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Activation of endothelial NADPH oxidase during normoxic lung ischemia is K_ATP channel dependent

Institute for Environmental Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Submitted 10 May 2005 ; accepted in final form 4 July 2005

Previous studies have shown endothelial cell membrane depolarization and generation of reactive oxygen species (ROS) in endothelial cells with abrupt reduction in shear stress (ischemia). This study evaluated the role of ATP-sensitive potassium (K_ATP) channels and NADPH oxidase in the ischemic response by using Kir6.2–/– and gp91^phox–/– mice. To evaluate ROS generation, we subjected isolated perfused mouse lungs labeled with 2',7'-dichlorodihydrofluorescein (DCF), hydroethidine (HE), or diphenyl-1-pyrenylphosphine (DPPP) to control perfusion followed by global ischemia. In wild-type C57BL/6J mice, imaging of subpleural endothelial cells showed a time-dependent increase in intensity for all three fluorescence probes with ischemia, which was blocked by preperfusion with cromakalim (a K_ATP channel agonist) or diphenyleneiodonium (DPI, a flavoprotein inhibitor). Endothelial cell fluorescence with bis-oxonol, a membrane potential probe, increased during lung ischemia indicating cell membrane depolarization. The change in membrane potential with ischemia in lungs of gp91^phox–/– mice was similar to wild type, but ROS generation did not occur. Lungs from Kir6.2–/– showed marked attenuation of the change in both membrane potential and ROS production. Thus membrane depolarization during lung ischemia requires the presence of a K_ATP channel and is required for activation of NADPH oxidase and endothelial ROS generation.

fluorescence microscopy; gp91^phox; Kir6.2; mechanotransduction; membrane depolarization; perfused lung; reactive oxygen species; shear stress; adenosine 5'-triphosphate-sensitive potassium channel; reduced nicotinamide adenine dinucleotide phosphate

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