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.

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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.

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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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Correspondence to James K. Liao.

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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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