© 1995 American Heart Association, Inc.
Articles |
Lack of Role for Nitric Oxide (NO) in the Selective Destabilization of Endothelial NO Synthase mRNA by Tumor Necrosis Factor–
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993, and published in Circulation. 1993;88(suppl I, pt 2): I-273. Abstract.
From the McGill Vascular Biology Group, Divisions of Cardiology (J.C.M., D.J.S.) and Medical Biochemistry (P.C.), Department of Medicine, Royal Victoria Hospital, and McGill University (F.M., A.G., D.B.), Montreal, Quebec, Canada.
Correspondence to Dr Duncan J. Stewart, Royal Victoria Hospital, 687 Pine Ave W, Rm M4.76, Montreal, Quebec, Canada H3A 1A1.
Abstract The constitutive expression of endothelial nitric
oxide (NO) synthase (cNOS) is essential for the physiological
regulation of vascular tone and structure. The mechanism of
downregulation of steady state cNOS mRNA in human umbilical vein
endothelial cells exposed to tumor necrosis factor–
(TNF-) was
investigated by using Northern blot analysis of total cellular RNA.
TNF- produced a dose- and time-dependent decrease in cNOS mRNA
expression that was near maximal at 10 U/mL and 6 hours of exposure,
respectively. In contrast, steady state expression of endothelin-1 and
plasminogen activator inhibitor–1 (PAI-1) mRNA was upregulated by
TNF-. The pharmacological generation of NO using sodium
nitroprusside (10 µmol/L) and
S-nitroso-acetylpenicillamine (100 to 400 µmol/L) had no
effect on cNOS mRNA levels, and TNF-–induced downregulation of cNOS
was not prevented by coincubation with the inhibitors of NO synthesis
N
-nitro-L-arginine methyl ester
(1 mmol/L) and NG-monomethyl
L-arginine (10 mmol/L). Under control conditions, cNOS
and PAI-1 mRNA were stable after treatment with actinomycin D for
periods greater than 24 hours, whereas endothelin-1 message was rapidly
degraded (half-life, <1 hour). Pretreatment with TNF- (30 U/mL)
selectively reduced the half-life of cNOS mRNA to less than 12 hours
without altering the stability of PAI-1 message. TNF-–induced
destabilization of cNOS mRNA could be partially prevented by
coincubation with cycloheximide (1 µmol/L) but was not reproduced by
addition of sodium nitroprusside. These findings indicate that TNF-
downregulation of cNOS expression in human endothelial cells results
predominantly from the selective destabilization of the mRNA by a
mechanism involving the synthesis of new protein. However, NO
production by a TNF-–inducible isoform of NOS did not appear to
contribute either to the decrease in steady state cNOS mRNA levels or
the shortening of its half-life.
Key Words: cytokines • endothelin-1 • plasminogen activator inhibitor–1 • endothelium-derived relaxing factor • regulation of gene expression
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