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Caveolin-1–eNOS Signaling Promotes p190RhoGAP-A Nitration and Endothelial Permeability

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Title: Caveolin-1–eNOS Signaling Promotes p190RhoGAP-A Nitration and Endothelial Permeability
Author(s): Siddiqui, M. Rizwan; Komarova, Yulia A.; Vogel, Stephen M.; Gao, Xiaopei; Bonini, Marcelo G.; Rajasingh, Johnson; Zhao, You-Yang; Brovkovych, Viktor; Malik, Asrar B.
Subject(s): nitric oxide synthase adherens junction 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.
Issue Date: 2011-05-30
Publisher: Rockefeller University Press
Citation Info: Siddiqui, M. R., Komarova, Y. A., Vogel, S. M., Gao, X., Bonini, M. G., Rajasingh, J., Zhao, Y. Y., Brovkovych, V., & Malik, A. B. 2011. Caveolin-1-eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability. Journal of Cell Biology, 193(5): 841-850. DOI: 10.1083/jcb.201012129
Type: Article
Description: © 2011 Siddiqui et al. The original version is available through Rockefeller University Press at DOI: 10.1083/jcb.201012129.
ISSN: 0021-9525
Sponsor: This work was supported by National Institutes of Health grants R01 HL 45638 and P01 HL 60678 to A.B. Malik and R01 HL103922 to Y. Komarova.
Date Available in INDIGO: 2012-03-09

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