title: Natriuretic peptides differentially attenuate thrombin-induced barrier dysfunction in pulmonary microvascular endothelial cells.
abstract: Previous studies have described a protective effect of atrial natriuretic peptide (ANP) against agonist-induced permeability in endothelial cells derived from various vascular beds. In the current study, we assessed the effects of the three natriuretic peptides on thrombin-induced barrier dysfunction in rat lung microvascular endothelial cells (LMVEC). Both ANP and brain natriuretic peptide (BNP) attenuated the effect of thrombin on increased endothelial monolayer permeability and significantly enhanced the rate of barrier restoration. C-type natriuretic peptide (CNP) had no effect on the degree of thrombin-induced monolayer permeability, but did enhance the restoration of the endothelial barrier, similar to ANP and BNP. In contrast, the non-guanylyl cyclase-linked natriuretic peptide receptor specific ligand, cyclic-atrial natriuretic factor (c-ANF), delayed the rate of barrier restoration following exposure to thrombin. All three natriuretic peptides promoted cGMP production in the endothelial cells; however, 8-bromo-cGMP alone did not significantly affect thrombin modulation of endothelial barrier function. ANP and BNP, but not CNP or c-ANF, blunted thrombin-induced RhoA GTPase activation. We conclude that ANP and BNP protect against thrombin-induced barrier dysfunction in the pulmonary microcirculation by a cGMP-independent mechanism, possibly by attenuation of RhoA activation.
authors.affiliation: Pulmonary Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, Brown Medical School, Research Services, Providence, RI 02908, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
authors.forename: Rod
authors.initials: R
authors.lastname: Warburton
authors.forename: Gerardo P
authors.initials: GP
authors.lastname: Carino
authors.forename: Josh
authors.initials: J
authors.lastname: Murray
authors.forename: Christopher
authors.initials: C
authors.lastname: Murphy
authors.forename: Melanie
authors.initials: M
authors.lastname: Napier
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Harrington
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000098:blood supply / Q000166:cytology; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology; D045265:Natriuretic Peptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors; D013917:Thrombin / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D045265:Natriuretic Peptides; D010446:Peptide Fragments; C065367:atrial natriuretic factor (4-23)NH2, de-Gln(18)-de-Ser(19)-de-Gly(20,22)-de-Leu(21)-; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009320:Atrial Natriuretic Factor; D013917:Thrombin; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP