title: A novel role for inhibitor of apoptosis (IAP) proteins as regulators of endothelial barrier function by mediating RhoA activation.
abstract: Inhibitor of apoptosis (IAP) proteins, such as XIAP or cIAP1/2, are important regulators of apoptosis in cancer cells, and IAP antagonists are currently evaluated as antitumor agents. Beyond their function in cancer cells, this study demonstrates a novel role of IAPs as regulators of vascular endothelial permeability. Two structurally different IAP antagonists, ABT and Smac085, as well as silencing of IAPs, reduced the thrombin receptor-activating peptide (TRAP)-induced barrier dysfunction in human endothelial cells as assessed by measuring macromolecular permeability or transendothelial electrical resistance. ABT diminished thrombin-evoked stress fiber formation, activation of myosin light chain 2, and disassembly of adherens junctions independent of calcium signaling, protein kinase C, and mitogen-activated protein kinases. Interestingly, ABT and silencing of IAPs, in particular XIAP, reduced the TRAP-evoked RhoA activation, whereas Rac1 was not affected. XIAP and, to a lesser extent, cIAP1 were found to directly interact with RhoA independently of the RhoA activation status. Under cell-free conditions, XIAP did not induce an ubiquitination of RhoA. In summary, our work discloses IAPs as crucial regulators of endothelial permeability and suggests IAP inhibition as interesting approach for the prevention of endothelial barrier dysfunction.
authors.affiliation: 2Institute of Pharmaceutical Biology, Biocenter, Goethe University Frankfurt/Main, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany. fuerst@em.uni-frankfurt.de.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hornburger
authors.forename: Bettina A
authors.initials: BA
authors.lastname: Mayer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Leonhardt
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Willer
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Andrea
authors.initials: A
authors.lastname: Beyerle
authors.forename: Krishnaraj
authors.initials: K
authors.lastname: Rajalingam
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Robert
authors.initials: R
authors.lastname: Fürst
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D017097:Electric Impedance; D004789:Enzyme Activation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018613:Microscopy, Confocal; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D022502:Stress Fibers / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; C532637:SMAC peptide; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C076901:thrombin receptor-activating peptide (P508-530); C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D020742:rhoA GTP-Binding Protein; D002118:Calcium
keywords: inflammation; permeability; small RhoA GTPases