| 15479985 |
Ichikawa H, Kokura S, Aw TY: Role of endothelial mitochondria in oxidant production and modulation of neutrophil adherence. J Vasc Res. 2004 Sep-Oct;41(5):432-44. Epub 2004 Oct 12.
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 (1) 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 (2) O (2) 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 kappaB 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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