TY - JOUR
T1 - Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice
AU - Weissmann, Norbert
AU - Sydykov, Akylbek
AU - Kalwa, Hermann
AU - Storch, Ursula
AU - Fuchs, Beate
AU - Mederos y Schnitzler, Michael
AU - Brandes, Ralf P.
AU - Grimminger, Friedrich
AU - Meissner, Marcel
AU - Freichel, Marc
AU - Offermanns, Stefan
AU - Veit, Florian
AU - Pak, Oleg
AU - Krause, Karl-Heinz
AU - Schermuly, Ralph Theo
AU - Brewer, Alison C.
AU - Schmidt, Harald H. H. W.
AU - Seeger, Werner
AU - Shah, Ajay M.
AU - Gudermann, Thomas
AU - Ghofrani, Hossein Ardeschir
AU - Dietrich, Alexander
PY - 2012/1
Y1 - 2012/1
N2 - 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-?, 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.
AB - 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-?, 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.
U2 - 10.1038/ncomms1660
DO - 10.1038/ncomms1660
M3 - Article
C2 - 22337127
SN - 2041-1723
VL - 3
SP - 649
JO - Nature Communications
JF - Nature Communications
ER -