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PMID: 22337127 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature communications ·Vol. 3 ·2012-01-31 ·Pages 649

Weissmann N, Sydykov A, Kalwa H, Storch U, Fuchs B, Mederos y Schnitzler M, Brandes RP, Grimminger F, Meissner M, Freichel M, Offermanns S, Veit F, Pak O, Krause KH, Schermuly RT, Brewer AC, Schmidt HH, Seeger W, Shah AM, Gudermann T, Ghofrani HA, Dietrich A

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 (Nox2(y/-)) 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 Ca(2+) influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2(y/-) 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.

MeSH Terms
Animals Calcium/metabolism Diacylglycerol Kinase/metabolism Edema/pathology,therapy Endothelial Cells/cytology Gene Deletion Lung/pathology Membrane Glycoproteins/genetics Mice Mice, Inbred C57BL Mice, Transgenic Models, Biological NADPH Oxidase 2 NADPH Oxidases/genetics Permeability Phospholipase C gamma/metabolism Reactive Oxygen Species Reperfusion Injury TRPC Cation Channels/genetics TRPC6 Cation Channel Time Factors
Chemicals
Membrane Glycoproteins Reactive Oxygen Species TRPC Cation Channels TRPC6 Cation Channel Trpc6 protein, mouse Cybb protein, mouse NADPH Oxidase 2 NADPH Oxidases Diacylglycerol Kinase Phospholipase C gamma Calcium
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Weissmann Norbert
Department of Internal Medicine II/V, University of Giessen Lung Center, Klinikstrasse 36, 35392 Giessen, Germany. Norbert.Weissmann@innere.med.uni-giessen.de
Sydykov Akylbek
Kalwa Hermann
Storch Ursula
Fuchs Beate
Mederos y Schnitzler Michael
Brandes Ralf P
Grimminger Friedrich
Meissner Marcel
Freichel Marc
Offermanns Stefan
Veit Florian
Pak Oleg
Krause Karl-Heinz
Schermuly Ralph T
Brewer Alison C
Schmidt Harald H H W
Seeger Werner
Shah Ajay M
Gudermann Thomas
Ghofrani Hossein A
Dietrich Alexander
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms1660
Email
norbert.weissmann@innere.med.uni-giessen.de
Published
2012-01-31
Epub
2012-00-31
Pages
649
Language
English
Region
England
NLM ID
101528555
PMCID
PMC3272568
Subset
IM
Grants
British Heart Foundation · RG/08/011/25922 · United Kingdom
External Links
PubMed source DOI: 10.1038/ncomms1660 PMC Full Text View journal details
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