Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs.
Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs.
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DOI：
10.1161/atvbaha.114.303425
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Jo H
中科院分区：
文献类型：
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作者：
Kumar S;Kim CW;Simmons RD;Jo H
动脉粥样硬化优先发生在动脉区域暴露于干扰流，部分原因是由于基因表达的改变。微小RNA（microRNAs，miRNAs）是一类非编码基因，通过靶向信使RNA转录物在转录后调节基因表达。新出现的证据表明，在体外和体内，流动条件的改变调节内皮细胞中miRNA的表达。这些流动敏感的microRNA被称为“mechano-miRs”，调节内皮基因表达，并且可以调节内皮功能障碍和动脉粥样硬化。miRNA如miR-10a、-19a、-23b、-17792、-21、-663、-92a、-143/145、-101、-126、-712、205和-155已被鉴定为机械miR。这些miRNAs中的许多最初在体外被鉴定为流动敏感的，并且后来发现通过功能获得或功能丧失方法在体内内皮功能和/或动脉粥样硬化中起关键作用。这些mechano-miR靶向的关键信号传导途径包括内皮细胞周期、炎症、凋亡和一氧化氮信号传导。此外，我们最近已经表明，miR-712/205家族，这是上调的干扰流，有助于内皮炎症和血管通透性过高，通过靶向组织抑制剂的金属蛋白酶-3（TIMP 3），调节金属蛋白酶（MMP）和去整合素和金属蛋白酶（亚当斯）。与动脉粥样硬化有关的机械-miR被称为“机械敏感性动脉粥样硬化-miR”，并且是预防或治疗动脉粥样硬化的潜在治疗靶点。本文综述了机械敏感性动脉粥样硬化miR及其在血管生物学和动脉粥样硬化中的作用。
Atherosclerosis preferentially occurs in arterial regions exposed to disturbed flow, in part, due to alterations in gene expression. MicroRNAs (miRNAs) are small, noncoding genes that post-transcriptionally regulate gene expression by targeting messenger RNA transcripts. Emerging evidence indicates that alteration of flow conditions regulate expression of miRNAs in endothelial cells both in vitro and in vivo. These flow-sensitive microRNAs, known as “mechano-miRs”, regulate endothelial gene expression, and can regulate endothelial dysfunction and atherosclerosis. MiRNAs such as, miR-10a, -19a, -23b, -17~92, -21, -663, -92a, -143/145, -101, -126, -712, 205, and -155, have been identified as mechano-miRs. Many of these miRNAs were initially identified as flow-sensitive in vitro and were later found to play a critical role in endothelial function and/or atherosclerosis in vivo through either gain-of-function or loss-of-function approaches. The key signaling pathways that are targeted by these mechano-miRs include the endothelial cell cycle, inflammation, apoptosis, and nitric oxide signaling. Furthermore, we have recently shown that the miR-712/205 family, which is upregulated by disturbed flow, contributes to endothelial inflammation and vascular hyper-permeability by targeting tissue inhibitor of metalloproteinase-3 (TIMP3), which regulates metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). The mechano-miRs that are implicated in atherosclerosis are termed as “mechanosensitive athero-miRs” and are potential therapeutic targets to prevent or treat atherosclerosis. This review summarizes the current knowledge of mechanosensitive athero-miRs and their role in vascular biology and atherosclerosis.