Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Werner-Felmayer, G; Werner, ER; Fuchs, D; Hausen, A; Reibnegger, G; Schmidt, K; Weiss, G; Wachter, H.
Pteridine biosynthesis in human endothelial cells. Impact on nitric oxide-mediated formation of cyclic GMP.
J Biol Chem. 1993; 268(3):1842-1846
Doi: 10.1016/S0021-9258(18)53931-4
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- Co-Autor*innen der Med Uni Graz
- Reibnegger Gilbert
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- Abstract:
- Stimulation of nitric oxide (NO) synthase in endothelial cells by Ca2+ influx leads to increased intracellular levels of cGMP. NO synthase from various sources is known to use tetrahydrobiopterin, flavins, and NADPH as cofactors. We studied the effect of interferon-gamma, tumor necrosis factor-alpha, and lipopolysaccharide on tetrahydrobiopterin biosynthetic activities in human umbilical vein endothelial cells (HUVEC). These stimuli led to an up to 40-fold increase of GTP cyclohydrolase I (EC 3.5.4.16) activity and to increased accumulation of neopterin and tetrahydrobiopterin in HUVEC. Further enzyme activities of tetrahydrobiopterin biosynthesis, i.e. 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153), remained unchanged. NO synthase activity in protein fractions from homogenates of cells treated with interferon-gamma plus tumor necrosis factor-alpha was not influenced as compared with untreated controls. However, interferon-gamma alone or in combination with tumor necrosis factor-alpha significantly increased intracellular cGMP formation in intact HUVEC by 50 and 80%, respectively. These stimuli increased intracellular tetrahydrobiopterin concentrations up to 14-fold. NO-triggered cGMP formation was similarly increased by incubation of otherwise untreated cells with sepiapterin, leading to elevated intracellular tetrahydrobiopterin levels. Thus, cytokines indirectly stimulate the activity of constitutive NO synthase in HUVEC by upregulating production of the cofactor tetrahydrobiopterin.
- Find related publications in this database (using NLM MeSH Indexing)
- Amino Acid Oxidoreductases - metabolism
- Biopterin - analogs and derivatives
- Cells, Cultured - analogs and derivatives
- Cyclic GMP - biosynthesis
- Endothelium, Vascular - metabolism
- GTP Cyclohydrolase - metabolism
- Humans - metabolism
- Hypoxanthines - pharmacology
- Interferon Type II - pharmacology
- Lipopolysaccharides - pharmacology
- Neopterin - pharmacology
- Nitric Oxide - metabolism
- Nitric Oxide Synthase - metabolism
- Pteridines - pharmacology
- Pterins - pharmacology
- Tumor Necrosis Factor-alpha - pharmacology
- Umbilical Veins - pharmacology