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ARTICLES

Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life.

M Yoshizumi, M A Perrella, J C Burnett, M E Lee
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https://doi.org/10.1161/01.RES.73.1.205
Circulation Research. 1993;73:205-209
Originally published July 1, 1993
M Yoshizumi
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115.
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M A Perrella
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115.
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J C Burnett
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115.
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M E Lee
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115.
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Abstract

Nitric oxide (NO), which accounts for the biological properties of endothelium-derived relaxing factor, is generated by NO synthase (NOS). The vascular endothelium contains two types of NOS: one is constitutively expressed (cNOS), and the other is inducible. Endothelium-mediated vasorelaxation is impaired in atherosclerotic vessels. To determine whether tumor necrosis factor (TNF)-alpha, which is commonly found in atherosclerotic lesions, has an effect on NOS message, we measured cNOS mRNA levels in TNF-treated human umbilical vein endothelial cells (HUVECs) by RNA blot analysis with a cNOS cDNA probe. TNF-alpha markedly reduced cNOS mRNA levels in HUVECs in a dose- and time-dependent manner. In response to 3 ng/mL TNF-alpha, cNOS mRNA levels began to decrease at 4 hours and diminished to only 5% of control levels at 24 hours. As little as 0.1 ng/mL TNF-alpha reduced cNOS mRNA levels by 50%. This reduction in cNOS message in response to TNF-alpha depended on protein synthesis as it was blocked by cycloheximide. In nuclear runoff experiments, TNF-alpha did not change the rate of cNOS gene transcription. cNOS mRNA is very stable under basal conditions, with a half-life of 48 hours; however, treatment with TNF-alpha shortened this half-life to 3 hours. TNF-alpha thus appears to decrease cNOS mRNA levels by increasing the rate of mRNA degradation. TNF-induced reductions in cNOS mRNA levels may have an important effect on impaired endothelium-mediated vasorelaxation in atherosclerosis.

  • Copyright © 1993 by American Heart Association
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July 1, 1993, Volume 73, Issue 1
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    Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life.
    M Yoshizumi, M A Perrella, J C Burnett and M E Lee
    Circulation Research. 1993;73:205-209, originally published July 1, 1993
    https://doi.org/10.1161/01.RES.73.1.205

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    Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life.
    M Yoshizumi, M A Perrella, J C Burnett and M E Lee
    Circulation Research. 1993;73:205-209, originally published July 1, 1993
    https://doi.org/10.1161/01.RES.73.1.205
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