Abstract
Background: Adenosine prevents myocardial TNF-α production induced by ischemia/reperfusion, but
the mechanisms are poorly understood. Transcription factors NF-κB and AP-1 have been
implicated in the regulation of a variety of inducible gene expressions in response
to oxidative stress and cellular defense. The effects of adenosine on NF-κB and AP-1
activation have not been clearly defined. This study demonstrated differential effects
of adenosine on NF-κB and AP-1 nuclear binding activity in ischemic myocardium. Methods: Isolated working rat hearts were subjected to 0, 1, 2, 3, 4, 5, 7.5, 10, 15, and
30 minutes of ischemia, with 4 to 6 hearts for each time point with and without adenosine
(100 μmol/L). NF-κB and AP-1 binding activity in the nucleus were analyzed by electrophoretic
mobility shift assay (EMSA). IκBα levels in the cytoplasm were measured by Western
blot analysis. TNF-α mRNA levels were determined by RT-PCR. Results: NF-κB binding activity in the nucleus significantly increased after 4 minutes of
ischemia and remained to 30 minutes. The levels of IκBα protein in the cytoplasm markedly
decreased after 4, 5, 7.5, and 10 minutes of ischemia. TNF-α mRNA levels peaked after
10 minutes of ischemia. AP-1 DNA binding activity was induced and persisted during
all ischemic periods. Adenosine significantly inhibited NF-κB binding activity in
the nucleus, markedly prevented the loss of IκBα proteins from the cytoplasm, and
concomitantly down-regulated TNF-α mRNA expression, but enhanced AP-1 binding activity
in the nucleus of ischemic myocardium. Conclusions: Adenosine modulation of NF-κB activation may be the cellular molecular mechanism
of down-regulation of TNF-α mRNA expression. The cardioprotective properties of adenosine
may be involved in the differential modulation of NF-κB and AP-1 activation during
myocardial ischemia. (Surgery 2000;127:161-9.)
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Article info
Publication history
Accepted:
July 3,
1999
Footnotes
*Supported in part by NIH Grant HL54286, a VA Merit Review Grant, and a Cardiovascular Research Institute Grant of East Tennessee State University.
**Reprint requests: Race L. Kao, PhD, Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, P.O. Box 70575, Johnson City, TN 37614-0575.
Identification
Copyright
© 2000 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
