Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis
Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis
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DOI：
10.1172/jci57275
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发表时间：
2011-07-01
影响因子：
15.9
通讯作者：
Moore, Kathryn J.
中科院分区：
文献类型：
--
作者：
Rayner, Katey J.;Sheedy, Frederick J.;Moore, Kathryn J.
血浆HDL水平在动脉粥样硬化中具有保护作用，但提高HDL水平的临床治疗仍然难以捉摸。脂质代谢的最新进展表明，miR-33（一种位于SREBF 2基因内的内含子microRNA）抑制胆固醇转运蛋白ABC转运蛋白A1（ABCA 1）的表达，并降低HDL水平。相反，抑制miR-33的机制增加ABCA 1和循环HDL水平，表明miR-33的拮抗作用可能具有动脉粥样硬化保护作用。由于动脉粥样硬化的消退在临床上是理想的，我们评估了miR-33抑制对LDL受体缺陷小鼠（Ldlr（-/-）小鼠）的影响，并建立了动脉粥样硬化斑块。用抗miR 33处理4周的小鼠显示循环HDL水平的增加和增强的胆固醇向血浆、肝脏和粪便的反向转运。与此一致，抗miR 33治疗的小鼠显示斑块大小和脂质含量减少，斑块稳定性标志物增加，炎症基因表达减少。值得注意的是，除了提高肝脏中的ABCA 1水平外，抗miR 33寡核苷酸直接靶向斑块巨噬细胞，其中它们增强ABCA 1表达和胆固醇去除。这些研究证实，通过抗miR 33寡核苷酸治疗提高HDL水平促进了胆固醇逆向转运和动脉粥样硬化消退，并表明这可能是治疗动脉粥样硬化性血管疾病的有希望的策略。
Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL levels have remained elusive. Recent advances in the understanding of lipid metabolism have revealed that miR-33, an intronic microRNA located within the SREBF2 gene, suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and circulating HDL levels, suggesting that antagonism of miR-33 may be atheroprotective. As the regression of atherosclerosis is clinically desirable, we assessed the impact of miR-33 inhibition in mice deficient for the LDL receptor (Ldlr(-/-) mice), with established atherosclerotic plaques. Mice treated with anti-miR33 for 4 weeks showed an increase in circulating HDL levels and enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with this, anti-miR33-treated mice showed reductions in plaque size and lipid content, increased markers of plaque stability, and decreased inflammatory gene expression. Notably, in addition to raising ABCA1 levels in the liver, anti-miR33 oligonucleotides directly targeted the plaque macrophages, in which they enhanced ABCA1 expression and cholesterol removal. These studies establish that raising HDL levels by anti-miR33 oligonucleotide treatment promotes reverse cholesterol transport and atherosclerosis regression and suggest that it may be a promising strategy to treat atherosclerotic vascular disease.