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ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinase-dependent neutrophil recruitment

ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinase-dependent neutrophil recruitment
ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinase-dependent neutrophil recruitment
Reactive oxygen species (ROS)-induced injury has been shown to occur during the reperfusion phase of ischemia–reperfusion and ROS are known to induce signaling events. We hypothesized that oxygen sensing in endothelial cells is also dependent on internal redox changes during hypoxia and that endothelial cells respond to changing oxygen environments via signaling, switching to an inflammatory phenotype. Endothelial cells exposed to relative hypoxia or the mitochondrial inhibitors rotenone, antimycin A, or FCCP show loss of mitochondrial membrane potential. During hypoxia, an increase in cytoplasmic ROS and glutathione S-transferase activity occurred, suggesting changes in intracellular redox state, mimicked with rotenone or FCCP but inhibited by antimycin A. Phosphorylation of stress-responsive mitogen-activated protein kinases occurred in hypoxia and was rapid and prolonged. Phosphorylation was inhibited by vitamin C, N-acetyl cysteine, or antimycin A. Chelation of intracellular calcium inhibits phosphorylation but the mitochondrial transition pore inhibitor cyclosporin A had no effect. Reoxygenation caused a further round of signaling, which was rapid but transient. Functionally, adhesion of neutrophils after hypoxia–reoxygenation under flow is ROS, P-selectin, and MAPK dependent. Therefore, changes in cellular signaling and phenotype are abrogated by ROS scavengers and suggest their use as therapeutic agents in ischemia–reperfusion.
endothelium, ros, map kinase, ischemia–reperfusion, free radicals
0891-5849
1165-1175
Millar, Timothy M.
ec88510c-ad88-49f6-8b2d-4277c84c1958
Phan, Van
8ddcb504-7dc0-4e81-af0e-5d2db1fa2603
Tibbles, Lee Anne
62cda21d-1dc8-4f3b-8c06-d28f73f38025
Millar, Timothy M.
ec88510c-ad88-49f6-8b2d-4277c84c1958
Phan, Van
8ddcb504-7dc0-4e81-af0e-5d2db1fa2603
Tibbles, Lee Anne
62cda21d-1dc8-4f3b-8c06-d28f73f38025

Millar, Timothy M., Phan, Van and Tibbles, Lee Anne (2007) ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinase-dependent neutrophil recruitment. Free Radical Biology & Medicine, 42 (8), 1165-1175. (doi:10.1016/j.freeradbiomed.2007.01.015). (PMID:17382198)

Record type: Article

Abstract

Reactive oxygen species (ROS)-induced injury has been shown to occur during the reperfusion phase of ischemia–reperfusion and ROS are known to induce signaling events. We hypothesized that oxygen sensing in endothelial cells is also dependent on internal redox changes during hypoxia and that endothelial cells respond to changing oxygen environments via signaling, switching to an inflammatory phenotype. Endothelial cells exposed to relative hypoxia or the mitochondrial inhibitors rotenone, antimycin A, or FCCP show loss of mitochondrial membrane potential. During hypoxia, an increase in cytoplasmic ROS and glutathione S-transferase activity occurred, suggesting changes in intracellular redox state, mimicked with rotenone or FCCP but inhibited by antimycin A. Phosphorylation of stress-responsive mitogen-activated protein kinases occurred in hypoxia and was rapid and prolonged. Phosphorylation was inhibited by vitamin C, N-acetyl cysteine, or antimycin A. Chelation of intracellular calcium inhibits phosphorylation but the mitochondrial transition pore inhibitor cyclosporin A had no effect. Reoxygenation caused a further round of signaling, which was rapid but transient. Functionally, adhesion of neutrophils after hypoxia–reoxygenation under flow is ROS, P-selectin, and MAPK dependent. Therefore, changes in cellular signaling and phenotype are abrogated by ROS scavengers and suggest their use as therapeutic agents in ischemia–reperfusion.

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More information

Published date: 15 April 2007
Keywords: endothelium, ros, map kinase, ischemia–reperfusion, free radicals

Identifiers

Local EPrints ID: 45373
URI: http://eprints.soton.ac.uk/id/eprint/45373
ISSN: 0891-5849
PURE UUID: 145ce9cf-88ee-4c05-bfc6-cd7f167a5c0d
ORCID for Timothy M. Millar: ORCID iD orcid.org/0000-0002-4539-2445

Catalogue record

Date deposited: 23 Mar 2007
Last modified: 15 Mar 2024 09:10

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Contributors

Author: Timothy M. Millar ORCID iD
Author: Van Phan
Author: Lee Anne Tibbles

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