Activation of TRPC6 Channels Is Essential for Lung Ischaemia–Reperfusion Induced Oedema in Mice

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Activation of TRPC6 Channels Is Essential for Lung Ischaemia–Reperfusion Induced Oedema in Mice

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dc.contributor.author Weissmann, Norbert
dc.contributor.author Sydykov, Akylbek
dc.contributor.author Storch, Ursula
dc.contributor.author Fuchs, Beate
dc.contributor.author Schnitzler, Michael Mederos y
dc.contributor.author Brandes, Ralf P.
dc.contributor.author Grimminger, Friedrich
dc.contributor.author Meissner, Marcel
dc.contributor.author Freichel, Marc
dc.contributor.author Offermanns, Stefan
dc.contributor.author Veit, Florian
dc.contributor.author Pak, Oleg
dc.contributor.author Krause, Karl-Heinz
dc.contributor.author Schermuly, Ralph T.
dc.contributor.author Brewer, Alison C
dc.contributor.author Schmidt, Harald H.H.W.
dc.contributor.author Seeger, Werner
dc.contributor.author Gudermann, Thomas
dc.contributor.author Ghofrani, Hossein A.
dc.contributor.author Dietrich, Alexander
dc.contributor.author Kalwa, Hermann H
dc.contributor.author Shah, Ajay Mukesh
dc.date.accessioned 2012-04-19T18:45:23Z
dc.date.issued 2012
dc.identifier.citation Weissmann, Norbert, Akylbek Sydykov, Hermann Kalwa, Ursula Storch, Beate Fuchs, Michael Mederos y Schnitzler, Ralf P. Brandes, et al. 2012. Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice. Nature Communications 3:649. en_US
dc.identifier.issn 2041-1723 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8603136
dc.description.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. en_US
dc.language.iso en_US en_US
dc.publisher Nature Publishing Group en_US
dc.relation.isversionof doi://10.1038/ncomms1660 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272568/pdf/ en_US
dash.license LAA
dc.title Activation of TRPC6 Channels Is Essential for Lung Ischaemia–Reperfusion Induced Oedema in Mice en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Nature Communications en_US
dash.depositing.author Kalwa, Hermann H
dc.date.available 2012-04-19T18:45:23Z

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