MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice.
MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice.
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DOI：
10.1161/jaha.112.003376
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发表时间：
2012-12
影响因子：
5.4
通讯作者：
Ono K
中科院分区：
文献类型：
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作者：
Horie T;Baba O;Kuwabara Y;Chujo Y;Watanabe S;Kinoshita M;Horiguchi M;Nakamura T;Chonabayashi K;Hishizawa M;Hasegawa K;Kume N;Yokode M;Kita T;Kimura T;Ono K
胆固醇通过ATP结合盒转运体ABCA 1和ABCG 1从细胞流出到载脂蛋白A-I（apoA-I）受体被认为是抗动脉粥样硬化机制的中心。已知microRNA（miR）-33在体内靶向ABCA 1和ABCG 1。我们评估了miR-33基因缺失对动脉粥样硬化小鼠模型的影响。与miR-33+/+ Apoe −/−小鼠相比，miR-33和apoE双敲除小鼠（miR-33−/− Apoe−/−）显示循环HDL-C水平升高，胆固醇流出能力增强。与miR-33 +/+ Apoe −/−巨噬细胞相比，miR-33−/−Apoe−/−小鼠的腹腔巨噬细胞显示出增强的胆固醇流出至apoA-I和HDL-C。与这些结果一致，miR-33−/−Apoe−/−小鼠显示斑块大小和脂质含量减少。为了阐明miR-33在血细胞中的作用，在这些小鼠中进行骨髓移植。与移植miR-33 +/+ Apoe −/−骨髓的小鼠相比，移植miR-33−/− Apoe −/−骨髓的小鼠动脉粥样硬化斑块中的脂质含量显著降低，而HDL-C没有升高。与miR-33+/+Apoe−/−小鼠相比，miR-33−/− Apoe −/−小鼠中一些经验证的miR-33靶点如RIP 140（NRIP 1）和CROT上调，而CPT 1a和AMPKα则没有。这些数据表明，miR-33缺乏可提高HDL-C，增加胆固醇通过ABCA 1和ABCG 1从巨噬细胞流出，并阻止动脉粥样硬化的进展。在miR-33缺陷小鼠中，许多基因发生了改变，需要进行详细的实验来建立人类miR-33靶向治疗。
Cholesterol efflux from cells to apolipoprotein A-I (apoA-I) acceptors via the ATP-binding cassette transporters ABCA1 and ABCG1 is thought to be central in the antiatherogenic mechanism. MicroRNA (miR)-33 is known to target ABCA1 and ABCG1 in vivo. We assessed the impact of the genetic loss of miR-33 in a mouse model of atherosclerosis. MiR-33 and apoE double-knockout mice (miR-33−/−Apoe−/−) showed an increase in circulating HDL-C levels with enhanced cholesterol efflux capacity compared with miR-33+/+Apoe−/− mice. Peritoneal macrophages from miR-33−/−Apoe−/− mice showed enhanced cholesterol efflux to apoA-I and HDL-C compared with miR-33+/+Apoe−/− macrophages. Consistent with these results, miR-33−/−Apoe−/− mice showed reductions in plaque size and lipid content. To elucidate the roles of miR-33 in blood cells, bone marrow transplantation was performed in these mice. Mice transplanted with miR-33−/−Apoe−/− bone marrow showed a significant reduction in lipid content in atherosclerotic plaque compared with mice transplanted with miR-33+/+Apoe−/− bone marrow, without an elevation of HDL-C. Some of the validated targets of miR-33 such as RIP140 (NRIP1) and CROT were upregulated in miR-33−/−Apoe−/− mice compared with miR-33+/+Apoe−/− mice, whereas CPT1a and AMPKα were not. These data demonstrate that miR-33 deficiency serves to raise HDL-C, increase cholesterol efflux from macrophages via ABCA1 and ABCG1, and prevent the progression of atherosclerosis. Many genes are altered in miR-33-deficient mice, and detailed experiments are required to establish miR-33 targeting therapy in humans.