Mammalian tissues produce nitric oxide (NO) to modify proteins at heme and sulfhydryl sites, thereby regulating vital cell functions. The majority of NO produced is widely assumed to be neutralized into supposedly inert oxidation products including nitrite (NO2−). Here we show that nitrite, also ubiquitous in dietary sources, is remarkably efficient at modifying the same protein sites, and that physiological nitrite concentrations account for the basal levels of these modifications in vivo. We further find that nitrite readily affects cyclic GMP production, cytochrome P450 activities, and heat shock protein 70 and heme oxygenase-1 expression in a variety of tissues. These cellular activities of nitrite, combined with its stability and abundance in vivo, suggest that this anion has a distinct and important signaling role in mammalian biology, perhaps by serving as an endocrine messenger and synchronizing agent. Thus, nitrite homeostasis may be of great importance to NO biology.
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We wish to thank F. Saijo and D. Perlman for skillful technical assistance and M. Kelm, M. Bausero and C. Brame for helpful comments. N.S.B. and B.O.F. are recipients of the Kirschstein–National Research Service Award Cardiovascular Training Grant from the US National Institutes of Health (NIH). This work was supported in part by a grant from the NIH (HL69029 to M.F.). T.R. is a research fellow sponsored by the Deutshe Forschungsgesellschaft.
M.F. is a paid consultant and member of the Scientific Advisory Board of Nitromed, Inc.
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Bryan, N., Fernandez, B., Bauer, S. et al. Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat Chem Biol 1, 290–297 (2005). https://doi.org/10.1038/nchembio734
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