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) 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.
Kim
K S
KS
Cardiology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Takeda
K
K
Sethi
R
R
Pracyk
J B
JB
Tanaka
K
K
Zhou
Y F
YF
Yu
Z X
ZX
Ferrans
V J
VJ
Bruder
J T
JT
Kovesdi
I
I
Irani
K
K
Goldschmidt-Clermont
P
P
Finkel
T
T
D000332:Aerobiosis; D000693:Anaerobiosis; D000818:Animals; D001011:Aorta / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016166:Free Radical Scavengers; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015427:Reperfusion Injury / Q000517:prevention & control; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology; D020744:rac GTP-Binding Proteins; D018631:ras Proteins / Q000378:metabolism
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D018631:ras Proteins; D010100:Oxygen