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Apoptosis occurs in established atherosclerotic plaques, with most cells demonstrated to be macrophages. Although macrophage apoptosis is implicated in formation of the necrotic core and co-localises with plaque rupture, the precise role of macrophages and macrophage apoptosis in established plaques in unknown. To study the effects of monocyte/macrophage apoptosis, we developed a transgenic macrophage ablation mouse (CD11b-DTR) in which administration of diphtheria toxin (DT) selectively kills monocyte/ macrophages. DT reduced both peripheral blood monocyte and tissue macrophage number by 84.4±8.4% and 84.3±2.5% respectively on flow cytometry and cell counts, and inhibited tissue macrophage function as demonstrated by a 88%±5.1 reduction in acetylated LDL uptake. To study the effects of monocyte/macrophage apoptosis in either plaque development or established atherosclerosis, ApoE-/- mice were transplanted with DTR +/+/ApoE-/- bone marrow and administered DT between 10-22w or 22-32weeks of age. Compared with controls, DT reduced plaque development of both aorta (5.4%±1.4 vs. 14.0%±1.9) and brachiocephalic arteries (9.5%±2.1 vs. 19.2%±2.4), but apparently did not significantly alter macrophage content, cell proliferation or apoptosis, or markers of plaque rupture (buried fibrous caps and intraplaque haemorrhage). However, necrotic cores were decreased as a % of plaque volume by DT (7.9%±1.6 vs 13.6%±2.0), and collagen content was also decreased. In contrast, despite a 41% reduction in circulating monocytes, DT did not alter plaque size, plaque composition or markers of plaque rupture in established plaques. We conclude that monocyte/macrophage apoptosis has profound effects on atherogenesis, but has minimal effect on plaque progression or plaque composition once advanced plaques have developed, and does not promote necrotic core formation or plaque rupture. The consequences of monocyte/macrophage apoptosis are thus critically dependent on extent of plaque development.
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J. Vasc. Biol. 42, Sup:2 (2005) p56