Van Eck Miranda, Singaraja Roshni R, Ye Dan, Hildebrand Reeni B, James Erick R, Hayden Michael R, Van Berkel Theo J C
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):929-34. doi: 10.1161/01.ATV.0000208364.22732.16. Epub 2006 Feb 2.
ATP-binding cassette transporter A1 (ABCA1) is a key regulator of cellular cholesterol and phospholipid transport. Previously, we have shown that inactivation of macrophage ABCA1 induces atherosclerosis in low-density lipoprotein receptor knockout (LDLr-/-) mice. However, the possibly beneficial effects of specific upregulation of macrophage ABCA1 on atherogenesis are still unknown.
Chimeras that specifically overexpress ABCA1 in macrophages were generated by transplantation of bone marrow from human ABCA1 bacterial artificial chromosome (BAC) transgenic mice into LDLr-/- mice. Peritoneal macrophages isolated from the ABCA1 BAC --> LDLr-/- chimeras exhibited a 60% (P=0.0006) increase in cholesterol efflux to apolipoprotein AI. To induce atherosclerosis, the mice were fed a Western-type diet containing 0.25% cholesterol and 15% fat for 9, 12, and 15 weeks, allowing analysis of effects on initial lesion development as well as advanced lesions. No significant effect of macrophage ABCA1 overexpression was observed on atherosclerotic lesion size after 9 weeks on the Western-type diet (245+/-36x10(3) microm2 in ABCA1 BAC --> LDLr-/- mice versus 210+/-20x10(3) microm2 in controls). However, after 12 weeks, the mean atherosclerotic lesion area in ABCA1 BAC --> LDLr-/- mice remained only 164+/-15x10(3) microm2 (P=0.0008) compared with 513+/-56x10(3) microm2 in controls (3.1-fold lower). Also, after 15 weeks on the diet, lesions in mice transplanted with ABCA1 overexpressing bone marrow were still 1.6-fold smaller (393+/-27x10(3) microm2 compared with 640+/-59x10(3) microm2 in control transplanted mice; P=0.0015).
ABCA1 upregulation in macrophages inhibits the progression of atherosclerotic lesions.
ATP结合盒转运蛋白A1（ABCA1）是细胞胆固醇和磷脂转运的关键调节因子。此前，我们已经表明巨噬细胞ABCA1失活会在低密度脂蛋白受体敲除（LDLr-/-）小鼠中诱发动脉粥样硬化。然而，巨噬细胞ABCA1特异性上调对动脉粥样硬化发生的潜在有益作用仍不清楚。
通过将来自人ABCA1细菌人工染色体（BAC）转基因小鼠的骨髓移植到LDLr-/-小鼠中，构建了巨噬细胞中特异性过表达ABCA1的嵌合体小鼠。从ABCA1 BAC→LDLr-/-嵌合体小鼠分离的腹腔巨噬细胞对载脂蛋白AI的胆固醇流出增加了60%（P = 0.0006）。为了诱发动脉粥样硬化，给小鼠喂食含0.25%胆固醇和15%脂肪的西式饮食9周、12周和15周，以便分析对初始病变发展以及晚期病变的影响。在西式饮食9周后，未观察到巨噬细胞ABCA1过表达对动脉粥样硬化病变大小有显著影响（ABCA1 BAC→LDLr-/-小鼠为245±36×10³平方微米，对照组为210±20×10³平方微米）。然而，12周后，ABCA1 BAC→LDLr-/-小鼠的平均动脉粥样硬化病变面积仅为164±15×10³平方微米（P = 0.0008），而对照组为513±56×10³平方微米（低3.1倍）。同样，在饮食15周后，移植了过表达ABCA1骨髓的小鼠的病变仍小1.6倍（393±27×10³平方微米，而对照移植小鼠为640±59×10³平方微米；P = 0.0015）。
巨噬细胞中ABCA1上调可抑制动脉粥样硬化病变的进展。
