Autocatalytic Nitration of Prostaglandin Endoperoxide Synthase-2 by Nitrite Inhibits Prostanoid Formation in Rat Alveolar Macrophages.

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2012
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Daiber, Andreas
Zhao, Cheng
Hamacher, Jürg
Perlman, David
Jung, Birgit
van der Loo, Bernd
O'Connor, Peter
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Antioxidants & Redox Signaling. 2012, 17(10), pp. 1393-1406. ISSN 1523-0864. eISSN 1557-7716. Available under: doi: 10.1089/ars.2011.4485
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Prostaglandin endoperoxide H(2) synthase (PGHS) is a well-known target for peroxynitrite-mediated nitration. In several experimental macrophage models, however, the relatively late onset of nitration failed to coincide with the early peak of endogenous peroxynitrite formation. In the present work, we aimed to identify an alternative, peroxynitrite-independent mechanism, responsible for the observed nitration and inactivation of PGHS-2 in an inflammatory cell model. Results: In primary rat alveolar macrophages stimulated with lipopolysaccharide (LPS), PGHS-2 activity was suppressed after 12 h, although the prostaglandin endoperoxide H(2) synthase (PGHS-2) protein was still present. This coincided with a nitration of the enzyme. Coincubation with a nitric oxide synthase-2 (NOS-2) inhibitor preserved PGHS-2 nitration and at the same time restored thromboxane A(2) (TxA(2)) synthesis in the cells. Formation of reactive oxygen species (ROS) was maximal at 4 h and then returned to baseline levels. Nitrite (NO(2)(-)) production occurred later than ROS generation. This rendered generation of peroxynitrite and the nitration of PGHS-2 unlikely. We found that the nitrating agent was formed from NO(2)(-), independent from superoxide ((•)O(2)(-)). Purified PGHS-2 treated with NO(2)(-) was selectively nitrated on the active site Tyr(371), as identified by mass spectrometry (MS). Exposure to peroxynitrite resulted in the nitration not only of Tyr(371), but also of other tyrosines (Tyr). Innovation and Conclusion: The data presented here point to an autocatalytic nitration of PGHS-2 by NO(2)(-), catalyzed by the enzyme's endogenous peroxidase activity and indicate a potential involvement of this mechanism in the termination of prostanoid formation under inflammatory conditions.

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ISO 690SCHILDKNECHT, Stefan, Christiaan KARREMAN, Andreas DAIBER, Cheng ZHAO, Jürg HAMACHER, David PERLMAN, Birgit JUNG, Bernd VAN DER LOO, Peter O'CONNOR, Marcel LEIST, Volker ULLRICH, Markus Michael BACHSCHMID, 2012. Autocatalytic Nitration of Prostaglandin Endoperoxide Synthase-2 by Nitrite Inhibits Prostanoid Formation in Rat Alveolar Macrophages.. In: Antioxidants & Redox Signaling. 2012, 17(10), pp. 1393-1406. ISSN 1523-0864. eISSN 1557-7716. Available under: doi: 10.1089/ars.2011.4485
BibTex
@article{Schildknecht2012-11-15Autoc-20353,
  year={2012},
  doi={10.1089/ars.2011.4485},
  title={Autocatalytic Nitration of Prostaglandin Endoperoxide Synthase-2 by Nitrite Inhibits Prostanoid Formation in Rat Alveolar Macrophages.},
  number={10},
  volume={17},
  issn={1523-0864},
  journal={Antioxidants & Redox Signaling},
  pages={1393--1406},
  author={Schildknecht, Stefan and Karreman, Christiaan and Daiber, Andreas and Zhao, Cheng and Hamacher, Jürg and Perlman, David and Jung, Birgit and van der Loo, Bernd and O'Connor, Peter and Leist, Marcel and Ullrich, Volker and Bachschmid, Markus Michael}
}
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