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Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids.

التفاصيل البيبلوغرافية
العنوان: Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids.
المؤلفون: Limbourg, Florian P, Huang, Zhihong, Plumier, Jean-Christophe, Simoncini, Tommaso, Fujioka, Masayuki, Tuckermann, Jan, Schutz, Gunther, Moskowitz, Michael A, Liao, James K
المصدر: Journal of Clinical Investigation, 110 (11), 1729-38 (2002)
بيانات النشر: American Society for Clinical Investigation, 2002.
سنة النشر: 2002
مصطلحات موضوعية: 1-Phosphatidylinositol 3-Kinase/metabolism, Adrenal Cortex Hormones/therapeutic use, Animals, Base Sequence, COS Cells, Cattle, Cells, Cultured, Cercopithecus aethiops, Cerebral Infarction/prevention & control, Cerebrovascular Circulation/physiology, DNA Primers, Endothelium, Vascular/physiology, Gene Expression Regulation, Enzymologic, Genes, Reporter, Humans, Ischemic Attack, Transient/enzymology/physiopathology, Mice, Mice, Inbred Strains, Neuroprotective Agents, Nitric Oxide Synthase/genetics, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Polymerase Chain Reaction, Receptors, Glucocorticoid/physiology, Recombinant Proteins/metabolism, Stroke/prevention & control, Transfection, Life sciences, Anatomy (cytology, histology, embryology...) & physiology, Sciences du vivant, Anatomie (cytologie, histologie, embryologie...) & physiologie
الوصف: 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.
نوع الوثيقة: journal article
http://purl.org/coar/resource_type/c_6501Test
article
اللغة: English
العلاقة: http://www.jci.org/articles/view/15481Test
DOI: 10.1172/JCI0215481
الوصول الحر: https://orbi.uliege.be/handle/2268/12175Test
حقوق: open access
http://purl.org/coar/access_right/c_abf2Test
info:eu-repo/semantics/openAccess
رقم الانضمام: edsorb.12175
قاعدة البيانات: ORBi
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