MPO generates nitrotyrosine in the subendothelial space

Inflamed vascular tissue provides an interesting example of a pathological form of protein modification occurring outside the cell. Vascular ECM components, particularly the prominent interstitial protein fibronectin, readily undergo tyrosine nitration during the inflammatory process. Still, as Baldus et al. note, the mechanism of this post-translational modification and the basis of its localization have been uncertain. Striking images in their present report show that the oxidative enzyme myeloperoxidase (MPO) colocalizes with fibronectin in inflamed vessels. This finding provides a ready explanation for the specific accumulation of nitrotyrosine residues in the subendothelial space, but it also raises the question of how an enzyme produced in the lumen of the vessel by activated neutrophils can then traverse the endothelium. Baldus et al. show that following degranulation of neutrophils, MPO associates with endothelial heparan sulfate proteoglycans and is transcytosed to the basolateral side of cultured endothelial cells (and to the corresponding ablumenal face of the endothelium in vivo). There, MPO, activated by peroxide, oxidizes free nitrite, which can then modify neighboring ECM proteins. Whereas nitrotyrosine has previously been thought to form spontaneously in the presence of the peroxynitrite radical (itself a secondary product of the simple signaling molecule NO), the present work places a new emphasis on MPO as a mediator of tyrosine nitration. Indeed, the authors show that, following treatment to provoke systemic inflammation, the liver of animals lacking MPO is significantly poorer in protein nitrotyrosine adducts than wild-type liver. The physiological significance of MPO transcytosis remains unresolved, but the MPO knockout mouse may provide a useful system for testing the role of localized protein nitration in the onset, progression, or termination of vascular inflammation.

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