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Loss of neutral endopeptidase (NEP) activity contributes to neutrophil oxidative activation during Mg‐deficiency
Author(s) -
Mak I. Tong,
Chmielinska Joanna J,
Kramer Jay,
Weglick William
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.785.9
Subject(s) - medicine , endocrinology , chemistry , neutrophile , respiratory burst , receptor , superoxide , oxidative phosphorylation , enzyme , biology , inflammation , biochemistry
NEP, a cell‐surface proteolytic enzyme, degrades substance P (SP). The effect of Mg‐deficiency on neutrophil NEP activity and cell activation were examined. Male SD rats (180g) were fed Mg‐sufficient (MgS) or ‐deficient (MgD, 9% RDA) diets for 5 wks. Enriched blood neutrophils were isolated at the end of 1, 3, 5 wks by step gradient centrifugation. NEP activity (by a fluorimetric method) decreased 15% (NS), 50% (p<0.025) and 57% (p<0.01) respectively for wks 1, 3, and 5 MgD rats. In association, neutrophil basal superoxide (·O2‐) generating activities were elevated, 33% at wk 1 (NS), 5–7 fold for wks 3, 5 (p<0.01) above MgS controls. The maximally stimulated (by PMA) ·O2‐ production increased 2‐fold from 5 wk MgD neutrophils. Also, plasma 8‐isoprostane levels were elevated 2–3‐fold and RBC GSH decreased 50% (p<0.01) during 3–5 wks of MgD. Plasma SP levels were elevated 5‐fold in wk 1 and 9–10‐fold (p<0.01) in 3–5 wks. When MgD rats were treated with a SP receptor blocker, L703,606 (1mg/kg/day s.c.), NEP activities were 75% (wk 3) and 77% (wk 5) preserved (p<0.05) comparing to MgS neutrophils; activation of neutrophil ·O2‐ and other oxidative indices were also significantly (p<0.05) attenuated. Since SP receptors are present on neutrophils, we conclude that NEP activity regulates neutrophil ·O2‐ formation by controlling SP availability; in turn, oxidative inactivation of NEP is prevented by SP receptor blockade. (Supported by NIH‐HL‐62282, HL‐65178)