title: Pulmonary endothelial cell signaling and function.
abstract: RhoA is an important modulator of endothelial monolayer permeability. Posttranslational carboxyl methylation of small GTPases, such as RhoA and Ras, regulates subcellular localization and GTPase activity, resulting in altered cellular function. In this study, we investigated the role of RhoA carboxyl methylation in modulating endothelial monolayer permeability. We found that inhibition of isoprenylcysteine-O-carboxyl methyltransferase (ICMT) with adenosine plus homocysteine (Ado/HC) or N-acetyl-S-geranylgeranyl-L-cysteine (AGGC) decreased RhoA carboxyl methylation and activation, which correlated with decreased monolayer permeability of bovine pulmonary artery endothelial cells (BPAEC). Conversely, BPAEC stably overexpressing ICMT had enhanced endothelial monolayer permeability, associated with elevated RhoA carboxyl methylation and activation. These results suggest that ICMT modulates endothelial monolayer permeability by altering RhoA carboxyl methylation and activation. In addition, we demonstrated that adenosine deaminase inhibitor not only attenuated, but also rescued, lung edema induced by a non-inflammatory edemagenic agent. Our data suggest that increasing intracellular adenosine is a useful therapeutic strategy against diseases characterized by increased vascular permeability.
authors.affiliation: Vascular Research Laboratory, Department of Medicine, Warren Alpert Medical School of Brown University, Providence VA Medical Center, Providence, Rhode Island 02903, USA. sharon_rounds@brown.edu
authors.forename: Sharon
authors.initials: S
authors.lastname: Rounds
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Harrington
authors.forename: Julie
authors.initials: J
authors.lastname: Newton
authors.forename: Brian
authors.initials: B
authors.lastname: Casserly
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D020742:rhoA GTP-Binding Protein; D013890:Thiourea; C005277:alpha-naphthyl thiourea