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Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life
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.
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“was shown to downregulate NOS3 expression and abundance [123, 131-134] by decreasing the stability of NOS3 mRNA [135, 136], effectively shortening its half-life [137].”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [137]
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Arginase pathway in human endothelial cells in pathophysiological conditions
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“Inflammatory molecules are also known to negatively modulate endothelial production of NO, the most important endothelium-derived vasodilating molecule, by destabilising endothelial NOS (eNOS) mRNA [17].”
BackgroundLocal nitric oxide synthase activity in a model of neuropathic pain
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Stress activated cytokines and the heart
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Role of cytokines in heart failure
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Expression and Regulation of Endothelial Nitric Oxide Synthase
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A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock
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“These same cytokines, including tumor necrosis factor- , have been shown to attenuate eNOS expression by reductions in eNOS mRNA stability at the later time points (Yoshizumi et al., 1993).”
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“TNF reduces expression of eNOS in cultured ECs by mRNA destabilization (17) and also contributes to iNOS induction (18).”
BackgroundEndothelial Cell Dysfunction and Injury in Subarachnoid Hemorrhage
Kumar, T. P., McBride, D. W., Dash, P. K., Matsumura, K., Rubí, A. F., & Blackburn, S. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1213-7 · Cited by 102
“Further, exposure of subendothelial basement membrane collagen by contracted or desquamated ECs supports the adhesion and activation of platelets [183].”
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Roles of tumor necrosis factor p55 and p75 receptors in TNF-α-induced vascular permeability
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Intradermal Delivery of Plasmid VEGF165 by Electroporation Promotes Wound Healing
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TNF-α in the cardiovascular system: from physiology to therapy
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“TNF-α signaling suppresses gene promoter activity and destabilizes eNOS mRNA, thus reducing eNOS protein expression.(37,38) These processes are mediated by TNFR1 signaling, whereas TNFR2 has little effect on eNOS expression.”
Obesity, blood vessels and metabolic syndrome
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“Indeed, circulating TNF-a may impair vascular function by altering the balance between endothelial-derived vasodilator and vasoconstrictor substances because it downregulates the expression of eNOS (Yoshizumi et al. 1993) and upregulates ET-1 production in endothelial cells (Mohamed et al.”
Background
Metadata
- Authors
- Yoshizumi, M., Perrella, M. A., Burnett, J. C., & Lee, M. E.
- Affiliations
- Harvard University (US)
- Venue
- Circulation Research
- Published
- 1993-07
- Volume
- 73
- Issue
- 1
- Pages
- 205-209
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2145570729
- Cited by
- 771
- References
- 0
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 10 · 2022: 13 · 2021: 15 · 2020: 16 · 2019: 12 · 2018: 16 · 2017: 14 · 2016: 11 · 2015: 17 · 2014: 35 · 2013: 19 · 2012: 18
- FWCI
- 21.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- TNF-α, endothelial nitric oxide synthase, constitutive nitric oxide synthase, mRNA stability, mRNA degradation, human umbilical vein endothelial cells, atherosclerosis, cycloheximide, gene transcription
- MeSH terms
- Amino Acid Oxidoreductases, Base Sequence, Endothelium, Vascular, Half-Life, Humans, Molecular Sequence Data, RNA, Messenger, Transcription, Genetic, Tumor Necrosis Factor-alpha, Umbilical Veins, Down-Regulation, Polymerase Chain Reaction, Nitric Oxide Synthase
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