Blood miR-1275 is associated with risk of ischemic stroke and inhibits macrophage foam cell formation by targeting ApoC2 gene
Blood miR-1275 is associated with risk of ischemic stroke and inhibits macrophage foam cell formation by targeting ApoC2 gene
复制标题
血液 miR-1275 与缺血性中风风险相关，并通过靶向 Apoc2 基因抑制巨噬细胞泡沫细胞形成
DOI：
10.1016/j.gene.2020.144364
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发表时间：
2020-03-20
期刊：
影响因子：
3.5
通讯作者：
Lv, Ziquan
中科院分区：
文献类型：
--
作者：
Li, Lu;Xu, Wang;Lv, Ziquan
载脂蛋白C2（ApoC 2）是载脂蛋白C家族的重要成员，是脂蛋白脂酶（LPL）的主要激活剂。在心血管和脑血管系统中，LPL-ApoC 2复合物的脂解活性对于富含磷脂酰肌醇的脂蛋白的代谢至关重要，并有助于缺血性卒中（IS）的发病机制。然而，ApoC 2在IS发展中的调控仍不清楚。本研究首先利用生物信息学技术对25例IS患者和25例正常对照者血细胞中ApoC 2靶向microRNAs（miRNAs）进行了研究，并利用miRNAs芯片比较了两组患者血细胞中miRNAs的表达谱。预测miR-1275与ApoC 2的3'非翻译区结合，并且在IS患者中观察到血液miR-1275水平显著降低。双荧光素酶报告基因分析和定量RT-PCR证实miR-1275在THP-1源性巨噬细胞中对ApoC 2的调控作用。miR-1275还抑制细胞摄取ox-LDL并抑制巨噬细胞泡沫细胞的形成。此外，通过TaqMan测定法在279名IS患者和279名对照受试者中验证了全血miR-1275水平。miR-1275水平在IS病例中显著降低，logistic回归分析显示miR-1275水平与IS的发生呈负相关（校正OR，0.76; 95%CI，0.69-0.85; p < 0.001）。将miR-1275添加到传统风险因素中显示出IS的附加预测值。我们的研究表明，血中miR-1275水平与IS的发生呈负相关，miR-1275可能通过靶向ApoC 2和阻断巨噬细胞泡沫细胞的形成而发挥抗IS发展的动脉粥样硬化保护作用。
Apolipoprotein C2 (ApoC2) is an important member of the apolipoprotein C family and functions as a major activator of lipoprotein lipase (LPL). In cardiovascular and cerebrovascular systems, the lipolytic activity of the LPL-ApoC2 complex is critical for the metabolism of triglyceride-rich lipoproteins and contributes to the pathogenesis of ischemic stroke (IS). However, the regulation of ApoC2 in IS development remains unclear. In this study, we first explored potential ApoC2-targeting microRNAs (miRNAs) by bioinformatics tool and compared the miRNA expression profiles in the blood cells of 25 IS patients and 25 control subjects by miRNA microarray. miR-1275 was predicted to bind with the 3' untranslated region of ApoC2, and a significant reduction of blood miR-1275 levels was observed in IS patients. Dual-luciferase reporter assay and quantitative RT-PCR confirmed the regulation of ApoC2 by miR-1275 in THP-1 derived macrophages. miR-1275 also inhibited cellular uptake of ox-LDL and suppressed formation of macrophage foam cell. Furthermore, the whole blood miR-1275 levels were validated in 279 IS patients and 279 control subjects by TaqMan assay. miR-1275 levels were significantly lower in IS cases and logistic regression analysis showed that miR-1275 level was negatively associated with the occurrence of IS (adjusted OR, 0.76; 95% CI, 0.69-0.85; p < 0.001). Addition of miR-1275 to traditional risk factors showed an additive prediction value for IS. Our study shows that blood miR-1275 levels were negatively associated with the occurrence of IS, and miR-1275 might exert an athero-protective role against the development of IS by targeting ApoC2 and blocking the formation of macrophage foam cells.