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Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration

Nature Chemical Biology volume 8, pages 714–724 (2012)Cite this article

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Abstract

An emerging aspect of redox signaling is the pathway mediated by electrophilic byproducts, such as nitrated cyclic nucleotide (for example, 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP)) and nitro or keto derivatives of unsaturated fatty acids, generated via reactions of inflammation-related enzymes, reactive oxygen species, nitric oxide and secondary products. Here we report that enzymatically generated hydrogen sulfide anion (HS−) regulates the metabolism and signaling actions of various electrophiles. HS− reacts with electrophiles, best represented by 8-nitro-cGMP, via direct sulfhydration and modulates cellular redox signaling. The relevance of this reaction is reinforced by the significant 8-nitro-cGMP formation in mouse cardiac tissue after myocardial infarction that is modulated by alterations in HS− biosynthesis. Cardiac HS−, in turn, suppresses electrophile-mediated H-Ras activation and cardiac cell senescence, contributing to the beneficial effects of HS− on myocardial infarction–associated heart failure. Thus, this study reveals HS−-induced electrophile sulfhydration as a unique mechanism for regulating electrophile-mediated redox signaling.

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Figure 1: Regulation of 8-nitro-cGMP–induced protein S-guanylation by HS−-producing enzymes via sulfhydration of 8-nitro-cGMP by HS−.
Figure 2: Electrophile sulfhydration by HS−.
Figure 3: Cellular formation of 8-SH-cGMP and its metabolic fate.
Figure 4: Cellular HS− formation and its physiological relevance to electrophile metabolism.
Figure 5: Electrophilic H-Ras activation regulated by HS− in cells and in vivo in cardiac tissues.
Figure 6: HS− regulation of H-Ras electrophile sensing and signaling.
Figure 7: 8-Nitro-cGMP–induced H-Ras activation in cardiac cells and their suppression by HS−.
Figure 8: Dissociation of H-Ras from rafts and its activation induced by H-Ras Cys184 S-guanylation.

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Acknowledgements

We thank J.B. Gandy for her editing of the manuscript. Thanks are also due to T. Okamoto, S. Fujii, Md. M. Rahaman, S. Khan, K.A. Ahmed, J. Yoshitake, T. Matsunaga, M.H.A. Rahman, J. Sakamoto, J. Minkyung, K. Hara, M. Goto, F. Sohma, K. Taguchi, T. Miura, T. Toyama, Y. Shinkai, I. Ishii and M. Toyataka for technical assistance; S. Kasamatsu, T. Ida and K. Kunieda for 8-nitro-cGMP preparation; Y. Kawai for technical assistance with LC/MS/MS experiments; H. Arimoto for helpful discussion; and J. Wu for reading our paper to evaluate its concepts and interdisciplinary accessibility. This work was supported in part by Grants-in-Aid for Scientific Research and Grants-in-Aid for Scientific Research on Innovative Areas (Research in a Proposed Area) from the Ministry of Education, Sciences, Sports and Technology, Japan; a grant from the Japan Science and Technology Agency PRESTO program; grants from the Ministry of Health, Labor and Welfare of Japan; and grants from the US National Institutes of Health.

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Author notes

  1. Motohiro Nishida and Tomohiro Sawa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Motohiro Nishida, Naoyuki Kitajima & Hitoshi Kurose

  2. Department of Drug Discovery and Evolution, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Motohiro Nishida & Naoyuki Kitajima

  3. Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Tomohiro Sawa, Katsuhiko Ono, Hirofumi Inoue & Takaaki Akaike

  4. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

    Tomohiro Sawa

  5. Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Osaka, Japan

    Hideshi Ihara

  6. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

    Hozumi Motohashi & Masayuki Yamamoto

  7. Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan

    Makoto Suematsu

  8. Department of Pathology, University of Vermont, Burlington, Vermont, USA

    Albert van der Vliet

  9. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Bruce A Freeman

  10. Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan

    Takahiro Shibata & Koji Uchida

  11. Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

    Yoshito Kumagai

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Contributions

M.N., T.A. and T. Sawa designed the experiment, performed analysis and wrote the paper; N.K., H. Inoue and T. Shibata performed MS analysis, cell biology and mouse and rat studies; K.O., H. Ihara, H.M., H.K., M.S. and M.Y. performed data analyses; B.A.F., A.v.d.V., K.U. and Y.K. designed the experiment and edited the paper.

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Correspondence to Takaaki Akaike.

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B.A.F. acknowledges financial interests in Complexa, Inc.

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Nishida, M., Sawa, T., Kitajima, N. et al. Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. Nat Chem Biol 8, 714–724 (2012). https://doi.org/10.1038/nchembio.1018

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