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      Role of Endothelial Mitochondria in Oxidant Production and Modulation of Neutrophil Adherence

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          Abstract

          This study is designed to test whether the postanoxic endothelial mitochondria is an important source of reactive oxygen species (ROS) using a chemical model of mitochondrial disruption to mimic the loss of mitochondrial integrity after anoxia/reoxygenation (A/R). The current objectives were to (1) determine the adhesion of human neutrophils to human umbilical vein endothelial cells exposed to antimycin A, a specific inhibitor of the mitochondrial cytochrome b–c<sub>1</sub> complex, and (2) define the mechanisms responsible for the early and late phases of neutrophil hyperadhesivity. Antimycin A caused a 5-fold increase in ROS generation and induced neutrophil adhesion at 30 min (phase 1) and 4 h (phase 2) that were quantitatively similar to that induced by A/R. Blockade of electron transport in antimycin A and A/R exposed cells with rotenone, amytal or thenoyltrifluoroacetate, but not myxothiazol, prevented neutrophil adhesion, confirming a role for mitochondrial ROS. Catalase inhibited phase 1 adhesion, indicating H<sub>2</sub>O<sub>2</sub> involvement. Anti-ICAM-1 or anti-P-selectin monoclonal antibodies (mAbs) attenuated phase 1 adhesion, while anti-E-selectin mAb attenuated phase 2 adhesion, consistent with roles for constitutive ICAM-1 and preformed P-selectin in early and E-selectin in late phase responses. Actinomycin D and cycloheximide or competing ds-oligonucleotides containing cognate DNA sequences of the nuclear factor ĸB or activator protein-1 attenuated phase 2 adhesion, implicating a role for de novo protein synthesis. Peak surface expression of the endothelial cell adhesion molecules correlated with peak adhesions at phases 1 and 2. These results show that disruption of mitochondrial respiratory chain elicits ROS production that mediates transcription-independent and -dependent surface expression of various adhesion molecules that leads to a two-phase neutrophil-HUVEC interaction similar to that induced by A/R.

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          Most cited references 13

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          Oxygen-derived free radicals in postischemic tissue injury.

          It is now clear that oxygen-derived free radicals play an important part in several models of experimentally induced reperfusion injury. Although there are certainly multiple components to clinical ischemic and reperfusion injury, it appears likely that free-radical production may make a major contribution at certain stages in the progression of the injury. The primary source of superoxide in reperfused reoxygenated tissues appears to be the enzyme xanthine oxidase, released during ischemia by a calcium-triggered proteolytic attack on xanthine dehydrogenase. Reperfused tissues are protected in a variety of laboratory models by scavengers of superoxide radicals or hydroxyl radicals or by allopurinol or other inhibitors of xanthine oxidase. Dysfunction induced by free radicals may thus be a major component of ischemic diseases of the heart, bowel, liver, kidney, and brain.
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            Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria.

            Much evidence indicates that superoxide is generated from O2 in a cyanide-sensitive reaction involving a reduced component of complex III of the mitochondrial respiratory chain, particularly when antimycin A is present. Although it is generally believed that ubisemiquinone is the electron donor to O2, little experimental evidence supporting this view has been reported. Experiments with succinate as electron donor in the presence of antimycin A in intact rat heart mitochondria, which contain much superoxide dismutase but little catalase, showed that myxothiazol, which inhibits reduction of the Rieske iron-sulfur center, prevented formation of hydrogen peroxide, determined spectrophotometrically as the H2O2-peroxidase complex. Similarly, depletion of the mitochondria of their cytochrome c also inhibited formation of H2O2, which was restored by addition of cytochrome c. These observations indicate that factors preventing the formation of ubisemiquinone also prevent H2O2 formation. They also exclude ubiquinol, which remains reduced under these conditions, as the reductant of O2. Since cytochrome b also remains fully reduced when myxothiazol is added to succinate- and antimycin A-supplemented mitochondria, reduced cytochrome b may also be excluded as the reductant of O2. These observations, which are consistent with the Q-cycle reactions, by exclusion of other possibilities leave ubisemiquinone as the only reduced electron carrier in complex III capable of reducing O2 to O2-.
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              The effect of hyperoxia on superoxide production by lung submitochondrial particles.

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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2004
                October 2004
                19 November 2004
                : 41
                : 5
                : 432-444
                Affiliations
                Department of Molecular & Cellular Physiology, LSU Health Sciences Center, Shreveport, La., USA
                Article
                81466 J Vasc Res 2004;41:432–444
                10.1159/000081466
                15479985
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 10, Tables: 3, References: 41, Pages: 13
                Categories
                Research Paper

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