Nitric Oxide Inhibits Caspase-3 by S-Nitrosationin Vivo
Open accessAbstract
In cultured human endothelial cells, physiological levels of NO prevent apoptosis and interfere with the activation of the caspase cascade. In vitro data have demonstrated that NO inhibits the activity of caspase-3 by S-nitrosation of the enzyme. Here we present evidence for the in vivo occurrence and functional relevance of this novel antiapoptotic mechanism. To demonstrate that the cysteine residue Cys-163 of caspase-3 is S-nitrosated, cells were transfected with the Myc-tagged p17 subunit of caspase-3. After incubation of the transfected cells with different NO donors, Myc-tagged p17 was immunoprecipitated with anti-Myc antibody. S-Nitrosothiol was detected in the immunoprecipitate by electron spin resonance spectroscopy after liberation and spin trapping of NO by N-methyl-D-glucamine-dithiocarbamate-iron complex. Transfection of cells with a p17 mutant, where the essential Cys-163 was mutated into alanine, completely prevented S-nitrosation of the enzyme. As a functional correlate, in human umbilical vein endothelial cells the NO donors sodium nitroprusside or PAPA NONOate (50 microM) significantly reduced the increase in caspase-3-like activity induced by overexpressing caspase-3 by 75 and 70%, respectively. When human umbilical vein endothelial cells were cotransfected with beta-galactosidase, morphological analysis of stained cells revealed that cell death induction by overexpression of caspase-3 was completely suppressed in the presence of sodium nitroprusside, PAPA NONOate, or S-nitroso-L-cysteine (50 microM). Thus, NO supplied by exogenous NO donors serves in vivo as an antiapoptotic regulator of caspase activity via S-nitrosation of the Cys-163 residue of caspase-3.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
S-nitrosation of caspase 3, a proapoptotic enzyme, inhibits its activity to attenuate apoptotic signaling.
“For example, S-nitrosation of caspase 3, a proapoptotic enzyme, inhibits its activity to attenuate apoptotic signaling (356).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [356]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The L-Arginine-Nitric Oxide Pathway
Epstein, F. H., Moncada, S., & Higgs, A. (1993) · New England Journal of Medicine · doi:10.1056/nejm199312303292706 · Cited by 6,678 · see citing works
Nagata, S. (1997) · Cell · doi:10.1016/s0092-8674(00)81874-7 · Cited by 4,908 · see citing works
Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis
Nicholson, D. W., Ali, A., Thornberry, N. A., Vaillancourt, J. P., Ding, C. K., Gallant, M., Gareau, Y., Griffin, P. R., Labelle, M., Lazebnik, Y. A., et al. (1995) · Nature · doi:10.1038/376037a0 · Cited by 3,980 · see citing works
A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD
Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A., & Nagata, S. (1998) · Nature · doi:10.1038/34112 · Cited by 3,181 · see citing works
Redox signaling: Nitrosylation and related target interactions of nitric oxide
Stamler, J. S. (1994) · Cell · doi:10.1016/0092-8674(94)90269-0 · Cited by 1,723 · see citing works
Stamler, J. S., Simon, D. I., Osborne, J. A., Mullins, M. E., Jaraki, O., Michel, T. M., Singel, D. J., & Loscalzo, J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.1.444 · Cited by 1,471 · see citing works
Life, death, and the pursuit of apoptosis.Preprint
White, E. (1996) · Genes & Development · doi:10.1101/gad.10.1.1 · Cited by 1,300 · see citing works
DNA damage and mutation in human cells exposed to nitric oxide in vitro.
