Nitroglycerin-Induced S-nitrosylation and Desensitization of Soluble Guanylyl Cyclase Contribute to Nitrate Tolerance
Open accessAbstract
Nitrates such as nitroglycerin (GTN) and nitric oxide donors such as S-nitrosothiols are clinically vasoactive through stimulation of soluble guanylyl cyclase (sGC), which produces the second messenger cGMP. Development of nitrate tolerance, after exposure to GTN for several hours, is a major drawback to a widely used cardiovascular therapy. We recently showed that exposure to nitric oxide and to S-nitrosothiols causes S-nitrosylation of sGC, which directly desensitizes sGC to stimulation by nitric oxide. We tested the hypothesis that desensitization of sGC by S-nitrosylation is a mechanism of nitrate tolerance. Our results established that vascular tolerance to nitrates can be recapitulated in vivo by S-nitrosylation through exposure to cell membrane-permeable S-nitrosothiols and that sGC is S-nitrosylated and desensitized in the tolerant, treated tissues. We next determined that (1) GTN treatment of primary aortic smooth muscle cells induces S-nitrosylation of sGC and its desensitization as a function of GTN concentration; (2) S-nitrosylation and desensitization are prevented by treatment with N-acetyl-cysteine, a precursor of glutathione, used clinically to prevent development of nitrate tolerance; and (3) S-nitrosylation and desensitization are reversed by cessation of GTN treatment. Finally, we demonstrated that in vivo development of nitrate tolerance and crosstolerance by 3-day chronic GTN treatment correlates with S-nitrosylation and desensitization of sGC in tolerant tissues. These results suggest that in vivo nitrate tolerance is mediated, in part, by desensitization of sGC through GTN-dependent S-nitrosylation.
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Topiroxostat is a potent inhibitor of XO and induces a covalent modification in the enzyme that inactivates XO after complex dissociation.
“Topiroxostat is a potent inhibitor of XO and induces a covalent modification in the enzyme that inactivates XO after complex dissociation (629, 703, 821).”
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Cites
Nitric Oxide and Peroxynitrite in Health and Disease
Pacher, P., Beckman, J. S., & Liaudet, L. (2007) · Physiological Reviews · doi:10.1152/physrev.00029.2006 · Cited by 6,390 · see citing works
Ignarro, L. J., Lippton, H., Edwards, J. C., Baricos, W. H., Hyman, A. L., Kadowitz, P. J., & Gruetter, C. A. (1981) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)32738-2 · Cited by 1,633 · see citing works
Protein S-nitrosylation: a physiological signal for neuronal nitric oxide
Jaffrey, S. R., Erdjument‐Bromage, H., Ferris, C. D., Tempst, P., & Snyder, S. H. (2001) · Nature Cell Biology · doi:10.1038/35055104 · Cited by 1,402 · see citing works
The Biotin Switch Method for the Detection of S -Nitrosylated Proteins
Jaffrey, S. R., & Snyder, S. H. (2001) · Science s STKE · doi:10.1126/stke.2001.86.pl1 · Cited by 805 · see citing works
Katsuki, S., Arnold, W. P., Mittal, C. K., & Murad, F. (1977) · PubMed · Cited by 701 · see citing works
Interactions of Peroxynitrite, Tetrahydrobiopterin, Ascorbic Acid, and Thiols
Kuzkaya, N., Weissmann, N., Harrison, D. G., & Dikalov, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302227200 · Cited by 692 · see citing works
Münzel, T. F., Sayegh, H. S., Freeman, B. Α., Tarpey, M. M., & Harrison, D. G. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117637 · Cited by 654 · see citing works
Identification of the enzymatic mechanism of nitroglycerin bioactivation
Chen, Z., Zhang, J., & Stamler, J. S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122225199 · Cited by 541 · see citing works
Explaining the Phenomenon of Nitrate Tolerance
Münzel, T., Daiber, A., & Mülsch, A. (2005) · Circulation Research · doi:10.1161/01.res.0000184694.03262.6d · Cited by 424 · see citing works
The Biochemistry and Physiology of S-Nitrosothiols
Hogg, N. (2002) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.42.092501.104328 · Cited by 412 · see citing works
Nitrate Therapy for Stable Angina Pectoris
