[en] Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by the glucocorticoid receptor (GR). A rapid, non-nuclear effect of GR was found to mediate neuroprotection. High-dose corticosteroids (20 mg/kg intraperitoneally), given within 2 hours of transient cerebral ischemia, acutely increased endothelial nitric oxide synthase (eNOS) activity, augmented regional cerebral blood flow (CBF) by 40% to 50%, and reduced cerebral infarct size by 32%. These neuroprotective effects of corticosteroids were abolished by the GR antagonist RU486 and by inhibition of phosphatidylinositol 3-kinase (PI3K), and were absent in eNOS(-/-) mice. To determine the mechanism by which GR activated eNOS, we measured the effect of corticosteroids on PI3K and the protein kinase Akt. In a ligand-dependent manner, GR activated PI3K and Akt in vitro and in vivo caused NO-dependent vasodilation, which was blocked by cotreatment with RU486 or the PI3K inhibitor LY294002 but not by transcriptional inhibitors. Indeed, a mutant GR, which cannot dimerize and bind to DNA, still activated PI3K and Akt in response to corticosteroids. These findings indicate that non-nuclear GR rapidly activates eNOS through the PI3K/Akt pathway and suggest that this mechanism mediates the acute neuroprotective effects of corticosteroids through augmentation of CBF.
Limbourg, Florian P; Brigham & Women's Hospital and Harvard Medical School > Cardiovascular Division
Huang, Zhihong; Massachusetts General Hospital and Harvard Medical School
Plumier, Jean-Christophe ; Université de Liège - ULiège > Département des sciences et gestion de l'environnement > Ecophysiologie et physiologie animale
Simoncini, Tommaso; University of Pisa > Reproductive Medicine and Child Development
Fujioka, Masayuki; Massachusetts General Hospital and Harvard Medical School
Tuckermann, Jan; Universität Heidelberg > German Cancer Research center
Schutz, Gunther; Universität Heidelberg > German Cancer Research Center
Moskowitz, Michael A; Massachusetts General Hospital and Harvard Medical School
Liao, James K; Brigham & Women's Hospital and Harvard Medical School > Cardiaovascular Division
Language :
English
Title :
Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids.
Publication date :
2002
Journal title :
Journal of Clinical Investigation
ISSN :
0021-9738
eISSN :
1558-8238
Publisher :
American Society for Clinical Investigation, Ann Arbor, United States - Michigan
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