Presentation of Nitric Oxide Regulates Monocyte Survival through Effects on Caspase-9 and Caspase-3 Activation

In the absence of survival factors, blood monocytes undergo spontaneous apoptosis, which involves the activation of caspase-3. Although nitric oxide can block caspase-3 activation and promote cell survival, it can also induce apoptosis. We hypothesized that nitrosothiols that promote protein S -nitr...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 278; no. 15; pp. 12894 - 12902
Main Authors:	Zeigler, Mandy M, Doseff, Andrea I, Galloway, Michelle F, Opalek, Judy M, Nowicki, Philip T, Zweier, Jay L, Sen, Chandan K, Marsh, Clay B
Format:	Journal Article
Language:	English
Published:	United States American Society for Biochemistry and Molecular Biology 11-04-2003
Subjects:	Caspase 3 Caspase 9 Caspases - blood Cell Survival - drug effects DNA Fragmentation - drug effects Enzyme Activation Glutathione - blood Humans Hydrazines - pharmacology In Vitro Techniques Kinetics Monocytes - cytology Monocytes - drug effects Monocytes - enzymology Nitric Oxide - pharmacology Nitric Oxide Donors - pharmacology Nitrogen Oxides S-Nitrosoglutathione
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Summary:	In the absence of survival factors, blood monocytes undergo spontaneous apoptosis, which involves the activation of caspase-3. Although nitric oxide can block caspase-3 activation and promote cell survival, it can also induce apoptosis. We hypothesized that nitrosothiols that promote protein S -nitrosylation would reduce caspase-3 activation and cell survival, whereas nitric oxide donors (such as 1-propamine 3-(2-hydroxy-2-nitroso-1-propylhydrazine (PAPA) NONOate and diethylamine (DEA) NONOate) that do not target thiol residues would not. Using human monocytes as a model, we observed that nitrosothiol donors S -nitrosoglutathione and S -nitroso- N -acetylpenicillamine suppressed caspase-9 and caspase-3 activity and DNA fragmentation. In contrast, PAPA or DEA NONOate did not promote monocyte survival events and appeared to inhibit monocyte survival induced by macrophage colony-stimulating factor. The caspase-3-selective inhibitor DEVD-fluoromethyl ketone reversed DNA fragmentation events, and the caspase-9 inhibitor LEHD-fluoromethyl ketone reversed caspase-3 activity in monocytes treated with PAPA or DEA NONOate in the presence of macrophage colony-stimulating factor. These results were not caused by differences in glutathione levels or the kinetics of nitric oxide release. Moreover, S -nitrosoglutathione and S -nitroso- N -acetylpenicillamine directly blocked the activity of recombinant caspase-3, which was reversed by the reducing agent dithiothreitol, whereas PAPA or DEA NONOate did not block the enzymatic activity of caspase-3. These data support the hypothesis that nitrosylation of protein thiol residues by nitric oxide is critical for promoting the survival of human monocytes.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M213125200