Inhibition of microRNA-103 attenuates inflammation and endoplasmic reticulum stress in atherosclerosis through disrupting the PTEN-mediated MAPK signaling
Inhibition of microRNA-103 attenuates inflammation and endoplasmic reticulum stress in atherosclerosis through disrupting the PTEN-mediated MAPK signaling
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DOI：
10.1002/jcp.28979
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Li, Jian
中科院分区：
文献类型：
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作者：
Jiang, Li;Qiao, Yanguo;Li, Jian
动脉粥样硬化(AS)是一种慢性大动脉疾病，是心脏病和卒中的潜在病理过程。前人的研究发现，microRNAs(MiRs)参与了AS的几个关键过程。载脂蛋白E基因敲除(ApoE(-/-))小鼠喂饲高脂饲料(HFD)建立AS模型。在小鼠模型中检测miR-103的表达。在高脂饲料喂养的ApoE(-/-)小鼠和氧化型低密度脂蛋白(ox-LDL)暴露的人主动脉内皮细胞(HAECs)中，观察miR-103对炎症反应和内质网应激(ERS)的影响。通过荧光素酶活性检测和实时定量聚合酶链式反应(RT-qPCR)鉴定miR-103与磷酸酶和张力蛋白同源物(PTEN)的关系。进一步应用增益函数和损失函数方法研究miR-103和PTEN对ERS的调节作用。用PD98059阻断该通路，分析MAPK信号转导途径的作用。在喂饲HFD的ApoEApoE(-/-)小鼠中，MIR-103高表达。MiR-103的下调抑制了喂养HFD和ox-LDL暴露的HAECs的ApoE(-/-)小鼠分离的内皮细胞的炎症和ERS。此外，miR-103还可以靶向PTEN并下调其表达。PTEN的过表达逆转了miR-103诱导的MAPK信号的激活。此外，PTEN的上调或MAPK信号的抑制可以减轻miR-103在体内和体外诱导的炎症和ERS。因此，miR-103的缺失通过阻断PTEN介导的MAPK信号通路来抑制AS的进展。
Atherosclerosis (AS), a chronic disorder of large arteries, is the underlying pathological process of heart disease and stroke. Former researchers have found that microRNAs (miRs) are involved in the several key processes of AS. Apolipoprotein E knockout (ApoE(-/-)) mice fed a high-fat-diet (HFD) to establish AS model. The expression of miR-103 was characterized in the mice model. The effects of miR-103 on inflammation and endoplasmic reticulum stress (ERS) were analyzed when the expression of miR-103 was inhibited in ApoE(-/-) mice fed an HFD and human aortic endothelial cells (HAECs) exposed to oxidized low-density lipoprotein (ox-LDL). The relationship between miR-103 and phosphatase and tensin homolog (PTEN) was identified by luciferase activity detection and real-time quantitative polymerase chain reaction (RT-qPCR). Gain- and loss-function approaches were further applied for investigating the regulatory effects of miR-103 and PTEN on ERS. Role of MAPK signaling was then analyzed using PD98059 to block this pathway. miR-103 was highly expressed in the ApoEApoE(-/-) mice fed an HFD. Downregulation of miR-103 suppressed inflammation and ERS in endothelial cells isolated from ApoE(-/-) mice fed a HFD and ox-LDL-exposed HAECs. In addition, miR-103 can target PTEN and downregulate its expression. Overexpression of PTEN reversed the miR-103-induced activation of MAPK signaling. Moreover, PTEN upregulation or MAPK signaling inhibition ease miR-103-induced inflammation and ERS in vivo and in vitro. Thus, miR-103 depletion restrains the progression of AS through blocking PTEN-mediated MAPK signaling.