© 2000 American Heart Association, Inc.
Molecular Medicine |
Transcriptional and Posttranscriptional Regulation of Endothelial Nitric Oxide Synthase Expression by Hydrogen Peroxide
From the Division of Cardiology, Emory University, Atlanta, Ga.
Correspondence to David G. Harrison, Division of Cardiology, Emory University, 1639 Pierce Dr, Atlanta, GA 30322. E-mail dharr02{at}emory.edu
Abstract—Diverse stimuli,
including shear stress, cyclic strain, oxidized LDL, hyperglycemia, and
cell growth, modulate endothelial nitric oxide synthase
(eNOS) expression. Although seemingly unrelated, these may all alter
cellular redox state, suggesting that reactive oxygen intermediates
might modulate eNOS expression. The present study was designed to
test this hypothesis. Exposure of bovine aortic
endothelial cells for 24 hours to paraquat, a
superoxide (O2-·)–generating compound,
did not affect eNOS mRNA levels. However, cotreatment with paraquat and
either Cu2+/Zn2+ superoxide dismutase or the
superoxide dismutase mimetic tetrakis(4-benzoic acid)porphyrin chloride
increased eNOS mRNA by 2.3- and 2.2-fold, respectively, implicating a
role for H2O2. Direct addition of 100 and
150 µmol/L H2O2 caused increases in
bovine aortic endothelial cell eNOS mRNA that were
dependent on concentration (ie, 3.1- and 5.2-fold increases) and time,
and elevated eNOS protein expression and enzyme activity, accordingly.
Nuclear run-on and
5,6-dichloro-1-ß-D-ribofuranosylbenzimidazole–chase
studies showed that H2O2 caused a 3.0-fold
increase in eNOS gene transcription and a 2.8-fold increase in eNOS
mRNA half-life. Induction of eNOS by H2O2 was
not affected by the hydroxyl radical scavenger DMSO, mannitol, or
N-tert-butyl-
-phenylnitrone, but it was inhibited by
the antioxidants N-acetylcysteine, ebselen, and
exogenously added catalase. Unlike H2O2, the
4.0-fold induction of eNOS by shear stress (15 dyne/cm2 for
6 hours) was not inhibited by N-acetylcysteine or
exogenous catalase. In conclusion, H2O2
increases eNOS expression through transcriptional and
post-transcriptional mechanisms. Although H2O2
does not mediate shear-dependent eNOS regulation, it is likely to be
involved in regulation of eNOS expression in response to other
physiological and/or pathophysiological
stimuli.
Key Words: paraquat • superoxide dismutase • eNOS mRNA stability • cultured endothelial cells
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