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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Title: Activation of TRPC6 Channels Is Essential for Lung Ischaemia–Reperfusion Induced Oedema in Mice
Author: Weissmann, Norbert; Sydykov, Akylbek; Storch, Ursula; Fuchs, Beate; Schnitzler, Michael Mederos y; 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; Gudermann, Thomas; Ghofrani, Hossein A.; Dietrich, Alexander; Kalwa, Hermann H; Shah, Ajay Mukesh

Note: Order does not necessarily reflect citation order of authors.

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.
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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.
Published Version: doi://10.1038/ncomms1660
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272568/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:8603136

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