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 expressed in human atherosclerotic lesions. The enzyme uses H2O2 generated by the cells to oxidize L-tyrosine to tyrosyl radical, a catalyst for protein dityrosine synthesis. We have explored the possibility that tyrosyl radical initiates lipid peroxidation, which may be of pivotal importance in transforming low density lipoprotein (LDL) into atherogenic particles. Exposure of LDL to L-tyrosine and activated human neutrophils caused peroxidation of LDL lipids. LDL oxidation required L-tyrosine but was independent of free metal ions; catalase and heme poisons were inhibitory. Incubation of LDL with L-tyrosine, myeloperoxidase, 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 oxidation by both activated neutrophils and myeloperoxidase. The antioxidants ascorbate and probucol, but not vitamin E, inhibited LDL oxidation by myeloperoxidase, H2O2, and L-tyrosine. Ascorbate blocked dityrosine synthesis, while probucol scavenged chain-propagating peroxyl radicals in the lipid phase of LDL. These results indicate that tyrosyl radical stimulates LDL lipid peroxidation. In striking contrast to other cell-mediated mechanisms for LDL oxidation, the myeloperoxidase-catalyzed reaction is independent of free metal ions. This raises the possibility that tyrosyl radical generated by myeloperoxidase is of physiological importance in making LDL atherogenic.
Savenkova
M L
ML
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Mueller
D M
DM
Heinecke
J W
JW
D001205:Ascorbic Acid / Q000494:pharmacology; D002384:Catalysis; D005609:Free Radicals; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008054:Lipid Peroxides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism*; D011341:Probucol / Q000494:pharmacology; D013379:Substrate Specificity; D014443:Tyrosine / Q000737:chemistry*; D014810:Vitamin E / Q000494:pharmacology
D005609:Free Radicals; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D014810:Vitamin E; D014443:Tyrosine; D009195:Peroxidase; D011341:Probucol; D001205:Ascorbic Acid