| Pulmonary endothelial cell barrier enhancement by FTY720 does not require the S1P1 receptor. | |
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MedLine Citation:
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PMID: 17475445 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Novel therapeutic strategies are needed to reverse the loss of endothelial cell (EC) barrier integrity that occurs during inflammatory disease states such as acute lung injury. We previously demonstrated potent EC barrier augmentation in vivo and in vitro by the platelet-derived phospholipid, sphingosine 1-phosphate (S1P) via ligation of the S1P1 receptor. The S1P analogue, FTY720, similarly exerts barrier-protective vascular effects via presumed S1P1 receptor ligation. We examined the role of the S1P1 receptor in sphingolipid-mediated human lung EC barrier enhancement. Both S1P and FTY-induced sustained, dose-dependent barrier enhancement, reflected by increases in transendothelial electrical resistance (TER), which was abolished by pertussis toxin indicating Gi-coupled receptor activation. FTY-mediated increases in TER exhibited significantly delayed onset and intensity relative to the S1P response. Reduction of S1P1R expression (via siRNA) attenuated S1P-induced TER elevations whereas the TER response to FTY was unaffected. Both S1P and FTY rapidly (within 5 min) induced S1P1R accumulation in membrane lipid rafts, but only S1P stimulated S1P1R phosphorylation on threonine residues. Inhibition of PI3 kinase activity attenuated S1P-mediated TER increases but failed to alter FTY-induced TER elevation. Finally, S1P, but not FTY, induced significant myosin light chain phosphorylation and dramatic actin cytoskeletal rearrangement whereas reduced expression of the cytoskeletal effectors, Rac1 and cortactin (via siRNA), attenuated S1P-, but not FTY-induced TER elevations. These results mechanistically characterize pulmonary vascular barrier regulation by FTY720, suggesting a novel barrier-enhancing pathway for modulating vascular permeability. |
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Authors:
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S M Dudek; S M Camp; E T Chiang; P A Singleton; P V Usatyuk; Y Zhao; V Natarajan; J G N Garcia |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-04-06 |
Journal Detail:
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Title: Cellular signalling Volume: 19 ISSN: 0898-6568 ISO Abbreviation: Cell. Signal. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-06-25 Completed Date: 2007-09-12 Revised Date: 2013-06-06 |
Medline Journal Info:
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Nlm Unique ID: 8904683 Medline TA: Cell Signal Country: England |
Other Details:
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Languages: eng Pagination: 1754-64 Citation Subset: IM |
Affiliation:
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Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 5841 South Maryland Ave. Chicago, IL 60637, United States. sdudek@medicine.bsd.uchicago.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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genetics Capillary Permeability Cells, Cultured Cytoskeleton / metabolism Electric Impedance Endothelial Cells / drug effects* Endothelium, Vascular / cytology Humans Immunosuppressive Agents / pharmacology* Lung / cytology Models, Biological Phosphorylation Propylene Glycols / pharmacology* Pulmonary Artery / cytology RNA, Small Interfering / metabolism Receptors, Lysosphingolipid / metabolism* Signal Transduction Sphingosine / analogs & derivatives*, pharmacology Threonine / metabolism rac1 GTP-Binding Protein / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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K08 HL070013-04/HL/NHLBI NIH HHS; K08 HL070013-05/HL/NHLBI NIH HHS; K08 HL70013/HL/NHLBI NIH HHS; P01 HL 58064/HL/NHLBI NIH HHS; P01 HL058064-110006/HL/NHLBI NIH HHS; R01 68071//PHS HHS; R01 HL 79396/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Immunosuppressive Agents; 0/Propylene Glycols; 0/RNA, Small Interfering; 0/Receptors, Lysosphingolipid; 123-78-4/Sphingosine; 3QN8BYN5QF/fingolimod; 72-19-5/Threonine; EC 3.6.5.2/rac1 GTP-Binding Protein |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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