Nguyen, T., Brunson, D. C., Crespi, C. L., Penman, B. W., Wishnok, J. S., & Tannenbaum, S. R. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.7.3030 · Cited by 972 · see citing works
Dimmeler, S., Haendeler, J., Nehls, M. C., & Zeiher, A. M. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.4.601 · Cited by 806 · see citing works
Self-citationHaunstetter, A., & Izumo, S. (1998) · Circulation Research · doi:10.1161/01.res.82.11.1111 · Cited by 802 · see citing works
Nitric oxide-mediated apoptosis in murine peritoneal macrophages
Albina, J. E., Cui, S., Mateo, R. B., & Reichner, J. S. (1993) · Parasitology Today · doi:10.1016/0169-4758(93)90226-6 · Cited by 782 · see citing works
Nitric oxide-mediated apoptosis in murine peritoneal macrophages
Albina, J. E., Cui, S., Mateo, R. B., & Reichner, J. S. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.150.11.5080 · Cited by 692 · see citing works
Geng, Y., & Libby, P. (1995) · PubMed · Cited by 641 · see citing works
Nitric Oxide Reversibly Inhibits Seven Members of the Caspase Family via S-Nitrosylation
Li, J., Billiar, T. R., Talanian, R. V., & Kim, Y. M. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7672 · Cited by 529 · see citing works
Kim, Y., de Vera, M. E., Watkins, S. C., & Billiar, T. R. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.2.1402 · Cited by 524 · see citing works
Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation
Mannick, J. B., Asano, K., Izumi, K. M., Kieff, E. D., & Stamler, J. S. (1994) · Cell · doi:10.1016/0092-8674(94)90005-1 · Cited by 498 · see citing works
Fluid Shear Stress Stimulates Phosphorylation of Akt in Human Endothelial Cells
Dimmeler, S., Aßmus, B., Hermann, C., Haendeler, J., & Zeiher, A. M. (1998) · Circulation Research · doi:10.1161/01.res.83.3.334 · Cited by 431 · see citing works
Self-citationNitrosative Stress: Activation of the Transcription Factor OxyR
Hausladen, A., Privalle, C. T., Keng, T., DeAngelo, J., & Stamler, J. S. (1996) · Cell · doi:10.1016/s0092-8674(00)80147-6 · Cited by 359 · see citing works
Moroi, M., Zhang, L., Yasuda, T., Virmani, R., Gold, H., Fishman, M. C., & Huang, P. L. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1293 · Cited by 339 · see citing works
Nitric Oxide Inhibits Fas-induced Apoptosis
Mannick, J. B., Miao, X. Q., & Stamler, J. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.39.24125 · Cited by 315 · see citing works
Nitric Oxide and Apoptosis: Another Paradigm for the Double-Edged Role of Nitric Oxide
Dimmeler, S., & Zeiher, A. M. (1997) · Nitric Oxide · doi:10.1006/niox.1997.0133 · Cited by 309 · see citing works
Self-citationNitric oxide-induced apoptosis: p53-dependent and p53-independent signalling pathways
Meßmer, U. K., & Brüne, B. (1996) · Biochemical Journal · doi:10.1042/bj3190299 · Cited by 284 · see citing works
Disruption of Fas Receptor Signaling by Nitric Oxide in Eosinophils
Hebestreit, H. F., Dibbert, B., Balatti, I., Braun, D., Schapowal, A., Blaser, K., & Simon, H. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.3.415 · Cited by 176 · see citing works
Spin trapping of nitric oxide produced in vivo in septic‐shock mice
Lai, C., & Komarov, A. M. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00422-6 · Cited by 175 · see citing works
Nitric oxide induces and inhibits apoptosis through different pathways
Shen, Y. H., Wang, X. L., & Wilcken, D. E. L. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00844-8 · Cited by 171 · see citing works
Estévez, Á. G., Spear, N., Thompson, J. A., et al. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-10-03708.1998 · Cited by 170 · see citing works
Nitric oxide: inducer or suppressor of apoptosis?
Nicotera, P., Brüne, B., & Bagetta, G. (1997) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(97)90619-2 · Cited by 103 · see citing works
Effects of Redox-Related Congeners of NO on Apoptosis and Caspase-3 Activity
Haendeler, J., Weiland, U., Zeiher, A. M., & Dimmeler, S. (1997) · Nitric Oxide · doi:10.1006/niox.1997.0134 · Cited by 100 · see citing works
Self-citationMikoyan, V. D., Kubrina, L. N., Сереженков, В. А., et al. (1997) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(97)00032-9 · Cited by 90 · see citing works
A Mechanistic Analysis of Nitric Oxide-Induced Cellular Toxicity
Burney, S., Tamir, S., Gal, A., & Tannenbaum, S. R. (1997) · Nitric Oxide · doi:10.1006/niox.1996.0114 · Cited by 90 · see citing works
Nitric oxide inhibits APO-1/Fas-mediated cell death.
