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Lipoxygenase-dependent superoxide release in skeletal muscle.

Authors: Zuo, L  Christofi, FL  Wright, VP  Bao, S  Clanton, TL 
Citation: Zuo L, etal., J Appl Physiol. 2004 Aug;97(2):661-8. Epub 2004 Apr 23.
Pubmed: (View Article at PubMed) PMID:15107407
DOI: Full-text: DOI:10.1152/japplphysiol.00096.2004

Superoxide anion radical (O(2)(*-)) is released from skeletal muscle at rest and is particularly elevated during conditions of heat stress (42 degrees C). Previous studies have shown that in isolated rat diaphragm O(2)(*-) release is not dependent on mitochondrial electron transport, reduced NADP oxidase activity, or the integrity of membrane anion channels. This study hypothesized that O(2)(*-) release, as measured by cytochrome c reduction, is linked to metabolism of arachidonic acid. Phospholipase A(2) inhibition with manoalide significantly decreased O(2)(*-) release. In downstream pathways, neither the blockage of cyclooxygenase with indomethacin nor the inhibition of cytochrome P-450-dependent monooxygenase with SKF-525A decreased O(2)(*-) release. However, lipoxygenase (LOX) inhibition with general LOX blockers 5,8,11,14-eicosatetraynoic acid and cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate greatly attenuated the signal. Furthermore, the specific 5-LOX inhibitor diethylcarbamazine also significantly decreased O(2)(*-) release. Immunohistochemistry localized 5- and 12-LOX to the cytosol and sarcolemma of muscle cells. Confocal studies, using the O(2)(*-)-sensitive fluorescent indicator hydroethidine, demonstrated that LOX inhibition had no significant influence on intracellular O(2)(*-) formation. When compared with the cytochrome c results, this indicates that intra- and extracellular O(2)(*-) must arise from different sources. These data show for the first time that arachidonic acid metabolism through LOX activity, is a major source of extracellular O(2)(*-) release in skeletal muscle.

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CRRD Object Information
CRRD ID: 1578311
Created: 2006-03-02
Species: All species
Last Modified: 2006-03-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.