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

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

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