Influence of plasma halide, pseudohalide and nitrite ions on myeloperoxidase-mediated protein and extracellular matrix damage

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Myeloperoxidase (MPO) mediates pathogen destruction by generating the bactericidal oxidant hypochlorous acid (HOCl). Formation of this oxidant is however associated with host tissue damage and disease. MPO also utilizes H2O2 to oxidize other substrates, and we hypothesized that mixtures of other plasma anions, including bromide (Br), iodide (I), thiocyanate (SCN) and nitrite (NO2), at normal or supplemented concentrations, might modulate MPO-mediated HOCl damage. For the (pseudo)halide anions, only SCN significantly modulated HOCl formation (IC50 ∼33 μM), which is within the normal physiological range, as judged by damage to human plasma fibronectin or extracellular matrix preparations detected by ELISA and LC-MS. NO2 modulated HOCl-mediated damage, in a dose-dependent manner, at physiologically-attainable anion concentrations. However, this was accompanied by increased tyrosine and tryptophan nitration (detected by ELISA and LC-MS), and the overall extent of damage remained approximately constant. Increasing NO2 concentrations (0.5–20 μM) diminished HOCl-mediated modification of tyrosine and methionine, whereas tryptophan loss was enhanced. At higher NO2 concentrations, enhanced tyrosine and methionine loss was detected. These analytical data were confirmed in studies of cell adhesion and metabolic activity. Together, these data indicate that endogenous plasma levels of SCN (but not Br or I) can modulate protein modification induced by MPO, including the extent of chlorination. In contrast, NO2 alters the type of modification, but does not markedly decrease its extent, with chlorination replaced by nitration. These data also indicate that MPO could be a major source of nitration in vivo, and particularly at inflammatory sites where NO2 levels are often elevated.

TidsskriftFree Radical Biology and Medicine
Sider (fra-til)162-174
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
This work was supported by the Novo Nordisk Foundation (Laureate Research Grants: NNF13OC0004294 and NNF20SA0064214 to MJD), the China Scholarship Council (PhD scholarship 201806270237 to Shuqi Xu) and the Lundbeck Foundation (post-doctoral fellowship R322-2019-2337 to LFG). We thank Dr. Eduardo Fuentes-Lemus for valuable scientific discussions and advice on the LC-MS experiments.

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© 2022 The Authors

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