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.

中文翻译：

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MicroRNA-144 沉默可以预防雄性小鼠的动脉粥样硬化，但不能预防雌性小鼠。

目的 动脉粥样硬化是发达国家死亡的主要原因。MicroRNA 作为基因表达的微调器，已被证明在动脉粥样硬化的病理生理学和进展中具有重要作用。我们和其他人之前证明 microRNA-144 (miR-144) 具有转录后调节 ABCA1（ATP 结合盒转运蛋白 A1）和血浆 HDL（高密度脂蛋白）胆固醇水平的功能。在这里，我们探讨 miR-144 抑制如何预防动脉粥样硬化。方法和结果：我们证明 miR-144 沉默可减少雄性而非雌性低密度脂蛋白受体无效 (Ldlr-/-) 小鼠的动脉粥样硬化。MiR-144 拮抗作用增加了循环 HDL 胆固醇水平，重塑 HDL 颗粒，并增强反向胆固醇转运。值得注意的是，对 HDL 和反向胆固醇转运的影响在雄性小鼠中更为明显，表明性别特异性差异可能导致沉默 miR-144 对动脉粥样硬化的影响。作为一种分子机制，我们将氧甾醇代谢酶 CYP7B1（细胞色素 P450 酶 7B1）确定为雄性小鼠而非雌性小鼠中的 miR-144 调节基因。与 CYP7B1 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）的 27-羟基胆固醇（一种已知的促动脉粥样硬化甾醇和 CYP7B1 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，并且用反义寡核苷酸靶向 miR-144 进行治疗可能会增强心血管疾病患者的反向胆固醇转运和氧甾醇代谢。