miR-499 released during myocardial infarction causes endothelial injury by targeting α7-nAchR
miR-499 released during myocardial infarction causes endothelial injury by targeting α7-nAchR
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DOI：
10.1111/jcmm.14474
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发表时间：
2019-07-03
影响因子：
5.3
通讯作者：
Dang, Xitong
中科院分区：
文献类型：
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作者：
Zhou, Rui;Huang, Wenjun;Dang, Xitong
急性心肌梗死（AMI）后全身血管炎症激增，加重动脉粥样硬化内皮损伤。探讨 AMI 期间心肌细胞释放的 miR-499 在内皮损伤中的作用。使用 qPCR 和 ELISA，我们发现 AMI 患者血浆 miR-499 显着升高，这与血清血栓调节蛋白（内皮损伤的标志物）直接相关。当 AMI 患者的血浆与人脐静脉内皮细胞 (HUVEC) 一起孵育时，内皮损伤标志物的表达显着增加，而 antagomiR-499 可以消除这种情况。在体外，缺氧/复氧（HX/R）的新生大鼠心肌细胞释放miR-499，该miR-499可以内化到大鼠肺微血管内皮细胞（RPMEC）中，从而加剧高糖诱导的损伤。计算机分析表明，编码 α 7-nAchR 的 CHRNA7 是 miR-499 的靶标，这在表达内源 α 7-nAchR 的细胞系中得到了验证。在高糖诱导的 RPMEC 损伤模型中，miR-499 加重，而强制 CHRNA7 表达则减轻损伤。此外，来自 Langendorff 灌注大鼠心脏的 HX/R 灌注液含有较高水平的 miR-499，显着损害导管和阻力动脉中缓激肽介导的内皮依赖性舒张，而 antagomiR-499 可以部分消除这种舒张。最后，血浆 miR-499 与内皮损伤之间的相关性在另一组 AMI 患者中得到进一步证实。我们得出结论，受损心肌细胞释放的 miR-499 通过靶向 α7-nAchR 导致内皮损伤。这项研究表明 miR-499 可能作为治疗 AMI 后血管炎症激增的潜在靶点。
The surged systemic vascular inflammation after acute myocardial infarction (AMI) aggravates the atherosclerotic endothelial injury. To explore roles of miR-499 released from cardiomyocytes during AMI in endothelial injury. Using qPCR and ELISA, we discovered that patients with AMI had significantly increased plasma miR-499, which was directly correlated with serum thrombomodulin, a marker for endothelial injury. Plasma of AMI patients, when incubated with human umbilical vein endothelial cells (HUVECs), significantly increased the expression of endothelial injury markers, which could be abrogated by antagomiR-499. In vitro, neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation (HX/R) released miR-499 that could be internalized into rat pulmonary microvascular endothelial cells (RPMECs), worsening the high glucose-induced injury. In silico analysis demonstrated that CHRNA7 encoding alpha 7-nAchR is a target of miR-499, which was validated in cell lines expressing endogenous alpha 7-nAchR. In high glucose-induced RPMECs injury model, miR-499 aggravated, whereas forced CHRNA7 expression ameliorated the injury. Moreover, the perfusate from Langendorff perfused rat heart subjected to HX/R contained higher level of miR-499 that significantly impaired the Bradykinin-mediated endothelium-dependent relaxation in both conduit and resistance arteries, which could be partially abrogated by antagomiR-499. Finally, the correlation between plasma miR-499 and endothelial injury was further confirmed in another cohort of AMI patients. We conclude that miR-499 released from injured cardiomyocytes contributes to the endothelial injury by targeting alpha 7-nAchR. This study implies that miR-499 may serve as a potential target for the treatment of the surged vascular inflammation post-AMI.