Role of myeloperoxidase in the neutrophil-induced oxidation of low densitylipoprotein as studied by myeloperoxidase-knockout mouse

Low density lipoprotein was oxidized by neutrophils derived from either C57 BL/6 mice or myeloperoxidase (MPO)-knockout mice. The generation of superox ide from neutrophils of MPO-knockout mice was about 70% of that from wild-t ype mice. The extent of the oxidation of human low density lipoprotein (LDL ) by phorbol myristate acetate (PMA)-activated neutrophils of wild-type and MPO-knockout mice was assessed by measuring consumption of ar-tocopherol a nd formation of phosphatidylcholine hydroperoxide (PCOOH) and cholesteryl e ster hydroperoxide (CEOOH). Little consumption of alpha-tocopherol was obse rved in both oxidations, It was found, however, that lipid hydroperoxides w ere accumulated with time in both oxidations and that the rates of formatio n of PCOOH and CEOOH in the oxidation by MPO-knockout neutrophils were abou t 66 and 44% of those by wild-type neutrophils, respectively. The lipid per oxidation was completely inhibited by adding superoxide dismutase (SOD) in both cases. The addition of L-tyrosine and SOD enhanced lipid peroxidation of LDL induced by wild-type neutrophils but not by MPO-knockout ones, These results suggest that, regardless of their MPO activity, neutrophils induce lipid peroxidation of LDL by a superoxide-dependent pathway, and that MPO- catalyzed lipid peroxidation is enhanced by the presence of an appropriate amount of free tyrosine and further enhanced by SOD.