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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1716-1724. Prepublished online as a Blood First Edition Paper on June 1, 2004; DOI 10.1182/blood-2003-11-3744. This Article Full Text (PDF) All Versions of this Article: 2003-11-3744v1 104/6/1716    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Li, X. Articles by Gamble, J. R Search for Related Content PubMed PubMed Citation Articles by Li, X. Articles by Gamble, J. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 4, 2003 Accepted April 30, 2004 Role of Protein Kinase C in Thrombin-Induced Endothelial Permeability Changes: Inhibition by Angiopoietin-1 Xiaochun Li, Christopher N Hahn, Michelle Parsons, Jenny Drew, Mathew A Vadas, and Jennifer R Gamble* Human Immunology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia University of Adelaide, Adelaide, South Australia, Australia * Corresponding author; email: Jennifer.Gamble{at}imvs.sa.gov.au. Endothelial cell leakiness is regulated by mediators such as thrombin, which promotes endothelial permeability, and anti-inflammatory agents, such as angiopoietin-1. Here we define a new pathway involved in thrombin-induced permeability that involves the atypical protein kinase C isoform, PKC[[zeta]}. Chemical inhibitor studies implicated the involvement of an atypical PKC isoform in thrombin-induced permeability changes in human umbilical vein endothelial cells. Thrombin stimulation resulted in PKC, but not the other atypical PKC isoform, PKC, translocating to the membrane, an event known to be critical to enzyme activation. The involvement of PKC was confirmed by over-expression of constitutively active PKC, resulting in enhanced basal permeability. Dominant-negative PKC prevented the thrombin mediated effects on EC permeability and inhibited thrombin-induced activation of PKC. Rho activation does not appear to play a role, either up or downstream of PKC, as C3 transferase does not block thrombin-induced PKC activation and dominant-negative PKC does not block thrombin-induced Rho activation. Finally, we show that angiopoietin-1 inhibits thrombin-induced PKC activation, Rho activation and Ca++ flux, thus demonstrating that the powerful anti-permeability action of angiopoietin-1 is mediated by its action on a number of signaling pathways induced by thrombin and implicated in permeability changes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Oubaha and J.-P. Gratton Phosphorylation of endothelial nitric oxide synthase by atypical PKC{zeta} contributes to angiopoietin-1-dependent inhibition of VEGF-induced endothelial permeability in vitro Blood, October 8, 2009; 114(15): 3343 - 3351. [Abstract] [Full Text] [PDF] X. Li, M. Stankovic, B. P.-L. Lee, M. Aurrand-Lions, C. N. Hahn, Y. Lu, B. A. Imhof, M. A. Vadas, and J. R. 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M. van Hinsbergh Thrombin-induced endothelial barrier disruption in intact microvessels: role of RhoA/Rho kinase-myosin phosphatase axis Am J Physiol Cell Physiol, May 1, 2008; 294(5): C1234 - C1241. [Abstract] [Full Text] [PDF] X. Li, M. Stankovic, C. S. Bonder, C. N. Hahn, M. Parsons, S. M. Pitson, P. Xia, R. L. Proia, M. A. Vadas, and J. R. Gamble Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1 Blood, April 1, 2008; 111(7): 3489 - 3497. [Abstract] [Full Text] [PDF] R. H. Adamson, J. C. Ly, R. K. Sarai, J. F. Lenz, A. Altangerel, D. Drenckhahn, and F. E. Curry Epac/Rap1 pathway regulates microvascular hyperpermeability induced by PAF in rat mesentery Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1188 - H1196. [Abstract] [Full Text] [PDF] J. R. Klinger, J. D. Murray, B. Casserly, D. F. Alvarez, J. A. King, S. S. An, G. Choudhary, A. N. Owusu-Sarfo, R. Warburton, and E. O. 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