Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity.
Open accessAbstract
We have examined cytokine regulation of nitric oxide synthase (NOS) in human umbilical vein endothelial cells (HUVEC). 24-h treatment with IFN-gamma (200 U/ml) plus TNF (200 U/ml) or IL-1 beta (5 U/ml) increased NOS activity in HUVEC lysates, measured as conversion of [14C]L-arginine to [14C]L-citrulline. Essentially, all NOS activity in these cells was calcium dependent and membrane associated. Histamine-induced nitric oxide release, measured by chemiluminescence, was greater in cytokine-treated cells than in control cells. Paradoxically, steady-state mRNA levels of endothelial NOS fell by 94 +/- 2.0% after cytokine treatment. Supplementation of HUVEC lysates with exogenous tetrahydrobiopterin (3 microM) greatly increased total NOS activity, and under these assay conditions, cytokine treatment decreased maximal NOS activity. IFN-gamma plus TNF or IL-1 beta increased endogenous tetrahydrobiopterin levels and GTP cyclohydrolase I activity, the rate-limiting enzyme of tetrahydrobiopterin synthesis. Intracellular tetrahydrobiopterin levels were higher in freshly isolated HUVEC than in cultured cells, but were still limiting. We conclude that inflammatory cytokines increase NOS activity in cultured human endothelial cells by increasing tetrahydrobiopterin levels in the face of falling total enzyme; similar regulation appears possible in vivo.
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Mathematical modeling of the reaction of Hb with nitrite at different oxygen tensions yields a bell-shaped dependence of observed rates versus oxygen concentration, with maximal NO generation around 50% Hb oxygen saturation, consistent with experimental data.
“In fact, the reaction of Hb with nitrite has been modeled mathematically at different oxygen tensions. The combination of a faster rate at higher oxygen, but increased availability of deoxyHb at low oxygen, leads to bell-shaped dependence of the observed rates versus the oxygen concentration with the maximal rates of NO generation around 50% Hb oxygen saturation, consistent with experimental data”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [794]
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- Authors
- Rosenkranz-Weiss, P., Sessa, W. C., Milstien, S., Kaufman, S., Watson, C. A., & Pober, J. S.
- Affiliations
- Yale University (US)
- National Institutes of Health (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1994-05-01
- Volume
- 93
- Issue
- 5
- Pages
- 2236-2243
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC294374
- OpenAlex
- W2107947903
- Cited by
- 362
- References
- 70
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 6 · 2015: 5 · 2014: 9 · 2013: 5 · 2012: 6
- FWCI
- 19.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Patrick and Catherine Weldon Donaghue Medical Research Foundation
- Yale University
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R37HL036003, R37 HL 36003)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007556, T32 DK07556)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- nitric oxide synthase, endothelial nitric oxide synthase, tetrahydrobiopterin, inflammatory cytokines, interferon-gamma, TNF-α, IL-1β, human umbilical vein endothelial cells, GTP cyclohydrolase I, endothelial inflammation, calcium-dependent enzyme activity
- MeSH terms
- Amino Acid Oxidoreductases, Biopterins, Calcium, Cells, Cultured, Endothelium, Vascular, GTP Cyclohydrolase, Humans, Interferon-gamma, Interleukin-1, Nitric Oxide, RNA, Messenger, Tumor Necrosis Factor-alpha, Umbilical Veins, Gene Expression Regulation, Enzymologic, Cytokines, Nitric Oxide Synthase
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