title: Caveolin-1-eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability.
abstract: Endothelial barrier function is regulated by adherens junctions (AJs) and caveolae-mediated transcellular pathways. The opening of AJs that is observed in caveolin-1(-/-) (Cav-1(-/-)) endothelium suggests that Cav-1 is necessary for AJ assembly or maintenance. Here, using endothelial cells isolated from Cav-1(-/-) mice, we show that Cav-1 deficiency induced the activation of endothelial nitric oxide synthase (eNOS) and the generation of nitric oxide (NO) and peroxynitrite. We assessed S-nitrosylation and nitration of AJ-associated proteins to identify downstream NO redox signaling targets. We found that the GTPase-activating protein (GAP) p190RhoGAP-A was selectively nitrated at Tyr1105, resulting in impaired GAP activity and RhoA activation. Inhibition of eNOS or RhoA restored AJ integrity and diminished endothelial hyperpermeability in Cav-1(-/-) mice. Thrombin, a mediator of increased endothelial permeability, also induced nitration of p120-catenin-associated p190RhoGAP-A. Thus, eNOS-dependent nitration of p190RhoGAP-A represents a crucial mechanism for AJ disassembly and resultant increased endothelial permeability.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: M Rizwan
authors.initials: MR
authors.lastname: Siddiqui
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Komarova
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Vogel
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Gao
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.forename: Johnson
authors.initials: J
authors.lastname: Rajasingh
authors.forename: You-Yang
authors.initials: YY
authors.lastname: Zhao
authors.forename: Viktor
authors.initials: V
authors.lastname: Brovkovych
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010539:Permeability; D030421:Peroxynitrous Acid / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020742:rhoA GTP-Binding Protein