Tetrahydropteridines suppress gene expression and induce apoptosis of activated RAW264.7 cells via formation of hydrogen peroxide

Free Radical Biology & Medicine
Guntram ThoeniGabriele Werner-Felmayer

Abstract

Tetrahydrobiopterin, a redox-active cofactor, is essential for nitric oxide (NO) biosynthesis. Previous work showed that intracellular tetrahydrobiopterin levels modulate activity of nitric oxide synthases (NOSs). The 4-amino analog of tetrahydrobiopterin is an effective inhibitor of all three purified NOS isoforms that, in intact cells, preferentially targets the inducible isoenzyme. In vivo, 4-amino-tetrahydrobiopterin prolonged allograft survival and rescued rats from septic shock. Here we investigated the effects of tetrahydrobiopterin and its 4-amino analog on RAW264.7 murine macrophages activated with lipopolysaccharide. Surprisingly, both tetrahydropteridines inhibited NO formation. This was caused by downregulation of inducible NOS expression rather than by affecting enzyme activity. In addition, expression of tumor necrosis factor-alpha was impaired, and apoptosis, as characterized by quantifying DNA content and caspase-3 activation and being associated with the formation of a 33 kDa fragment of nuclear factor-kappaB p65, was induced. The effects of tetrahydropteridines were scavenged by catalase or glutathione but not by superoxide dismutase. Like tetrahydropteridines, hydrogen peroxide at concentrations comparable to...Continue Reading

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Citations

Apr 24, 2014·The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology·Bijay AryalHyung-Gun Kim
Jun 2, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kaiwei HuangChengfeng Wu
Jun 10, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Guntram ThoeniErnst R Werner
Apr 13, 2021·Biomedical Chromatography : BMC·Yunxia YuanLongshan Zhao

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