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.
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References
Barnes, P.J. Inhaled glucocorticoids for asthma. N. Engl. J. Med. 332, 868–875 (1995).
McGregor, A.M. Immunoendocrine interactions and autoimmunity. N. Engl. J. Med. 322, 1739–1741 (1990).
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).
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).
Mangelsdorf, D.J. et al. The nuclear receptor superfamily: The second decade. Cell 83, 835–839 (1995).
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).
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).
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).
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).
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).
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).
Hammerman, H., Schoen, F.J., Braunwald, E. & Kloner, R.A. Drug-induced expansion of infarct: Morphologic and functional correlations. Circulation 69, 611–617 (1984).
Sholter, D.E. & Armstrong, P.W. Adverse effects of corticosteroids on the cardiovascular system. Can. J. Cardiol. 16, 505–511 (2000).
Loscalzo, J. Nitric oxide and vascular disease. N. Engl. J. Med. 333, 251–253 (1995).
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).
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).
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).
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).
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).
Rameh, L.E. & Cantley, L.C. The role of phosphoinositide 3-kinase lipid products in cell function. J. Biol. Chem. 274, 8347–8350 (1999).
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).
Burgering, B.M. & Coffer, P.J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599–602 (1995).
Simoncini, T. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000).
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).
Dimmeler, S. et al. Activation of nitric oxide synthase in endothelial cells by Akt- dependent phosphorylation. Nature 399, 601–605 (1999).
Fulton, D. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597–601 (1999).
Kubes, P., Suzuki, M. & Granger, D.N. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc. Natl. Acad. Sci. USA 88, 4651–465 (1991).
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).
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).
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).
Frangogiannis, N.G. et al. Cytokines and the microcirculation in ischemia and reperfusion. J. Mol. Cell. Cardiol. 30, 2567–2576 (1998).
Vyden, J.K. et al. Effects of methylprednisolone administration in acute myocardial infarction. Am. J. Cardiol. 34, 677–686 (1974).
Beato, M., Herrlich, P. & Schutz, G. Steroid hormone receptors: Many actors in search of a plot. Cell 83, 851–857 (1995).
Karin, M. New twists in gene regulation by glucocorticoid receptor: Is DNA binding dispensable? Cell 93, 487–490 (1998).
Reichardt, H.M. et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93, 531–541 (1998).
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).
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).
Laufs, U. et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J. Clin. Invest. 106, 15–24 (2000).
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).
Mulvany, M.J. & Halpern, W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ. Res. 41, 19–26 (1977).
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).
Shesely, E.G. et al. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 93, 13176–131781 (1996).
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).
Yang, Z., Zingarelli, B. & Szabo, C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation 101, 1019–1026 (2000).
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.
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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
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DOI: https://doi.org/10.1038/nm0502-473
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