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PMID: 11984591 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Nature medicine ·Vol. 8 ·No. 5 ·2002-05-00 ·Pages 473-9

Hafezi-Moghadam A, Simoncini T, Yang Z, Limbourg FP, Plumier JC, Rebsamen MC, Hsieh CM, Chui DS, Thomas KL, Prorock AJ, Laubach VE, Moskowitz MA, French BA, Ley K, Liao JK

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.

MeSH Terms
Adrenal Cortex Hormones/pharmacology Animals Aorta/drug effects,physiology Cardiotonic Agents/pharmacology Cells, Cultured Dexamethasone/pharmacology Endothelium, Vascular/enzymology,physiology Enzyme Activation/drug effects Humans In Vitro Techniques Mice Muscle Contraction/drug effects,physiology Muscle, Smooth, Vascular/physiology NG-Nitroarginine Methyl Ester/pharmacology Nitric Oxide Synthase/metabolism Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Potassium Chloride
Chemicals
Adrenal Cortex Hormones Cardiotonic Agents Potassium Chloride Dexamethasone NOS3 protein, human Nitric Oxide Synthase Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Nos3 protein, mouse NG-Nitroarginine Methyl Ester
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Hafezi-Moghadam Ali
The Center for Blood Research, Harvard Medical School, Boston, Massachusetts, USA.
Simoncini Tommaso
Yang Zequan
Limbourg Florian P
Plumier Jean-Christophe
Rebsamen Michael C
Hsieh Chung-Ming
Chui Dao-Shan
Thomas Kennard L
Prorock Alyson J
Laubach Victor E
Moskowitz Michael A
French Brent A
Ley Klaus
Liao James K
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1078-8956
DOI
10.1038/nm0502-473
Published
2002-05-00
Pages
473-9
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC2668717
Subset
IM
Grants
NHLBI NIH HHS · HL58582 · United States
NHLBI NIH HHS · P01 HL048743-090008 · United States
NHLBI NIH HHS · P01 HL048743 · United States
NHLBI NIH HHS · HL70274 · United States
NHLBI NIH HHS · HL54136 · United States
NHLBI NIH HHS · HL65754 · United States
NHLBI NIH HHS · R01 HL052233-05 · United States
NHLBI NIH HHS · HL62602 · United States
NHLBI NIH HHS · HL48743 · United States
NHLBI NIH HHS · P01 HL048743-080008 · United States
NHLBI NIH HHS · R01 HL052233-07 · United States
NHLBI NIH HHS · F32 HL067574 · United States
NHLBI NIH HHS · R01 HL052233-06 · United States
NHLBI NIH HHS · R01 HL058582 · United States
NHLBI NIH HHS · R01 HL052233 · United States
NHLBI NIH HHS · R01 HL070274 · United States
NHLBI NIH HHS · P01 HL048743-100008 · United States
Corrections
CommentIn
PMID: 11984585
External Links
PubMed source DOI: 10.1038/nm0502-473 PMC Full Text View journal details
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