Autocatalytic nitration of prostaglandin endoperoxide synthase-2 by nitrite inhibits prostanoid formation in rat alveolar macrophages.

Antioxidants & Redox Signaling
Stefan SchildknechtMarkus Michael Bachschmid

Abstract

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. 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)(-)). Pu...Continue Reading

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Citations

Jan 15, 2013·Antioxidants & Redox Signaling·Bernhard BrüneAndreas Weigert
Oct 14, 2018·Neurologia i neurochirurgia polska·Karol WiśniewskiDariusz J Jaskólski

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Methods Mentioned

BETA
bronchoalveolar lavage
Immunoprecipitation
bronchoalveolar
lavages
lavage
electrophoresis
Assay
X-ray

Software Mentioned

ImageQuant
CuDips
Graph Pad Prism

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