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.

  • Article
  • Published:

Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase

Abstract

Corticosteroids have been shown to exert beneficial effects in the treatment of acute myocardial infarction, but the precise mechanisms underlying their protective effects are unknown. Here we show that high-dose corticosteroids exert cardiovascular protection through a novel mechanism involving the rapid, non-transcriptional activation of endothelial nitric oxide synthase (eNOS). Binding of corticosteroids to the glucocorticoid receptor (GR) stimulated phosphatidylinositol 3-kinase and protein kinase Akt, leading to eNOS activation and nitric oxide–dependent vasorelaxation. Acute administration of pharmacological concentrations of corticosteroids in mice led to decreased vascular inflammation and reduced myocardial infarct size following ischemia and reperfusion injury. These beneficial effects of corticosteroids were abolished by GR antagonists or eNOS inhibitors in wild-type mice and were completely absent in eNOS-deficient (Nos3−/−) mice. The rapid activation of eNOS by the non-nuclear actions of GR, therefore, represents an important cardiovascular protective effect of acute high-dose corticosteroid therapy.

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: Non-transcriptional activation of eNOS by corticosteroids.
Figure 2: Activation of GRE-mediated gene transcription by corticosteroids.
Figure 3: Activation of PI3K/Akt pathway by corticosteroids.
Figure 4: Vascular protective effects of corticosteroids.
Figure 5: NO-mediated cardioprotective effects of corticosteroids.

Similar content being viewed by others

References

  1. Barnes, P.J. Inhaled glucocorticoids for asthma. N. Engl. J. Med. 332, 868–875 (1995).

    Article  CAS  Google Scholar 

  2. McGregor, A.M. Immunoendocrine interactions and autoimmunity. N. Engl. J. Med. 322, 1739–1741 (1990).

    Article  CAS  Google Scholar 

  3. Kirwan, J.R. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N. Engl. J. Med. 333, 142–146 (1995).

    Article  CAS  Google Scholar 

  4. Cronstein, B.N., Kimmel, S.C., Levin, R.I., Martiniuk, F. & Weissmann, G. A mechanism for the antiinflammatory effects of corticosteroids: The glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leuk 1 and intercellular adhesion molecule 1. Proc. Natl. Acad. Sci. USA 89, 9991–9995 (1992).

    Article  CAS  Google Scholar 

  5. Mangelsdorf, D.J. et al. The nuclear receptor superfamily: The second decade. Cell 83, 835–839 (1995).

    Article  CAS  Google Scholar 

  6. Becker, P.B., Gloss, B., Schmid, W., Strahle, U. & Schutz, G. In vivo protein-DNA interactions in a glucocorticoid response element require the presence of the hormone. Nature 324, 686–688 (1986).

    Article  CAS  Google Scholar 

  7. Flower, R.J. & Blackwell, G.J. Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation. Nature 278, 456–459 (1979).

    Article  CAS  Google Scholar 

  8. Lewis, G.P. & Piper, P.J. Inhibition of release of prostaglandins as an explanation of some of the actions of anti-inflammatory corticosteroids. Nature 254, 308–311 (1975).

    Article  CAS  Google Scholar 

  9. Brostjan, C. et al. Glucocorticoid-mediated repression of NFκB activity in endothelial cells does not involve induction of IκBα synthesis. J. Biol. Chem. 271, 19612–19616 (1996).

    Article  CAS  Google Scholar 

  10. Libby, P., Maroko, P.R., Bloor, C.M., Sobel, B.E. & Braunwald, E. Reduction of experimental myocardial infarct size by corticosteroid administration. J. Clin. Invest. 52, 599–607 (1973).

    Article  CAS  Google Scholar 

  11. Spath, J.A. Jr, Lane, D.L. & Lefer, A.M. Protective action of methylprednisolone on the myocardium during experimental myocardial ischemia in the cat. Circ. Res. 35, 44–51 (1974).

    Article  CAS  Google Scholar 

  12. Hammerman, H., Schoen, F.J., Braunwald, E. & Kloner, R.A. Drug-induced expansion of infarct: Morphologic and functional correlations. Circulation 69, 611–617 (1984).

    Article  CAS  Google Scholar 

  13. Sholter, D.E. & Armstrong, P.W. Adverse effects of corticosteroids on the cardiovascular system. Can. J. Cardiol. 16, 505–511 (2000).

    CAS  PubMed  Google Scholar 

  14. Loscalzo, J. Nitric oxide and vascular disease. N. Engl. J. Med. 333, 251–253 (1995).

    Article  CAS  Google Scholar 

  15. De Caterina, R. et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J. Clin. Invest. 96, 60–68 (1995).

    Article  CAS  Google Scholar 

  16. Ishida, A., Sasaguri, T., Kosaka, C., Nojima, H. & Ogata, J. Induction of the cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells. J. Biol. Chem. 272, 10050–10057 (1997).

    Article  CAS  Google Scholar 

  17. Kawashima, S. et al. Endothelial NO synthase overexpression inhibits lesion formation in mouse model of vascular remodeling. Arterioscler. Thromb. Vasc. Biol. 21, 201–207 (2001).

    Article  CAS  Google Scholar 

  18. Moroi, M. et al. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J. Clin. Invest. 101, 1225–1232 (1998).

    Article  CAS  Google Scholar 

  19. Huang, Z. et al. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-l-arginine. J. Cereb. Blood Flow Metab. 16, 981–987 (1996).

