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MBC in Press, published online ahead of print March 14, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0830

A more recent version of this article appeared on June 1, 2007
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Submitted on September 18, 2006
Revised on January 10, 2007
Accepted on March 2, 2007

Superoxide Flux in Endothelial Cells via the Chloride Channel-3 Mediates Intracellular Signaling

Brian J. Hawkins,* Muniswamy Madesh,* C. J. Kirkpatrick,{dagger} and Aron B. Fisher*

*Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA 19104; {dagger}Institute of Pathology, Johannes-Gutenberg University, D-55101 Mainz, Germany

Monitoring Editor: John Cleveland

Reactive oxygen species (ROS) have been implicated in both cell signaling and pathology. A major source of ROS in endothelial cells is NADPH oxidase, which generates superoxide (O2·-) on the extracellular side of the plasma membrane but can result in intracellular signaling. To study possible transmembrane flux of O2·-, pulmonary microvascular endothelial cells were pre-loaded with the O2·--sensitive fluorophore hydroethidine (HE). Application of an extracellular bolus of O2·- resulted in rapid and concentration-dependent transient HE oxidation that was followed by a progressive and nonreversible increase in nuclear HE fluorescence. These fluorescence changes were inhibited by superoxide dismutase (SOD), the anion channel blocker DIDS, and selective silencing of the chloride channel-3 (ClC-3) by treatment with siRNA. Extracellular O2·- triggered Ca2+ release in turn triggered mitochondrial membrane potential alterations that were followed by mitochondrial O2·- production and cellular apoptosis. These ‘signaling’ effects of O2·- were prevented by DIDS treatment, by depletion of intracellular Ca2+ stores with thapsigargin, and by chelation of intracellular Ca2+. This study demonstrates that O2·- flux across the endothelial cell plasma membrane occurs through ClC-3 channels and induces intracellular Ca2+ release which activates mitochondrial O2·- generation.

Address correspondence to: Aron B. Fisher (abf{at}mail.med.upenn.edu)




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