Increased atherosclerosis in myeloperoxidase-deficient mice

Myeloperoxidase (MPO), a heme enzyme secreted by activated phagocytes, gene rates an array of oxidants proposed to play critical roles in host defense and local tissue damage, Both MPO and its reaction products are present in human atherosclerotic plaque, and it has been proposed that MPO oxidatively modifies targets in the artery wall. We have now generated MPO-deficient m ice, and show here that neutrophils from homozygous mutants lack peroxidase and chlorination activity in vitro and fail to generate chlorotyrosine or to kill Candida albicans in vivo. To examine the potential role of MPO in a therosclerosis, we subjected LDL receptor-deficient mice to lethal irradiat ion, repopulated their marrow with MPO-deficient or wild-type cells, and pr ovided them a high-fat, high-cholesterol diet for 14 weeks. White cell coun ts and plasma lipoprotein profiles were similar between the two groups at s acrifice, Cross-sectional analysis of the aorta indicated that lesions in M PO-deficient mice were about 50% larger than controls, Similar results were obtained in a genetic cross with LDL receptor-deficient mice. In contrast to advanced human atherosclerotic lesions, the chlorotyrosine content of ao rtic lesions from wild-type as well as MPO-deficient mice was essentially u ndetectable, These data suggest an unexpected, protective role for MPO-gene rated reactive intermediates in murine atherosclerosis, They also identify an important distinction between murine and human atherosclerosis with rega rd to the potential involvement of MPO in protein oxidation.