166 (1997).
Devchand, P. R. et al. The PPARα-leukotriene B4 pathway to inflammation control. Nature 384, 39–43 (1996).
Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993).
Saitoh, K. et al. Anti-atheromatous effects of fenofibrate, a hypolipidemic drug. I: Anti-atheromatous effects are independent of its hypolipidemic effect in cholesterol-fed rabbits. Folia Pharmacol. Japon. 106, 41–50 (1995).
Ericsson, C. G. et al. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 347, 849–853 (1996).
Auboeuf, D. et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-α in humans. No alterations in adipose tissue of obese and NIDDM patients. Diabetes 46, 1319–1327 (1997).
Loppnow, H. & Libby, P. Proliferating or interleukin-1 activated human vascular smooth muscle cells secrete copious interleukin 6. J. Clin. Invest. 85, 731–738 (1990).
Forman, B. M., Chen, J. & Evans, R. M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc. Natl Acad. Sci. USA 94, 4312–4317 (1997).
Vu-Dac, N. et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J. Clin. Invest. 96, 741–750 (1995).
Balfour, J. A., McTavish, D. & Heel, R. C. Fenofibrate, a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia. Drugs 40, 260–290 (1990).
Todd, P. A. & Ward, A. Gemfibrozil, a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 36, 314–339 (1988).
Lehmann, J. M. et al. An antidiabetic thiazolidinedione is a high affinity ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ). J. Biol. Chem. 270, 12953–12956 (1995).
Newton, R., Kuitert, L. M. E., Bergmann, M., Adcock, I. M. & Barnes, P. J. Evidence for involvement of NF-κB in the transcriptional control of COX-2 gene expression by IL-1β. Biochem. Biophys. Res. Commun. 237, 28–32 (1997).
Kutchera, W. et al. Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. Proc. Natl Acad. Sci. USA 93, 4816–4820 (1996).
Xie, W. & Herschman, H. R. Transcriptional regulation of prostaglandin synthase 2 gene expression by platelet-derived growth factor and serum. J. Biol. Chem. 271, 31742–31748 (1996).
Yamamoto, K., Arakawa, T., Ueda, N. & Yamamoto, S. Transcriptional roles of nuclear factor κB and nuclear factor-interleukin-6 in the tumor necrosis factor α-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. J. Biol. Chem. 270, 31315–31320 (1995).
Liuzzo, G. et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N. Engl. J. Med. 331, 417–424 (1994).
Thompson, S. G., Kienast, J., Pyke, S. D. M., Haverkate, F. & van de Loo, J. C. W. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N. Engl. J. Med. 332, 635–641 (1995).
Ricote, M., Li, A. C., Willsson, T. M., Kelly, C. J. & Glass, C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).
Jiang, C., Ting, A. T. & Seed, B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998).
Galis, Z. S., Sukhova, G. K., Lark, M. W. & Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest. 94, 2493–2503 (1994).
Brand, K. et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J. Clin. Invest. 97, 1715–1722 (1996).
Bourcier, T., Sukhova, G. & Libby, P. The nuclear factor κ-B signalling pathway participates in dysregulation of vascular smooth muscle cells in vitro and in human atherosclerosis. J. Biol. Chem. 272, 15817–15824 (1997).
Rich, B. E. & Steitz, J. A. Human acidic ribosomal phosphoprotein P0, P1 and P2: analysis of cDNA clones, in vitro synthesis and assembly. Mol. Cell. Biol. 7, 4065–4074 (1987).
Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).
Clauss, A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 17, 237–246 (1957).
Belmin, J. et al. Increased production of tumor necrosis factor and interleukin 6 by the arterial wall of aged rats. Am. J. Physiol. 268, H2288–H2293 (1995).
Pradelles, P., Grassi, J. & Maclouf, J. Enzyme immunoassay of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Analyt. Chem. 57, 1170–1173 (1985).
Habib, A. et al. Demonstration of an inducible cyclooxygenase in human endothelial cells using antibodies raised against the carboxyl-terminal region of the cyclooxygenase-2. J. Biol. Chem. 268, 23448–23454 (1993).
Jones, D. A., Carlton, D. P., McIntyre, M. P., Zimmerman, G. A. & Prescott, S. M. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J. Biol. Chem. 268, 9049–9054 (1993).
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.
About this article
Cite this article
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
Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation
Journal of Chemical Information and Modeling (2020)
Probiotic Bifidobacterium lactis V9 attenuates hepatic steatosis and inflammation in rats with non-alcoholic fatty liver disease
AMB Express (2020)
Effect of 6-Benzoyl-benzothiazol-2-one scaffold on the pharmacological profile of α-alkoxyphenylpropionic acid derived PPAR agonists
Journal of Enzyme Inhibition and Medicinal Chemistry (2020)
Exploration of combined effect of peroxisome proliferator activated receptor (PPAR) agonist and retinoic acid receptor (RAR) agonist on experimental models of inflammation in rats
Obesity Medicine (2020)