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Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice

Author

Listed:
  • Norbert Weissmann

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Akylbek Sydykov

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Hermann Kalwa

    (Institute of Pharmacology and Toxicology, School of Medicine, University of Marburg, Karl-von-Frisch-Street 1, 35033 Marburg, Germany.
    Present address: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.)

  • Ursula Storch

    (Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.)

  • Beate Fuchs

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Michael Mederos y Schnitzler

    (Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.)

  • Ralf P. Brandes

    (Vascular Research Center, Medical Faculty, J.W. Goethe University Frankfurt, Theodor-Stern Kai 7, 60596 Frankfurt/Main, Germany.)

  • Friedrich Grimminger

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Marcel Meissner

    (Experimental and Clinical Pharmacology, Medical Faculty, University of the Saarland, Universitätskliniken Geb. 46)

  • Marc Freichel

    (Experimental and Clinical Pharmacology, Medical Faculty, University of the Saarland, Universitätskliniken Geb. 46
    Present address: Institute for Pharmacology, Im Neuenheimer Feld 366, 69120 Heidelberg Germany.)

  • Stefan Offermanns

    (Max-Planck-Institut für Herz und Lungenforschung, Ludwigsstrasse 43, 61231 Bad Nauheim, Germany.)

  • Florian Veit

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Oleg Pak

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Karl-Heinz Krause

    (Geneva Faculty of Medicine, Centre Médical Universitaire, 1, rue Michel-Servet, 1211 Geneva 4, Switzerland.)

  • Ralph T. Schermuly

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Alison C Brewer

    (King's College London British Heart Foundation Centre)

  • Harald H.H.W. Schmidt

    (Universiteitssingel 50, 6229 ER Maastricht, 6200 MD Maastricht, The Netherlands.)

  • Werner Seeger

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Ajay M. Shah

    (King's College London British Heart Foundation Centre)

  • Thomas Gudermann

    (Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.)

  • Hossein A. Ghofrani

    (University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.)

  • Alexander Dietrich

    (Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.)

Abstract

Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.

Suggested Citation

  • Norbert Weissmann & Akylbek Sydykov & Hermann Kalwa & Ursula Storch & Beate Fuchs & Michael Mederos y Schnitzler & Ralf P. Brandes & Friedrich Grimminger & Marcel Meissner & Marc Freichel & Stefan Off, 2012. "Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice," Nature Communications, Nature, vol. 3(1), pages 1-10, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1660
    DOI: 10.1038/ncomms1660
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