Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Schoonjans, K., Martin, G., Staels, B. & Auwerx, J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr. Opin. Lipidol. 8, 159–166 (1997).

    Article  CAS  Google Scholar 

  2. Devchand, P. R. et al. The PPARα-leukotriene B4 pathway to inflammation control. Nature 384, 39–43 (1996).

    Article  ADS  CAS  Google Scholar 

  3. Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993).

    Article  ADS  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. 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).

    Article  ADS  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. Todd, P. A. & Ward, A. Gemfibrozil, a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 36, 314–339 (1988).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  ADS  CAS  Google Scholar 

  15. 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).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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).

    Article  ADS  CAS  Google Scholar 

  20. Jiang, C., Ting, A. T. & Seed, B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998).

    Article  ADS  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Brand, K. et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J. Clin. Invest. 97, 1715–1722 (1996).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. Clauss, A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 17, 237–246 (1957).

    Article  CAS  Google Scholar 

  27. 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).

    ADS  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bart Staels.

Supplementary Information

Rights and permissions

Reprints and permissions

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/31701

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing