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PP2A: a new link between peroxynitrite and endothelial barrier dysfunction?

Recent studies have identified many important signalling pathways that regulate endothelial cell (EC) barrier functions during physiological and pathological conditions. Understanding how these signalling pathways target their downstream effectors and thereby coordinate changes in EC cytoskeleton, junctional adhesion molecules and integrins to regulate EC barrier functions has been the focus of many recent studies. An interesting study by Wu and Wilson addresses the role of protein phosphatase 2A (PP2A) in regulating microvascular EC barrier dysfunction induced by LPS plus interferon (IFNγ).1 The authors used mouse skeletal microvascular ECs and demonstrate that PP2A is required for the development of EC barrier dysfunction induced by LPS plus IFNγ. Moreover, the investigators presented a series of carefully conducted biochemical analyses showing that LPS plus IFNγ cause an increase in the activity of PP2A, tyrosine nitration of the catalytic subunit of PP2A (PP2Ac), and a decrease in tyrosine phosphorylation of PP2Ac, in a manner that depends on NADPH oxidase and inducible NO synthase (iNOS). These data raise the hypothesis that peroxynitrite targets PP2Ac by inducing its tyrosine nitration, a response that correlates with decreased tyrosine phosphorylation of PP2Ac and increases in its activity. The experiments … 

*Corresponding author. Tel: +1 212 342 0237; fax: +1 212 305 5337. E-mail address : qw2109{at}columbia.edu