TYROSYL RADICAL GENERATED BY MYELOPEROXIDASE IS A PHYSIOLOGICAL CATALYST FOR THE INITIATION OF LIPID-PEROXIDATION IN LOW-DENSITY-LIPOPROTEIN

Myeloperoxidase, a heme protein secreted by activated phagocytes, is e xpressed in human atherosclerotic lesions. The enzyme uses H2O2 genera ted by the cells to oxidize L-tyrosine to tyrosyl radical, a catalyst for protein dityrosine synthesis. We have explored the possibility tha t tyrosyl radical initiates lipid peroxidation, which may be of pivota l importance in transforming low density lipoprotein (LDL) into athero genic particles. Exposure of LDL to L-tyrosine and activated human neu trophils caused peroxidation of LDL lipids. LDL oxidation required L-t yrosine but was independent of free metal ions; catalase and heme pois ons were inhibitory. Incubation of LDL with L-tyrosine, myeloperoxidas e, and H2O2 likewise caused lipid peroxidation, and this reaction was inhibited by heme poisons and catalase. Replacement of L-tyrosine with O-methyltyrosine, which cannot form tyrosyl radical, inhibited LDL ox idation by both activated neutrophils and myeloperoxidase. The antioxi dants ascorbate and probucol, but not vitamin E, inhibited LDL oxidati on by myeloperoxidase, H2O2, and L-tyrosine. Ascorbate blocked dityros ine synthesis, while probucol scavenged chain-propagating peroxyl radi cals in the lipid phase of LDL. These results indicate that tyrosyl ra dical stimulates LDL lipid peroxidation. In striking contrast to other cell-mediated mechanisms for LDL oxidation, the myeloperoxidase-catal yzed reaction is independent of free metal ions. This raises the possi bility that tyrosyl radical generated by myeloperoxidase is of physiol ogical importance in making LDL atherogenic.