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Cardiovascular Research Advance Access first published online on September 13, 2008
This version [Corrected Proof] published online on October 3, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn246
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Peroxynitrite-dependent activation of protein phosphatase type 2A mediates microvascular endothelial barrier dysfunction

Feng Wu* and John X. Wilson

Department of Exercise and Nutrition Sciences, University at Buffalo, 3435 Main Street, G10 Farber Hall, Buffalo, NY 14214-8028, USA

* Corresponding author. Tel: +1 716 829 3680; fax: +1 716 829 3700. E-mail address: fengwu{at}buffalo.edu

Aims: We investigated the mechanism by which proinflammatory stimulation induces microvascular endothelial barrier dysfunction. Since protein phosphatase type 2A (PP2A) can mediate paracellular leak and can be inactivated by tyrosine phosphorylation in its catalytic subunit (PP2Ac), we hypothesized that microvascular endothelial cells exposed to proinflammatory stimulation produce peroxynitrite that nitrates PP2Ac, and this nitration inhibits tyrosine phosphorylation of PP2Ac and thereby increases PP2A activity to mediate endothelial barrier dysfunction.

Methods and results: Exposure of mouse skeletal muscle microvascular endothelial cell monolayers to a proinflammatory stimulus [lipopolysaccharide (LPS) + interferon (IFN){gamma}] increased permeability to albumin, and this barrier dysfunction was attenuated by PP2A inhibitor okadaic acid or by siRNA (small interfering ribonucleic acid) against PP2Ac. LPS + IFN{gamma} increased synthesis of peroxynitrite precursors nitric oxide (NO) and superoxide by inducible NO synthase (iNOS) and NADPH oxidase, respectively. PP2Ac immunoprecipitates isolated from LPS + IFN{gamma}- or peroxynitrite-treated cells showed increased tyrosine nitration, decreased tyrosine phosphorylation and increased phosphatase activity. 3-Nitrotyrosine immunoprecipitates from LPS + IFN{gamma}-stimulated cells also exhibited increased PP2A activity. Further, iNOS inhibitor 1400W, iNOS deficiency, NADPH oxidase inhibitor apocynin, or p47phox deficiency prevented the increase in PP2A activity and preserved barrier function.

Conclusion: LPS + IFN{gamma} stimulates endothelial cells to produce iNOS-derived NO and NADPH oxidase-derived superoxide, which form peroxynitrite that nitrates tyrosine residues in PP2Ac and inhibits their phosphorylation. This nitration in PP2Ac is correlated with PP2A activation that mediates endothelial barrier dysfunction.

KEYWORDS Protein phosphatase type 2A; Peroxynitrite; Nitration; Endothelial cells; Permeability; Cytokines

Time for primary review: 20 days


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