Parker, J. D., & Parker, J. O. (1998) · New England Journal of Medicine · doi:10.1056/nejm199802193380807 · Cited by 366 · see citing works
Mecanismos de lesión hepatocelular
Muntané, J., González, R., Ranchal, I., Collado, J. A., Lopez-Sanchez, L. M., Herencia, C., Rodríguez‐Ariza, A., Muñoz-Castañeda, J. R., & de la Mata, M. (2007) · Revista Española de Enfermedades Digestivas · doi:10.4321/s1130-01082007000700007 · Cited by 349 · see citing works
Sydow, K., Daiber, A., Oelze, M., Chen, Z., August, M., Wendt, M., Ullrich, V., Mülsch, A., Schulz, E., Keaney, J. F., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200419267 · Cited by 300 · see citing works
Scharfstein, J., Keaney, J. F., Slivka, A., Welch, G. N., Vita, J. A., Stamler, J. S., & Loscalzo, J. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117480 · Cited by 288 · see citing works
Mechanisms of Liver Injury. III. Role of glutathione redox status in liver injury
Han, D., Hanawa, N., Saberi, B., & Kaplowitz, N. (2006) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00001.2006 · Cited by 281 · see citing works
SULFHYDRYL REQUIREMENT FOR RELAXATION OF VASCULAR SMOOTH MUSCLE
Needleman, P., Jakschik, B. A., & Johnson, E. M. (1973) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)29678-1 · Cited by 253 · see citing works
Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation
Sayed, N., Baskaran, P., Ma, X., van den Akker, F., & Beuve, A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703944104 · Cited by 221 · see citing works
Self-citationKim, D., Rybalkin, S. D., Pi, X., Wang, Y., Zhang, C., Münzel, T. F., Beavo, J. A., Berk, B. C., & Chen, Y. (2001) · Circulation · doi:10.1161/hc4401.098432 · Cited by 196 · see citing works
Self-citationPossible involvement of S‐nitrosothiols in the activation of guanylate cyclase by nitroso compounds
Ignarro, L. J., Edwards, J. C., Gruetter, D. Y., Barry, B. K., & Gruetter, C. A. (1980) · FEBS Letters · doi:10.1016/0014-5793(80)80091-3 · Cited by 174 · see citing works
Axelsson, K. L., & Andersson, R. G. G. (1983) · European Journal of Pharmacology · doi:10.1016/0014-2999(83)90393-x · Cited by 140 · see citing works
Mülsch, A., Oelze, M. W., Klöss, S., Mollnau, H., Töpfer, A., Smolenski, A., Walter, U., Stasch, J., Warnholtz, A., Hink, U., et al. (2001) · Circulation · doi:10.1161/01.cir.103.17.2188 · Cited by 133 · see citing works
Molina, C. R., Andresen, J. W., Rapoport, R. M., Waldman, S. A., & Murad, F. (1987) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-198710000-00001 · Cited by 128 · see citing works
Detection and proteomic identification of S-nitrosylated proteins in endothelial cells
Martı́nez-Ruiz, A., & Lamas, S. (2004) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2003.12.006 · Cited by 120 · see citing works
Biochemical Mechanism of Nitroglycerin Action and Tolerance: Is This Old Mystery Solved?
Fung, H. (2004) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121646 · Cited by 117 · see citing works
Prevention and Reversal of Tolerance to Nitroglycerine with N-Acetylcysteine
Torresi, J., Horowitz, J. D., & Dusting, G. J. (1985) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-198507000-00024 · Cited by 110 · see citing works
Clinical Pharmacokinetics and Pharmacodynamics of Glyceryl Trinitrate and its Metabolites
Hashimoto, S., & Kobayashi, A. (2003) · Clinical Pharmacokinetics · doi:10.2165/00003088-200342030-00001 · Cited by 97 · see citing works
Janero, D. R., Bryan, N. S., Saijo, F., DHAWAN, V. M., Schwalb, D. J., Warren, M. C., & Feelisch, M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0406075101 · Cited by 87 · see citing works
Bauer, J. A., & Fung, H. L. (1990) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)23090-7 · Cited by 84 · see citing works
Lamothe, M., Chang, F., Balashova, N. V., Shirokov, R. E., & Beuve, A. V. (2004) · Biochemistry · doi:10.1021/bi0360051 · Cited by 82 · see citing works
Self-citationKim, D. D., Sánchez, F. A., Durán, R. G., et al. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01027.2006 · Cited by 74 · see citing works
Self-citationNitrate tolerance in vivo is not associated with depletion of arterial or venous thiol levels.
