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

Weissmann, Norbert
Sydykov, Akylbek
Kalwa, Hermann
Storch, Ursula
Fuchs, Beate
Mederos y Schnitzler, Michael
Brandes, Ralf P
Grimminger, Friedrich
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Published in Nature communications. 2012, vol. 3, 649
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.
Keywords AnimalsCalcium/metabolismDiacylglycerol Kinase/metabolismEdema/pathology/therapyEndothelial Cells/cytologyGene DeletionLung/pathologyMembrane Glycoproteins/geneticsMiceMice, Inbred C57BLMice, TransgenicModels, BiologicalNADPH Oxidase/geneticsPermeabilityPhospholipase C gamma/metabolismReactive Oxygen SpeciesReperfusion InjuryTRPC Cation Channels/geneticsTime Factors
PMID: 22337127
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Research group Radicaux libres et cellules souches embryonnaires (60)
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WEISSMANN, Norbert et al. Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice. In: Nature communications, 2012, vol. 3, p. 649. doi: 10.1038/ncomms1660 https://archive-ouverte.unige.ch/unige:32460

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Deposited on : 2013-12-18

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