© 1999 American Heart Association, Inc.
Original Contribution |
Anoxia/Reoxygenation-Induced Tolerance With Respect to Polymorphonuclear Leukocyte Adhesion to Cultured Endothelial Cells
A Nuclear Factor-
B–Mediated Phenomenon
From the Vascular Cell Biology Laboratory, London Health Sciences Centre-Research Inc, London, Ontario, Canada.
Correspondence to Peter R. Kvietys, PhD, Vascular Cell Biology Laboratory, London Health Sciences Centre-Research Inc, 375 South St, Room C210, London, Ontario, Canada N6A 4G5. E-mail pkvietys{at}julian.uwo.ca
Abstract—Exposing human
umbilical vein endothelial cells (HUVECs) to
anoxia/reoxygenation (A/R) results in an increase in
polymorphonuclear leukocyte (PMN) adhesion to HUVECs. This
A/R-induced hyperadhesion is completely prevented by a previous (24
hours earlier) exposure of HUVECs to A/R. This phenomenon has been
termed "A/R tolerance." Exposing HUVECs to A/R induces an increase
in nuclear factor 
B (NF-B) in HUVEC nuclei within 4 hours.
Interfering with either NF-B activation (proteasome
inhibitor) or translocation (double-stranded
oligonucleotides containing NF-B binding sequence)
prevents the development of A/R tolerance (ie, the increase in
A/R-induced PMN adhesion to HUVECs is the same after the first and
second A/R challenges). NO production by HUVECs is increased
after the second A/R challenge, but not after the first A/R challenge.
Inhibition of NO synthase (NOS) during the second A/R challenge
prevents the development of A/R tolerance with respect to PMN adhesion.
However, while HUVECs contained endothelial NOS
protein, no inducible NOS was detected in either tolerant or
nontolerant cells. Further studies indicated that inhibition of
GTP-cyclohydrolase I (an enzyme involved in de novo synthesis of an
important cofactor for NOS activity, tetrahydrobiopterin) prevented the
generation of NO in A/R-tolerant cells. Extracellular generation of NO
(NO donor) did not effect the hyperadhesion response induced by the
initial A/R challenge. A/R also induced an oxidant stress in naive
HUVECs, but not in A/R-tolerant HUVECs. Inhibition of NOS during the
second A/R insult results in the generation of an oxidant stress
similar to that observed after the first A/R challenge. Taken together,
the findings of the present study are consistent with a
role for NF-B in the development of A/R tolerance (with respect to
PMN adhesion), perhaps by transcriptional regulation of
GTP-cyclohydrolase. The increased NO production during the
second A/R insult reduces PMN adhesion most likely by reducing the
intracellular oxidant stress induced by A/R.
Key Words: nitric oxide • nitric oxide synthase • GTP-cyclohydrolase I • tetrahydrobiopterin
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