| Mechanism of thrombin mediated eNOS phosphorylation in endothelial cells is dependent on ATP levels after stimulation. | |
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MedLine Citation:
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PMID: 18687367 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Conflicting results have been reported concerning the role of AMP-activated protein kinase (AMPK) in mediating thrombin stimulation of endothelial NO-synthase (eNOS). We examined the involvement of two upstream kinases in AMPK activation in cultured human umbilical endothelial cells, LKB1 stimulated by a rise in intracellular AMP/ATP ratio, and Ca(+2)/CaM kinase kinase (CaMKK) responding to elevation of intracellular Ca(+2). We also studied the effects of AMPK activation on the downstream target eNOS. In culture medium 1640 the level of intracellular ATP was unchanged after thrombin stimulation and the CaMKK inhibitor STO-609 totally inhibited phosphorylation of AMPK and acetyl coenzyme A carboxylase (ACC) but not eNOS. In Morgan's medium 199 thrombin caused a significant lowering of intracellular ATP and STO-609 only partially inhibited the phosphorylation of AMPK, ACC and eNOS. Inhibition of AMPK by Compound C or AMPK downregulation using siRNA partially inhibited the phosphorylation of eNOS in medium 199 but not in 1640, underscoring a clear difference in the pathways mediating thrombin-stimulated eNOS phosphorylation in different culture media. Thus, conditions subjecting endothelial cells to a fall in ATP after thrombin stimulation facilitate activation of pathways partly dependent on AMPK causing downstream phosphorylation of eNOS. In contrast, under culture conditions that do not facilitate a fall in ATP after stimulation, AMPK activation is exclusively mediated by CaMKK and does not contribute to the phosphorylation of eNOS. |
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Authors:
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Brynhildur Thors; Haraldur Halldórsson; Gudbjorg Jónsdóttir; Gudmundur Thorgeirsson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-07-18 |
Journal Detail:
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Title: Biochimica et biophysica acta Volume: 1783 ISSN: 0006-3002 ISO Abbreviation: Biochim. Biophys. Acta Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-09-09 Completed Date: 2008-11-13 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0217513 Medline TA: Biochim Biophys Acta Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1893-902 Citation Subset: IM |
Affiliation:
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Institute of Pharmacy, Pharmacology and Toxicology, University of Iceland, Hagi Hofsvallagotu 53, Reykjavik, Iceland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases Acetyl-CoA Carboxylase / metabolism Adenosine Triphosphate / metabolism*, secretion Calcimycin / pharmacology Cells, Cultured Culture Media, Conditioned Endothelial Cells / drug effects, enzymology* Humans Multienzyme Complexes / metabolism Nitric Oxide / biosynthesis Nitric Oxide Synthase Type III / metabolism* Phosphorylation Protein-Serine-Threonine Kinases / metabolism Thrombin / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Culture Media, Conditioned; 0/Multienzyme Complexes; 10102-43-9/Nitric Oxide; 52665-69-7/Calcimycin; 56-65-5/Adenosine Triphosphate; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.4.21.5/Thrombin; EC 6.4.1.2/Acetyl-CoA Carboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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