Low-density lipoprotein modification by normal, myeloperoxidase-deficient and NADPH oxidase-deficient granulocytes and the impact of redox active transition metal ions.
The modification of low-density lipoprotein (LDL) by normal, myeloperoxidase (MPO)-deficient and NADPH oxidase-deficient granulocytes was investigated using the monoclonal antibody (mAb) OB/04, which was originally generated against copper-oxidized LDL. Incubation of LDL with normal granulocytes increased the reactivity of LDL with mAb OB/04. These effects were even more pronounced using MPO-deficient granulocytes. Inhibitors of oxidative reactions (the NADPH oxidase inhibitor diphenyleneiodonium chloride [DPI], catalase, superoxide dismutase [SOD]) did not significantly reduce LDL oxidation by normal granulocytes. Furthermore, granulocytes of a patient with NADPH oxidase deficiency were almost equally effective as normal granulocytes, indicating that oxidative burst-derived reactive oxygen species are of only minor importance in the generation of mAb OB/04-detectable new epitopes on LDL in vitro. In contrast, incubation of LDL with iron and copper prior to and during incubation with normal granulocytes markedly enhanced the generation of OB/04-detectable epitopes. It is supposed that, besides superoxide (in normal and MPO-deficient granulocytes) or instead of superoxide (in NADPH oxidase-deficient granulocytes), lytic enzymes released by activated granulocytes may enhance the availability of transition metals for oxidation of LDL. Our results support the concept that transition-metal-dependent pathways of LDL oxidation in combination with degranulation products of granulocytes are important.
Gerber
Claudia E
CE
Department of Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
Bruchelt
Gernot
G
Ledinski
Gerhard
G
Greilberger
Joachim
J
Niethammer
Dietrich
D
Jürgens
Günther
G
D000328:Adult; D003676:Deferoxamine / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005260:Female; D006098:Granulocytes / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D019255:NADPH Oxidases / Q000097:blood* / Q000172:deficiency; D010084:Oxidation-Reduction; D004369:Pentetic Acid / Q000494:pharmacology; D009195:Peroxidase / Q000097:blood* / Q000172:deficiency; D010618:Phenanthrolines / Q000494:pharmacology; D012016:Reference Values
D008077:Lipoproteins, LDL; D010618:Phenanthrolines; D004369:Pentetic Acid; C002701:neocuproine; D004492:Edetic Acid; D009195:Peroxidase; D019255:NADPH Oxidases; D003676:Deferoxamine; C025205:1,10-phenanthroline