Boesgaard, S., Aldershvile, J., Poulsen, H. E., Loft, S. H., Anderson, M. E., & Meister, A. (1994) · Circulation Research · doi:10.1161/01.res.74.1.115 · Cited by 73 · see citing works
S-Nitrosating Nitric Oxide Donors Induce Long-Lasting Inhibition of Contraction in Isolated Arteries
de Alencar, J. L., Lobysheva, I. I., Chalupský, K., Geffard, M., Nepveu, F., Stoclet, J., & Müller, B. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.052605 · Cited by 42 · see citing works
The Chemical Dynamics of NO and Reactive Nitrogen Oxides: A Practical Guide
Mancardi, D., Ridnour, L. A., Thomas, D. D., Katori, T., Tocchetti, C. G., Espey, M. G., Miranda, K. M., Paolocci, N., & Wink, D. A. (2004) · Current Molecular Medicine · doi:10.2174/1566524043359854 · Cited by 39 · see citing works
Broniowska, K. A., Zhang, Y., & Hogg, N. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603248200 · Cited by 37 · see citing works
Nitroglycerin Tolerance at the Platelet Level in Patients With Angina Pectoris
Chirkov, Y. Y., Chirkova, L. P., & Horowitz, J. D. (1997) · The American Journal of Cardiology · doi:10.1016/s0002-9149(97)00305-6 · Cited by 36 · see citing works
Effects of Nitroglycerin on Erythrocyte Rheology and Oxygen Unloading
Bin, J., Doctor, A., Lindner, J., Hendersen, E. M., Le, D. E., Leong-Poi, H. M., Fisher, N. G., Christiansen, J., & Kaul, S. (2006) · Circulation · doi:10.1161/circulationaha.106.627091 · Cited by 28 · see citing works
Interactions of nitroglycerin and sulfhydryl-donating compounds in coronary microvessels
Wheatley, R. M., Dockery, S., Kurz, M. A., et al. (1994) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1994.266.1.h291 · Cited by 25 · see citing works
Kim, D. D., ́rez, M. ́. M. R., & ́n, W. N. D. (2000) · Microvascular Research · doi:10.1006/mvre.1999.2195 · Cited by 22 · see citing works
Self-citationGraves, J. E., Bates, J. N., Kooy, N. W., et al. (2005) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2005.04310.x · Cited by 12 · see citing works
Mp, S., Sj, H., Sw, K., et al. (1994) · PubMed · Cited by 8 · see citing works
Watanabe, Y., Kusama, N., & Itoh, T. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707562 · Cited by 7 · see citing works
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Foster, M. W., Hess, D. T., & Stamler, J. S. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.06.007 · Cited by 752 · see citing works
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
<i>S</i> -Nitrosylation in Cardiovascular Signaling
Lima, B., Forrester, M. T., Hess, D. T., & Stamler, J. S. (2010) · Circulation Research · doi:10.1161/circresaha.109.207381 · Cited by 490 · see citing works
Structure and Regulation of Soluble Guanylate Cyclase
Derbyshire, E. R., & Marletta, M. A. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-050410-100030 · Cited by 466 · see citing works
Major, T. C., Brant, D. O., Burney, C. P., Amoako, K. A., Annich, G. M., Meyerhoff, M. E., Handa, H., & Bartlett, R. H. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.03.036 · Cited by 118 · see citing works
Role of sGC-dependent NO signalling and myocardial infarction risk
Wobst, J., Kessler, T., Dang, T. A., Erdmann, J., & Schunkert, H. (2015) · Journal of Molecular Medicine · doi:10.1007/s00109-015-1265-3 · Cited by 28 · see citing works
Sharina, I. G., & Martin, E. (2017) · Antioxidants & Redox Signaling · doi:10.1089/ars.2016.6687 · Cited by 19 · see citing works
- Authors
- Sayed, N., Kim, D. D., Fioramonti, X., Iwahashi, T., Durán, W. N., & Beuve, A.
- Affiliations
- Rutgers New Jersey Medical School (US)
- From the Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark.
- Venue
- Circulation Research
- Published
- 2008-09-12
- Volume
- 103
- Issue
- 6
- Pages
- 606-614
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2737267
- OpenAlex
- W2170220747
- Cited by
- 115
- References
- 41
- Citations by year
- 2025: 5 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 7 · 2013: 11 · 2012: 9
- FWCI
- 6.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL089771, HL-070634, R01HL070634, R21HL089771)
- National Institute of General Medical Sciences (R01GM067640, GM067640)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- nitrate tolerance, nitroglycerin, soluble guanylate cyclase, S-nitrosylation, receptor desensitization, S-nitrosothiols, nitric oxide signaling, cyclic GMP, aortic smooth muscle cells, N-acetylcysteine
- MeSH terms
- Soluble Guanylyl Cyclase, Animals, Arterioles, Cysteine, Drug Tolerance, Enzyme Activation, Nitroglycerin, Guanylate Cyclase, Cricetinae, Mouth Mucosa, Nitrates, Vasodilation, Receptors, Cytoplasmic and Nuclear, S-Nitrosothiols
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