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

Autor: Friedrich Grimminger, Stefan Offermanns, Florian Veit, Beate Fuchs, Werner Seeger, Oleg Pak, Hermann Kalwa, Ajay M. Shah, Alison C. Brewer, Thomas Gudermann, Michael Mederos y Schnitzler, Norbert Weissmann, Alexander Dietrich, Karl-Heinz Krause, Akylbek Sydykov, Ralph T. Schermuly, Ursula Storch, Hossein Ardeschir Ghofrani, Harald H.H.W. Schmidt, Ralf P. Brandes, Marc Freichel, Marcel Meissner
Přispěvatelé: Pharmacology and Personalised Medicine, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Time Factors
General Physics and Astronomy
Phospholipase C gamma/metabolism
Pharmacology
ddc:616.07
TRPC6
chemistry.chemical_compound
Mice
0302 clinical medicine
Edema
Endothelial dysfunction
Lung
chemistry.chemical_classification
0303 health sciences
Membrane Glycoproteins
Multidisciplinary
NADPH oxidase
biology
TRPC Cation Channels/genetics
Superoxide
3. Good health
Biochemistry
Reperfusion Injury
NADPH Oxidase 2
NADPH Oxidase/genetics
cardiovascular system
Edema/pathology/therapy
Nicotinamide adenine dinucleotide phosphate
hormones
hormone substitutes
and hormone antagonists
circulatory and respiratory physiology
Diacylglycerol Kinase
Calcium/metabolism
Lung/pathology
Mice
Transgenic
Models
Biological
Article
General Biochemistry
Genetics and Molecular Biology
Permeability
03 medical and health sciences
TRPC6 Cation Channel
medicine
Animals
Diacylglycerol Kinase/metabolism
ddc:610
TRPC Cation Channels
030304 developmental biology
Diacylglycerol kinase
Reactive oxygen species
Phospholipase C gamma
urogenital system
Endothelial Cells
NADPH Oxidases
General Chemistry
Membrane Glycoproteins/genetics
medicine.disease
Mice
Inbred C57BL
chemistry
biology.protein
Calcium
Reactive Oxygen Species
Reperfusion injury
Endothelial Cells/cytology
030217 neurology & neurosurgery
Gene Deletion
Zdroj: Nature Communications, Vol. 3 (2012) P. 649
Nature Communications, 3. Nature Publishing Group
Nature communications
Nature Communications
ISSN: 2041-1723
Popis: 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 (Nox2y/−) 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 Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− 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.
The signalling cascade involved in lung ischaemia–reperfusion-induced oedema is poorly understood. Using knockout mice, Weissmann et al. propose a model in which reactive oxygen species production by endothelial NOX2 leads to phospholipase C-γ activation, DAG kinase inhibition and subsequent TRPC6 activation.
Databáze: OpenAIRE
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