Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-4-2
pubmed:abstractText
Acute lung injury, sepsis, lung inflammation, and ventilator-induced lung injury are life-threatening conditions associated with lung vascular barrier dysfunction, which may lead to pulmonary edema. Increased levels of atrial natriuretic peptide (ANP) in lung circulation reported in these pathologies suggest its potential role in the modulation of lung injury. Besides well recognized physiological effects on vascular tone, plasma volume, and renal function, ANP may exhibit protective effects in models of lung vascular endothelial cell (EC) barrier dysfunction. However, the molecular mechanisms of ANP protective effects are not well understood. The recently described cAMP-dependent guanine nucleotide exchange factor (GEF) Epac activates small GTPase Rap1, which results in activation of small GTPase Rac-specific GEFs Tiam1 and Vav2 and Rac-mediated EC barrier protective responses. Our results show that ANP stimulated protein kinase A and the Epac/Rap1/Tiam/Vav/Rac cascade dramatically attenuated thrombin-induced pulmonary EC permeability and the disruption of EC monolayer integrity. Using pharmacological and molecular activation and inhibition of cAMP-and cGMP-dependent protein kinases (PKA and PKG), Epac, Rap1, Tiam1, Vav2, and Rac we linked ANP-mediated protective effects to the activation of Epac/Rap and PKA signaling cascades, which dramatically inhibited the Rho pathway of thrombin-induced EC hyper-permeability. These results suggest a novel mechanism of ANP protective effects against agonist-induced pulmonary EC barrier dysfunction via inhibition of Rho signaling by Epac/Rap1-Rac and PKA signaling cascades.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Actins, http://linkedlifedata.com/resource/pubmed/chemical/Atrial Natriuretic Factor, http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP, http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP-Dependent Protein Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Guanine Nucleotide Exchange Factors, http://linkedlifedata.com/resource/pubmed/chemical/Monomeric GTP-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-vav, http://linkedlifedata.com/resource/pubmed/chemical/RAPGEF3 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/TIAM1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Thrombin, http://linkedlifedata.com/resource/pubmed/chemical/VAV2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/rac GTP-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/rho GTP-Binding Proteins
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1097-4652
pubmed:author
pubmed:copyrightInfo
(c) 2007 Wiley-Liss, Inc.
pubmed:issnType
Electronic
pubmed:volume
215
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
715-24
pubmed:meshHeading
pubmed-meshheading:18064650-Actins, pubmed-meshheading:18064650-Atrial Natriuretic Factor, pubmed-meshheading:18064650-Blood-Air Barrier, pubmed-meshheading:18064650-Cells, Cultured, pubmed-meshheading:18064650-Cyclic AMP, pubmed-meshheading:18064650-Cyclic AMP-Dependent Protein Kinases, pubmed-meshheading:18064650-Cyclic GMP, pubmed-meshheading:18064650-Endothelial Cells, pubmed-meshheading:18064650-Enzyme Activation, pubmed-meshheading:18064650-Enzyme Inhibitors, pubmed-meshheading:18064650-Guanine Nucleotide Exchange Factors, pubmed-meshheading:18064650-Humans, pubmed-meshheading:18064650-Lung, pubmed-meshheading:18064650-Monomeric GTP-Binding Proteins, pubmed-meshheading:18064650-Proto-Oncogene Proteins c-vav, pubmed-meshheading:18064650-Stress Fibers, pubmed-meshheading:18064650-Thrombin, pubmed-meshheading:18064650-rac GTP-Binding Proteins, pubmed-meshheading:18064650-rho GTP-Binding Proteins
pubmed:year
2008
pubmed:articleTitle
Epac/Rap and PKA are novel mechanisms of ANP-induced Rac-mediated pulmonary endothelial barrier protection.
pubmed:affiliation
Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. abirukov@medicine.bsd.uchicago.edu
pubmed:publicationType
Journal Article