    Article  CAS  Google Scholar 

  20. Rameh, L.E. & Cantley, L.C. The role of phosphoinositide 3-kinase lipid products in cell function. J. Biol. Chem. 274, 8347–8350 (1999).

    Article  CAS  Google Scholar 

  21. Stephens, L. et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5- trisphosphate-dependent activation of protein kinase B. Science 279, 710–714 (1998).

    Article  CAS  Google Scholar 

  22. Burgering, B.M. & Coffer, P.J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599–602 (1995).

    Article  CAS  Google Scholar 

  23. Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000).

    Article  CAS  Google Scholar 

  24. Cross, D.A., Alessi, D.R., Cohen, P., Andjelkovich, M. & Hemmings, B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995).

    Article  CAS  Google Scholar 

  25. Dimmeler, S. et al. Activation of nitric oxide synthase in endothelial cells by Akt- dependent phosphorylation. Nature 399, 601–605 (1999).

    Article  CAS  Google Scholar 

  26. Fulton, D. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597–601 (1999).

    Article  CAS  Google Scholar 

  27. Kubes, P., Suzuki, M. & Granger, D.N. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc. Natl. Acad. Sci. USA 88, 4651–465 (1991).

    Article  CAS  Google Scholar 

  28. Barzilai, D. et al. Use of hydrocortisone in the treatment of acute myocardial infarction. Summary of a clinical trial in 446 patients. Chest 61, 488–491 (1972).

    Article  CAS  Google Scholar 

  29. Wenting-Van Wijk, M.J., Blankenstein, M.A., Lafeber, F.P. & Bijlsma, J.W. Relation of plasma dexamethasone to clinical response. Clin. Exp. Rheumatol. 17, 305–312 (1999).

    CAS  PubMed  Google Scholar 

  30. Charmandari, E., Johnston, A., Brook, C.G. & Hindmarsh, P.C. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Endocrinol. 169, 65–70 (2001).

    Article  CAS  Google Scholar 

  31. Frangogiannis, N.G. et al. Cytokines and the microcirculation in ischemia and reperfusion. J. Mol. Cell. Cardiol. 30, 2567–2576 (1998).

    Article  CAS  Google Scholar 

  32. Vyden, J.K. et al. Effects of methylprednisolone administration in acute myocardial infarction. Am. J. Cardiol. 34, 677–686 (1974).

    Article  CAS  Google Scholar 

  33. Beato, M., Herrlich, P. & Schutz, G. Steroid hormone receptors: Many actors in search of a plot. Cell 83, 851–857 (1995).

    Article  CAS  Google Scholar 

  34. Karin, M. New twists in gene regulation by glucocorticoid receptor: Is DNA binding dispensable? Cell 93, 487–490 (1998).

    Article  CAS  Google Scholar 

  35. Reichardt, H.M. et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93, 531–541 (1998).

    Article  CAS  Google Scholar 

  36. Cole, T.J. et al. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 9, 1608–16021 (1995).

    Article  CAS  Google Scholar 

  37. Radomski, M.W., Palmer, R.M. & Moncada, S. An l-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc. Natl. Acad. Sci. USA 87, 5193–5197 (1990).

    Article  CAS  Google Scholar 

  38. Laufs, U. et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J. Clin. Invest. 106, 15–24 (2000).

    Article  CAS  Google Scholar 

  39. Laufs, U., La Fata, V., Plutzky, J. & Liao, J.K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97, 1129–1135 (1998).

    Article  CAS  Google Scholar 

  40. Mulvany, M.J. & Halpern, W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ. Res. 41, 19–26 (1977).

    Article  CAS  Google Scholar 

  41. Walsh, J.P., Caldwell, K.K. & Majerus, P.W. Formation of phosphatidylinositol 3-phosphate by isomerization from phosphatidylinositol 4-phosphate. Proc. Natl. Acad. Sci. USA 88, 9184–9187 (1991).

    Article  CAS  Google Scholar 

  42. Shesely, E.G. et al. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 93, 13176–131781 (1996).

    Article  CAS  Google Scholar 

  43. Damiano, E.R., Westheider, J., Tozeren, A. & Ley, K. Variation in the velocity, deformation, and adhesion energy density of leukocytes rolling within venules. Circ. Res. 79, 1122–1130 (1996).

    Article  CAS  Google Scholar 

  44. Yang, Z., Zingarelli, B. & Szabo, C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation 101, 1019–1026 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Institutes of Health grants HL70274 and HL48743 (to J.K.L.), HL62602 (to M.A.M.), HL54136 (to K.L.), HL58582 (to B.A.F.), HL67574 (to C.M.H.), the American Heart Association Established Investigator Grants (to J.K.L. and B.A.F.) and Bugher Foundation Award (to J.K.L.), and the Mary Horrigan Connors Center for Women's Health. T.S. is supported by the Scuola Superiore di Studi e di Perfezionamento 'S. Anna' and the University of Pisa. J.C.P. is a recipient of an American Heart Association New England Affiliate Beginning Grant-in-Aid Award. F.P.L. is a recipient of a grant from the Deutsche Forschungsgemeinschaft. M.C.R. is a recipient of a Swiss National Science Foundation Fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James K. Liao.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hafezi-Moghadam, A., Simoncini, T., Yang, Z. et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8, 473–479 (2002). https://doi.org/10.1038/nm0502-473

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0502-473

This article is cited by

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