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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents



ID: 723956.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock
Authors:Mikelis, C. M.; Simaan, M.; Ando, K.; Fukuhara, S.; Sakurai, A.; Amornphimoltham, P.; Masedunskas, A.; Weigert, R.; Chavakis, T.; Adams, R. H.; Offermanns, S.; Mochizuki, N.; Zheng, Y.; Gutkind, J. S.
Date of Publication (YYYY-MM-DD):2015
Title of Journal:Nat Commun
Volume:6
Start Page:6725
Audience:Not Specified
Abstract / Description:Histamine-induced vascular leakage is an integral component of many highly prevalent human diseases, including allergies, asthma and anaphylaxis. Yet, how histamine induces the disruption of the endothelial barrier is not well defined. By using genetically modified animal models, pharmacologic inhibitors and a synthetic biology approach, here we show that the small GTPase RhoA mediates histamine-induced vascular leakage. Histamine causes the rapid formation of focal adherens junctions, disrupting the endothelial barrier by acting on H1R Galphaq-coupled receptors, which is blunted in endothelial Galphaq/11 KO mice. Interfering with RhoA and ROCK function abolishes endothelial permeability, while phospholipase Cbeta plays a limited role. Moreover, endothelial-specific RhoA gene deletion prevents vascular leakage and passive cutaneous anaphylaxis in vivo, and ROCK inhibitors protect from lethal systemic anaphylaxis. This study supports a key role for the RhoA signalling circuitry in vascular permeability, thereby identifying novel pharmacological targets for many human diseases characterized by aberrant vascular leakage.
Free Keywords:Adherens Junctions/drug effects/metabolism/pathology; Amides/pharmacology; Anaphylaxis/chemically induced/*genetics/metabolism/pathology; Animals; Capillary Permeability/drug effects; Endothelial Cells/drug effects/*metabolism/pathology; Endothelium, Vascular/drug effects/*metabolism/pathology; Female; GTP-Binding Protein alpha Subunits, Gq-G11/deficiency/genetics; Gene Expression Regulation; Histamine/*pharmacology; Humans; Male; Mice; Mice, Knockout; Phospholipase C beta/genetics/metabolism; Protein Kinase Inhibitors/pharmacology; Pyridines/pharmacology; RNA, Small Interfering/genetics/metabolism; Receptors, Histamine H1/genetics/metabolism; Signal Transduction; Skin/drug effects/metabolism/pathology; rho-Associated Kinases/antagonists & inhibitors/*genetics/metabolism; rhoA GTP-Binding Protein/deficiency/*genetics
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Department of Cell Biology, CREST-JST, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan. Intracellular Membrane Trafficking Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA. Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universitat Dresden, Dresden 01307, Germany. 1] Department of Tissue Morphogenesis, Max-Planck Institute for Molecular Biomedicine, Munster D-48149, Germany [2] Faculty of Medicine, University of Munster, Munster 48149, Germany. Department of Pharmacology, Max-Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Identifiers:ISSN:2041-1723 (Electronic) 2041-1723 (Linking) %R 10.1038/ncomms7725
URL:http://www.ncbi.nlm.nih.gov/pubmed/25857352
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