Objective-Using bone marrow transplantation, we assessed the impact of macrophage-derived phospholipid transfer protein (PLTP) on lesion development in hypercholesterolemic mice that expressed either normal levels of mouse apolipoprotein AI (apoAI) or elevated levels of only human apoAI. Methods and Results-Bone marrow transplantations were performed in low-density lipoprotein receptor-deficient mice (LDLrϪ/Ϫ) that expressed either normal levels of mouse apoAI (msapoAI) or high levels of only human apoAI (msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg). Mice were lethally irradiated, reconstituted with either PLTP-expressing or PLTP-deficient bone marrow cells, and fed a high-fat diet over 16 weeks. Macrophage PLTP deficiency increased atherosclerosis in LDLrϪ/Ϫ mice with minimal changes in total plasma cholesterol levels. In contrast, the extent of atherosclerosis in msapoAIϪ/Ϫ, LDLrϪ/Ϫ, huapoAITg mice was not significantly different between groups that had received PLTPϪ/Ϫ or PLTPϩ/ϩ bone marrow. In vitro studies indicated that PLTP deficiency led to a significant decrease in ␣-tocopherol content and increased oxidative stress in bone marrow cells. Key Words: phospholipid transfer protein Ⅲ apolipoprotein AI Ⅲ atherosclerosis Ⅲ transgenic mice Ⅲ bone marrow transplant P hospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in phospholipid and vitamin E transfers among plasma lipoproteins as well as between lipoproteins and cell membranes. [1][2][3] In addition, PLTP participates in the formation of pre-␤-highdensity lipoproteins (HDLs) that promote the efflux of excess cellular cholesterol 4 -6 via the ATP-binding cassette transporter A1 (ABCA1) pathway. 7 Recent in vivo studies of PLTP transgenic and PLTP knockout mice report that PLTP plays a role in the control of plasma levels of both HDLs and apolipoprotein B (apoB)-containing lipoproteins. 8 -11 Systemic PLTP deficiency is atheroprotective in different strains of hypercholesterolemic mice, and transgenic mice overexpressing human PLTP have an increased risk of atherosclerosis. 9,12,13 To further support a proatherogenic potential of plasma PLTP in vivo, a positive correlation between circulating PLTP and the risk of coronary artery disease is observed in humans. 14 These studies have emphasized the action of PLTP at the systemic level and suggest that its proatherogenicity is likely a result of its actions on circulating lipoproteins. Although the impact of systemic PLTP on lipoprotein metabolism and antioxidant potential was studied, its tissue-specific actions have not been addressed. Conclusions-OurPLTP is synthesized and secreted by most cell types in humans and mice, and although first described as a plasma protein, it was recently shown to be expressed in macrophages within the intima of human atherosclerotic arteries. 15 We and others reported that PLTP is synthesized and secreted by cultured macrophages, and that the gene is upregulated by liver X receptor (LXR) ligands. 15,16 Macrophages are ess...

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Lyst beige (beige) mice crossed with LDL receptordeficient (LDLr ؊ / ؊ ) mice had a distinct atherosclerotic lesion morphology that was not observed in LDLr ؊ / ؊ mice. This morphology is often associated with a stable plaque phenotype. We hypothesized that macrophage expression of the beige mutation accounted for this distinct morphology. Cultured bone marrow-derived macrophages from LDLr ؊ / ؊ and beige,LDLr ؊ / ؊ mice were compared for their ability to accumulate cholesterol, efflux cholesterol, migrate in response to chemotactic stimuli through Matrigel ® -coated membranes, and express matrix metalloproteinase 9 (MMP9). No differences in cholesterol metabolism were identified. Beige,LDLr ؊ / ؊ macrophage invasion in vitro appeared to be less than LDLr ؊ / ؊ macrophage invasion but did not achieve significance. Nevertheless, tumor necrosis factor-␣ -induced MMP9 expression, secretion, and enzymatic activity of beige,LDLr ؊ / ؊ macrophages were all significantly decreased compared with those of LDLr ؊ / ؊ macrophages ( P Ͻ 0.05).

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