Dimmeler, S., Haendeler, J., Sause, A., & Zeiher, A. M. (1998) · PubMed · Cited by 90 · see citing works
Self-citationIn Vivo Spin Trapping of Glyceryl Trinitrate–Derived Nitric Oxide in Rabbit Blood Vessels and Organs
Mülsch, A., Mordvintcev, P. I., Bassenge, E., Jung, F., Clement, B., & Busse, R. (1995) · Circulation · doi:10.1161/01.cir.92.7.1876 · Cited by 76 · see citing works
Self-citationSensitive quantitation of nitric oxide by EPR spectroscopy
Tsuchiya, K., TAKASUGI, M., Minakuchi, K., & Fukuzawa, K. (1996) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(96)00221-3 · Cited by 69 · see citing works
Diethyl Dithiocarbamate-Induced Decomposition ofS-Nitrosothiols
Arnelle, D. R., Day, B. J., & Stamler, J. S. (1997) · Nitric Oxide · doi:10.1006/niox.1996.0107 · Cited by 36 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Stamler, J. S., Simon, D. I., Osborne, J. A., Mullins, M. E., Jaraki, O., Michel, T., Singel, D. J., and Loscalzo, J. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 444 -448
- Nguyen, T., Brunson, D., Crespi, C. L., Penman, B. W., Wishnok, J. S., and Tannenbaum, S. R. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 3030 -3034
Cited by
Sorted by citations
Reactive oxygen species, cellular redox systems, and apoptosis
Circu, M. L., & Aw, T. Y. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.12.022 · Cited by 3,340 · see citing works
Redox regulation of mitochondrial function
Handy, D. E., & Loscalzo, J. (2012) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4123 · Cited by 588 · see citing works
Brookes, P. S., Salinas, E. P., Darley-Usmar, K., Eiserich, J. P., Freeman, B. A., Darley-Usmar, V. M., & Anderson, P. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001077200 · Cited by 321 · see citing works
Nitric Oxide in Vascular Biology
Walford, G., & Loscalzo, J. (2003) · Journal of Thrombosis and Haemostasis · doi:10.1046/j.1538-7836.2003.00345.x · Cited by 302 · see citing works
Cooke, J. P. (2003) · Atherosclerosis Supplements · doi:10.1016/s1567-5688(03)00034-5 · Cited by 266 · see citing works
Thioredoxin and Thioredoxin Reductase in Relation to Reversible <i>S</i> -Nitrosylation
Sengupta, R., & Holmgren, A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4716 · Cited by 156 · see citing works
West, M. B., Rokosh, G., Obal, D., Velayutham, M., Xuan, Y.-T., Hill, B. G., Keith, R. J., Schrader, J., Guo, Y., Conklin, D. J., et al. (2008) · Circulation · doi:10.1161/circulationaha.108.791533 · Cited by 121 · see citing works
The role of thioredoxin in the regulation of cellular processes by S-nitrosylation
Sengupta, R., & Holmgren, A. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.08.012 · Cited by 110 · see citing works
Samengo, G., Avik, A., Fedor, B., Whittaker, D., Myung, K. H., Wehling‐Henricks, M., & Tidball, J. G. (2012) · Aging Cell · doi:10.1111/acel.12003 · Cited by 95 · see citing works
Nedospasov, A. A. (2002) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.10029 · Cited by 38 · see citing works
- Authors
- Rössig, L., Fichtlscherer, B., Breitschopf, K., Haendeler, J., Zeiher, A. M., Mülsch, A., & Dimmeler, S.
- Affiliations
- Goethe University Frankfurt (DE)
- Corresponding author
- Dimmeler, Stefanie
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-03
- Volume
- 274
- Issue
- 11
- Pages
- 6823-6826
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1987576919
- Cited by
- 432
- References
- 34
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 9 · 2023: 2 · 2022: 10 · 2021: 3 · 2020: 16 · 2019: 5 · 2018: 5 · 2017: 9 · 2016: 5 · 2015: 13 · 2014: 11 · 2013: 14 · 2012: 17
- FWCI
- 11.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- nitric oxide, caspase-3, S-nitrosylation, apoptosis, anti-apoptotic mechanisms, endothelial cells, sodium nitroprusside, S-nitroso-L-cysteine, nitric oxide donors
- MeSH terms
- Cells, Cultured, Cysteine, Endothelium, Vascular, Humans, Nitrates, Nitric Oxide, Nitrosation, Cysteine Proteinase Inhibitors, Apoptosis, Nitric Oxide Donors, Caspases, Caspase 3, Caspase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
