MicroRNA-144 Silencing Protects Against Atherosclerosis in Male, but Not Female Mice
MicroRNA-144 Silencing Protects Against Atherosclerosis in Male, but Not Female Mice
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DOI：
10.1161/atvbaha.119.313633
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发表时间：
2020-02-01
影响因子：
8.7
通讯作者：
Vallim, Thomas Q. de Aguiar
中科院分区：
文献类型：
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作者：
Cheng, Joan;Cheng, Angela;Vallim, Thomas Q. de Aguiar
目的：动脉粥样硬化是发达国家的主要死亡原因。microRNA作为基因表达的微调因子，在动脉粥样硬化的病理生理和进展中发挥重要作用。我们和其他人之前证明了microRNA-144（miR-144）的功能是转录后调节ABCA 1（ATP结合盒转运蛋白A1）和血浆HDL（高密度脂蛋白）胆固醇水平。在这里，我们探讨了miR-144抑制如何防止动脉粥样硬化。方法和结果：我们证明，miR-144沉默减少了雄性低密度脂蛋白受体缺失（Ldlr（-/-））小鼠的动脉粥样硬化，但对雌性小鼠没有影响。miR-144拮抗作用增加循环HDL胆固醇水平，重塑HDL颗粒，并增强胆固醇逆向转运。值得注意的是，对HDL和胆固醇逆向转运的影响在雄性小鼠中更明显，表明性别特异性差异可能有助于沉默miR-144对动脉粥样硬化的影响。作为一种分子机制，我们确定了氧化固醇代谢酶CYP 7 B1（细胞色素P450酶7 B1）作为雄性而非雌性小鼠中的miR-144调控基因。与CYP 7 B1活性的miR-144依赖性变化一致，我们发现雄性小鼠而非雌性小鼠中27-羟基胆固醇（一种已知的促动脉粥样硬化固醇和CYP 7 B1的内源性底物）水平降低。结论：我们的数据表明沉默miR-144具有性别特异性效应，并且用靶向miR-144的反义寡核苷酸治疗可能导致心血管疾病患者胆固醇逆向转运和氧固醇代谢的增强。
Objective: Atherosclerosis is a leading cause of death in developed countries. MicroRNAs act as fine-tuners of gene expression and have been shown to have important roles in the pathophysiology and progression of atherosclerosis. We, and others, previously demonstrated that microRNA-144 (miR-144) functions to post-transcriptionally regulate ABCA1 (ATP binding cassette transporter A1) and plasma HDL (high-density lipoprotein) cholesterol levels. Here, we explore how miR-144 inhibition may protect against atherosclerosis. Approach and Results: We demonstrate that miR-144 silencing reduced atherosclerosis in male, but not female low-density lipoprotein receptor null (Ldlr(-/-)) mice. MiR-144 antagonism increased circulating HDL cholesterol levels, remodeled the HDL particle, and enhanced reverse cholesterol transport. Notably, the effects on HDL and reverse cholesterol transport were more pronounced in male mice suggesting sex-specific differences may contribute to the effects of silencing miR-144 on atherosclerosis. As a molecular mechanism, we identify the oxysterol metabolizing enzyme CYP7B1 (cytochrome P450 enzyme 7B1) as a miR-144 regulated gene in male, but not female mice. Consistent with miR-144-dependent changes in CYP7B1 activity, we show decreased levels of 27-hydroxycholesterol, a known proatherogenic sterol and the endogenous substrate for CYP7B1 in male, but not female mice. Conclusions: Our data demonstrate silencing miR-144 has sex-specific effects and that treatment with antisense oligonucleotides to target miR-144 might result in enhancements in reverse cholesterol transport and oxysterol metabolism in patients with cardiovascular disease.