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Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues

Nature Chemical Biology volume 1, pages 290–297 (2005)Cite this article

Abstract

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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Figure 1: Distribution kinetics of nitrite and nitrite-related nitrosation/nitrosylation and oxidation products after i.p. administration of 1.0 mg kg−1 nitrite in vivo.
Figure 2: Dose-dependent effects on nitrosation/nitrosylation, blood pressure and platelet aggregation upon nitrite administration.
Figure 3: Modulation of key signaling pathways in vivo by nitrite.
Figure 4: In vitro handling of nitrite in representative compartments.
Figure 5: Changes in steady-state concentrations of nitrite in blood and tissues and accompanying changes in basal cGMP levels, cytochrome P450 activity and Hsp70/HO-1 expression upon acute nitrite depletion.

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Acknowledgements

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.

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Author notes

  1. Tienush Rassaf

    Present address: Division of Cardiology, Pulmonary Diseases and Angiology, Department of Medicine, Heinrich-Heine University, Düsseldorf, Germany

Authors and Affiliations

  1. Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, 02118, Massachusetts, USA

    Nathan S Bryan, Bernadette O Fernandez, Selena M Bauer, Maria Francisca Garcia-Saura, Alexandra B Milsom & Martin Feelisch

  2. Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, 71130, Louisiana, USA

    Tienush Rassaf, Ronald E Maloney & Juan Rodriguez

  3. Center for Molecular Stress Response, Boston University School of Medicine, Boston, 02118, Massachusetts, USA

    Ajit Bharti

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Correspondence to Martin Feelisch.

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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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