MicroRNA-24 Regulates Macrophage Behavior and Retards Atherosclerosis
MicroRNA-24 Regulates Macrophage Behavior and Retards Atherosclerosis
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DOI：
10.1161/atvbaha.114.304088
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发表时间：
2014-09-01
影响因子：
8.7
通讯作者：
Johnson, Jason L.
中科院分区：
文献类型：
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作者：
Di Gregoli, Karina;Jenkins, Nicholas;Johnson, Jason L.
我们最近的研究强调了膜1型基质金属蛋白酶（MMP）-14作为与动脉粥样硬化斑块进展潜在相关的巨噬细胞侵袭性亚群的选择性标志物。此外，集落刺激因子（CSF）可能通过microRNA对巨噬细胞MMP表达产生不同的影响。因此，我们的目的是确定和测试的病理生理作用的microRNAs，调节巨噬细胞MMP-14的表达在动脉粥样硬化plaque progression.Approach和结果相比，巨噬细胞CSF分化的巨噬细胞，粒细胞/巨噬细胞CSF成熟的巨噬细胞表现出降低MMP-14的mRNA水平，但增加蛋白质的表达和活性，这导致在提高巨噬细胞的侵袭。与粒细胞/巨噬细胞CSF巨噬细胞相比，鉴定为靶向MMP-14的MicroRNA-24在巨噬细胞CSF中相应地增加。沉默巨噬细胞CSF巨噬细胞中的microRNA-24显著增加MMP-14表达并增强其侵袭能力，模拟粒细胞/巨噬细胞CSF巨噬细胞，并表明粒细胞/巨噬细胞CSF以microRNA-24依赖性方式调节MMP-14蛋白表达和随后的巨噬细胞侵袭。在人冠状动脉粥样硬化斑块中，泡沫细胞巨噬细胞中MMP-14蛋白表达增加与病变表现出与不稳定表型相关的组织学特征相关。此外，microRNA-24在这些动脉粥样硬化斑块中的表达与MMP-14蛋白表达呈负相关。此外，稳定斑块比不稳定斑块含有更高的microRNA-24水平，并且microRNA-24与表现出低MMP-14蛋白表达的泡沫细胞巨噬细胞共定位。最后，在动脉粥样硬化小鼠（载脂蛋白E缺陷），microRNA-24抑制增加斑块大小和巨噬细胞MMP-14 expressions.Conclusions-Taken在一起，我们的数据表明，下调microRNA-24促进侵入性巨噬细胞亚群，并发挥了新的调节作用，MMP-14蛋白水解活性，因此，斑块的稳定性，突出其治疗潜力。
Objective-Our recent studies have highlighted membrane type-1 matrix metalloproteinase (MMP)-14 as a selective marker for an invasive subset of macrophages potentially related to atherosclerotic plaque progression. Moreover, colony stimulating factors (CSF) may exert divergent effects on macrophage MMP expression, possibly through microRNAs. We, therefore, aim to identify and test the pathophysiological role of microRNAs, which modulate macrophage MMP-14 expression in atherosclerotic plaque progression.Approach and Results-Compared with macrophage CSF-differentiated macrophages, granulocyte/macrophage CSF-matured macrophages exhibited reduced MMP-14 mRNA levels but increased protein expression and activity, which resulted in heightened macrophage invasion. MicroRNA-24, identified to target MMP-14, was accordingly increased in macrophage CSF compared with granulocyte/macrophage CSF macrophages. Silencing microRNA-24 in macrophage CSF macrophages significantly increased MMP-14 expression and enhanced their invasive capacity, mimicking granulocyte/macrophage CSF macrophages, and suggesting that granulocyte/macrophage CSF modulates MMP-14 protein expression and subsequent macrophage invasion in a microRNA-24-dependent manner. In human coronary atherosclerotic plaques, increased MMP-14 protein expression in foam cell macrophages was associated with lesions exhibiting histological characteristics associated with an unstable phenotype. Furthermore, microRNA-24 expression in these atherosclerotic plaques was inversely related to MMP-14 protein expression. Moreover, stable plaques contained higher microRNA-24 levels than unstable plaques, and microRNA-24 colocalized with foam cell macrophages that exhibited low MMP-14 protein expression. Finally, in atherosclerotic mice (apolipoprotein E-deficient), microRNA-24 inhibition increased plaque size and macrophage MMP-14 expression.Conclusions-Taken together, our data demonstrates that downregulation of microRNA-24 promotes an invasive macrophage subset and plays a novel regulatory role in MMP-14 proteolytic activity and, therefore, plaque stability, highlighting its therapeutic potential.