From the Department of Pathology, University of Chicago, IL.
Arterioscler Thromb Vasc Biol. 2014 Feb;34(2):262-9. doi: 10.1161/ATVBAHA.113.302831. Epub 2013 Dec 12.
Inbred mouse strains have different susceptibilities to experimental atherosclerosis. The C57BL/6 strain is among the most sensitive and has, therefore, been the most widely used in atherosclerosis studies, whereas many strains are resistant. The FVB/N strain is highly resistant to atherosclerosis on the apolipoprotein E (apoE)- and low-density lipoprotein (LDL) receptor-deficient backgrounds. High-density lipoprotein and its major apoprotein, apoA-I, have been shown to be protective against atherogenesis on the C57BL/6 background. We here examine the influence of genetic background on the atheroprotective nature of apoA-I.
ApoE-deficient/apoA-I-deficient mice were generated in the C57BL/6 and FVB/N strains from apoE-deficient mice. After 6 to 10 weeks on a Western-type diet, plasma lipids and atherosclerotic lesion size were assessed. Macrophage recruitment, cholesterol regulation, and blood monocyte levels were examined as potential mechanisms driving lesion size differences. FVB/N knockout mice had higher plasma very-LDL/LDL cholesterol than their C57BL/6 counterparts. ApoA-I deficiency decreased very-LDL/LDL cholesterol in C57BL/6 mice but not in FVB/N mice. FVB/N single and double knockout mice had less lesion than C57BL/6 6 to 10 weeks on diet. ApoA-I deficiency augmented lesion development only in C57BL/6 mice. Macrophage recruitment to thioglycollate-treated peritoneum and diet-induced blood monocyte levels reflected the pattern of lesion development among the 4 genotypes. ApoA-I deficiency increased macrophage cholesterol content only in C57BL/6. FVB/N plasma was a better acceptor for macrophage cholesterol efflux than C57BL/6.
ApoA-I is atheroprotective only in certain genetic contexts. In the C57BL/6 context, but not FVB/N, apoA-I decreases inflammatory macrophage recruitment and monocytosis, contributors to lesion formation.
近交系小鼠对实验性动脉粥样硬化有不同的易感性。C57BL/6 品系是最敏感的品系之一，因此在动脉粥样硬化研究中被广泛应用，而许多品系则具有抗性。FVB/N 品系在载脂蛋白 E（apoE）和低密度脂蛋白（LDL）受体缺陷背景下对动脉粥样硬化高度抵抗。高密度脂蛋白及其主要载脂蛋白 apoA-I 已被证明在 C57BL/6 背景下具有抗动脉粥样硬化形成的作用。我们在此研究遗传背景对 apoA-I 抗动脉粥样硬化形成的影响。
从 apoE 缺陷小鼠中生成了 C57BL/6 和 FVB/N 品系的 apoE/apoA-I 双缺陷小鼠。在 Western 饮食 6 至 10 周后，评估血浆脂质和动脉粥样硬化病变大小。研究了巨噬细胞募集、胆固醇调节和血液单核细胞水平作为驱动病变大小差异的潜在机制。FVB/N 敲除小鼠的血浆非常低密度脂蛋白/低密度脂蛋白胆固醇高于 C57BL/6 对照小鼠。apoA-I 缺陷降低了 C57BL/6 小鼠的非常低密度脂蛋白/低密度脂蛋白胆固醇，但对 FVB/N 小鼠没有影响。在饮食 6 至 10 周时，FVB/N 单敲除和双敲除小鼠的病变小于 C57BL/6 小鼠。apoA-I 缺陷仅在 C57BL/6 小鼠中增强了病变发展。巨噬细胞募集到巯基醋酸处理的腹腔和饮食诱导的血液单核细胞水平反映了 4 种基因型之间病变发展的模式。apoA-I 缺陷仅在 C57BL/6 中增加了巨噬细胞胆固醇含量。FVB/N 血浆比 C57BL/6 血浆更能接受巨噬细胞胆固醇外流。
apoA-I 仅在某些遗传背景下具有抗动脉粥样硬化作用。在 C57BL/6 背景下，但不是在 FVB/N 背景下，apoA-I 减少了炎症性巨噬细胞募集和单核细胞增多症，这是病变形成的原因。
