TY - JOUR
T1 - Influence of plasma halide, pseudohalide and nitrite ions on myeloperoxidase-mediated protein and extracellular matrix damage
AU - Xu, Shuqi
AU - Chuang, Christine Y.
AU - Malle, Ernst
AU - Gamon, Luke F.
AU - Hawkins, Clare L.
AU - Davies, Michael J.
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Extracellular matrix
KW - Fibronectin
KW - Hypochlorous acid
KW - Myeloperoxidase
KW - Nitration
KW - Nitrite
KW - Smooth muscle cells
KW - Thiocyanate
UR - http://www.scopus.com/inward/record.url?scp=85132516042&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2022.06.222
DO - 10.1016/j.freeradbiomed.2022.06.222
M3 - Journal article
C2 - 35718304
AN - SCOPUS:85132516042
VL - 188
SP - 162
EP - 174
JO - Free Radical Biology & Medicine
JF - Free Radical Biology & Medicine
SN - 0891-5849
ER -