title: Cyclic AMP response element-binding protein prevents endothelial permeability increase through transcriptional controlling p190RhoGAP expression.
abstract: Increased endothelial permeability contributes to the morbidity and mortality associated with chronic inflammatory diseases, including acute lung injury. Cyclic AMP response element-binding protein (CREB) transcriptional factor induces genes that regulate inflammation and vascular remodeling. However, the role of CREB in regulating endothelial barrier function is unknown. Here, we demonstrate that CREB maintains basal endothelial barrier function and suppresses endothelial permeability increase by diverse agonists such as thrombin, lipopolysaccharide, histamine, and VEGF. We show that CREB transcriptionally controls the expression of p190RhoGAP-A, a GTPase-activating protein that inhibits small GTPase RhoA. Impairing CREB function using small interfering RNA or dominant-negative (dn)-CREB mutant (dn-CREB) markedly suppressed p190RhoGAP-A expression, increased RhoA activity, induced actin stress fiber formation, and produced an amplified and protracted increase in endothelial permeability in response to thrombin. Rescuing p190RhoGAP-A expression restored the permeability defect in dn-CREB-transducing endothelial cells. These findings were recapitulated in vivo because dn-CREB expression in mice vasculature increased basal lung microvessel permeability and exaggerated permeability increase induced by thrombin and lipopolysaccharide. Inhibiting RhoA signaling restored endothelial barrier dysfunction in the dn-CREB-expressing lung microvasculature. These results uncover a pivotal role of CREB in regulating endothelial barrier function by restricting RhoA signaling through controlling p190RhoGAP-A expression.
authors: Department of Pharmacology and Center for Lung and Vascular Biology, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
authors: Koteswara Rao
authors: KR
authors: Chava
authors: Mohammad
authors: M
authors: Tauseef
authors: Tiffany
authors: T
authors: Sharma
authors: Dolly
authors: D
authors: Mehta
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006490:Hemostatics / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000494:pharmacology
chemical_list: C074560:ARHGAP35 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D020662:Guanine Nucleotide Exchange Factors; D006490:Hemostatics; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D006632:Histamine; D008156:Luciferases; D013917:Thrombin