Deficiency of Myeloperoxidase Increases Infarct Volume and Nitrotyrosine Formation in Mouse Brain

Abstract

Peroxynitrite is responsible for nitration in vivo, whereas myeloperoxidase can also catalyze protein nitration in the presence of high NO2(-) levels. Recent reports of myeloperoxidase-mediated enzyme inactivation or lipid peroxidation have suggested a role of myeloperoxidase in various pathological conditions. To clarify the role of myeloperoxidase in ischemic brain injury, the authors measured nitrotyrosine formation and infarct volume in myeloperoxidase-deficient or wild-type mice subjected to 2-hour focal cerebral ischemia-reperfusion. Twenty-four hours after reperfusion, infarct volume was significantly larger in myeloperoxidase-deficient mice than in wild-type mice (81 +/- 20 mm(3) vs. 52 +/- 13 mm(3), P < 0.01), and nitrotyrosine levels in the infarct region were higher in myeloperoxidase-deficient mice than in wild-type mice (13.4 +/- 6.1 microg/mg vs. 9.8 +/- 4.4 microg/mg, P = 0.13). Fourteen hours after reperfusion, the nitrotyrosine level was significantly higher in myeloperoxidase-deficient mice than in wild-type mice (3.3 +/- 2.9 microg/mg vs. 1.4 +/- 0.4 microg/mg, P < 0.05). The authors conclude that the absence of myeloperoxidase increases ischemic neuronal damage in vivo, and that the myeloperoxidase-mediated pathway is not responsible for the nitration reaction in cerebral ischemia-reperfusion.

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

“…4-6). Tyrosine nitration is involved in many postischemic modifications [55][56][57]. Examples of proteins susceptible to inactivation by tyrosine nitration include mitochondrial superoxide dismutase [58,59] and several enzymes involved in oxidative energy metabolism, including aconitase [60], glutamate dehydrogenase [46], α-ketoglutarate dehydrogenase [61], and PDHC [46].…”

Protein nitration is mediated by heme and free metals through Fenton-type chemistry: An alternative to the NO/O\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\setlength{\oddsidemargin}{-69pt}\begin{document}\begin{equation*}{\mathrm{_{2}^{-}}}\end{equation*}\end{document} reaction

“…3) and MPO (data not shown) generate NT from NO͞O 2 Ϫ , but only after conversion of each reactant to NO 2 Ϫ and H 2 O 2 , respectively. Although peroxidases unmistakably account for significant amounts of NT formation in vivo, this mechanism may not adequately explain the nitrated proteins detected in a MPO Ϫ/Ϫ mouse model (25) or under acute pathologic conditions void of inflammatory cells, such as ischemia reperfusion injury to the brain (51). Brennan et al (50) have recently shown, using an EPO Ϫ/Ϫ ͞MPO Ϫ/Ϫ mouse inflammatory model, that leukocyte peroxidase-dependant formation of the peroxidase activity markers bromo-and chloro-tyrosine does not necessarily parallel formation of NT.…”

“…Although leukocyte peroxidases likely account for a substantial amount of NT production in vivo, this mechanism fails to explain NT formation in the absence of inflammatory cells or peroxidases [i.e., a MPO Ϫ/Ϫ mouse model (25)]. …”

Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase

“…MPO-mediated radicalization of molecules induces apoptosis (7) and nitro-tyrosination of proteins (8). Therefore, MPO is a key component of inflammation and has been shown to play a major role in animal models of stroke in the posthypoxic inflammatory response (9,10). In human cerebral ischemia, certain MPO genotypes are associated with increased brain infarct size and poorer functional outcome (11).…”