Expression of Human Myeloperoxidase by Macrophages Promotes Atherosclerosis in Mice

Abstract

Background— Myeloperoxidase (MPO) colocalizes with macrophages in the human artery wall, and its characteristic oxidation products have been detected in atherosclerotic lesions. Thus, oxidants produced by the enzyme might promote atherosclerosis. However, macrophages in mouse atherosclerotic tissue do not express MPO. Therefore, mice are an inappropriate model for testing the role of MPO in vascular disease. To overcome this problem, we generated and studied transgenic (Tg) mice that contained the human MPO gene. Methods and Results— We produced human MPO -Tg mice with use of a Visna virus promoter. To confine MPO expression to macrophages, we lethally irradiated LDL receptor–deficient mice and repopulated their bone marrow with cells from wild-type mice or MPO -Tg mice. Despite having similarly high levels of cholesterol after maintenance on a high-fat, high-cholesterol diet, the MPO -Tg animals developed a 2-fold greater atherosclerotic area in the aorta than did mice transplanted with wild-type bone marrow ( P =0.00003). Conclusions— Our observations indicate that expression of human MPO in macrophages promotes atherosclerosis in hypercholesterolemic mice, raising the possibility that the enzyme might be a potential therapeutic target for preventing cardiovascular disease in humans.