Protection from reoxygenation injury by inhibition of rac1

We demonstrate that adenoviral-mediated gene transfer of a dominant negative rac1 gene product (N17rac1) inhibits the intracellular burst of reactive oxygen species (ROS) that occurs after reoxygenation of vascular smooth muscle cells. In contrast, expression of a dominant negative ras gene (N17ras)...

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Bibliographic Details
Published in:The Journal of clinical investigation 1998-05, Vol.101 (9), p.1821-1826
Main Authors: Kim, K S, Takeda, K, Sethi, R, Pracyk, J B, Tanaka, K, Zhou, Y F, Yu, Z X, Ferrans, V J, Bruder, J T, Kovesdi, I, Irani, K, Goldschmidt-Clermont, P, Finkel, T
Format: Article
Language:English
Subjects:
Aerobiosis
Anaerobiosis
Animals
Aorta - cytology
Cell Death - drug effects
Cells, Cultured
Free Radical Scavengers
GTP-Binding Proteins - antagonists & inhibitors
GTP-Binding Proteins - genetics
Humans
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - pathology
Oxygen - pharmacology
rac GTP-Binding Proteins
ras Proteins - metabolism
Rats
Reactive Oxygen Species - metabolism
Recombinant Proteins - antagonists & inhibitors
Reperfusion Injury - prevention & control
Signal Transduction
Umbilical Veins - cytology
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Summary:We demonstrate that adenoviral-mediated gene transfer of a dominant negative rac1 gene product (N17rac1) inhibits the intracellular burst of reactive oxygen species (ROS) that occurs after reoxygenation of vascular smooth muscle cells. In contrast, expression of a dominant negative ras gene (N17ras) had no effect. Challenge of control cells and cells expressing N17rac1 with a direct oxidant stress produced an equivalent increase in intracellular ROS levels and subsequent cell death. This suggests that N17rac1 expression appears to block production of harmful oxygen radicals and does not act directly or indirectly to scavenge ROS generated during reoxygenation. Expression of N17rac1 results in protection from hypoxia/reoxygenation-induced cell death in a variety of cell types including vascular smooth muscle cells, fibroblasts, endothelial cells, and ventricular myocytes. These results suggest that reoxygenation injury requires the activation of rac proteins, and that inhibition of rac-dependent pathways may be a useful strategy for the prevention of reperfusion injury in ischemic tissues.
ISSN:0021-9738
DOI:10.1172/jci1830