MicroRNA-141 regulates the expression level of ICAM-1 on endothelium to decrease myocardial ischemia-reperfusion injury
MicroRNA-141 regulates the expression level of ICAM-1 on endothelium to decrease myocardial ischemia-reperfusion injury
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DOI：
10.1152/ajpheart.00290.2015
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发表时间：
2015-10-15
影响因子：
4.8
通讯作者：
Chen, Li Hua
中科院分区：
文献类型：
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作者：
Liu, Rong Rong;Li, Jun;Chen, Li Hua
越来越多的研究表明，microRNAs(MiRNAs)参与了心肌缺血再灌注(MI/R)损伤的调节，然而，针对内皮细胞(ECs)的内源性miRNAs在MI/R中的作用及其与ICAM-1的相互作用尚不清楚。我们的芯片结果显示，在经肿瘤坏死因子-α作用6h的内皮细胞中，miR-146a、miR-146b-5p、miR-155*、miR-155、miR-497和miR-451的表达显著上调，而miR-141和miR-564的表达显著下调。通过Target Scan软件和报告基因系统鉴定ICAM-1为miR-141的新靶点。进一步的功能实验表明，在体外，miR-141水平的升高抑制了ICAM-1的表达，并减少了白细胞与内皮细胞的黏附。在MI/R损伤的小鼠体内模型中，尾静脉注射miR-141可模拟抑制ICAM-1的表达，从而减轻MI/R损伤，表现为心肌梗死面积缩小，血清心肌肌钙蛋白I(CTnI)和乳酸脱氢酶(LDH)浓度下降。MiR-141模拟物的心肌保护作用可能与减少CD11b(+)细胞和F4/80(+)巨噬细胞在缺血心肌组织中的浸润有关。综上所述，我们的研究结果表明，miR-141作为ICAM-1的一种新的阻滞剂，通过对ICAM-1的反向调节和炎性细胞的浸润参与了对MI/R损伤的保护作用。因此，miR-141可能成为治疗缺血性心脏病的新靶点。
A growing number of studies have suggested microRNAs (miRNAs) are involved in the modulation of myocardial ischemia-reperfusion (MI/R) injury; however, the role of endogenous miRNAs targeting endothelial cells (ECs) and its interaction with ICAM-1 in the setting of MI/R remain poorly understood. Our microarray results showed that miR-146a, miR-146b-5p, miR-155*, miR-155, miR-497, and miR-451 were significantly upregulated, whereas, miR-141 and miR-564 were significantly downregulated in the ECs challenged with TNF-alpha for 6 h. Real-time PCR analyses additionally validated that the expression levels of miR-146a, miR-155*, and miR-141 were consistent with the microarray results. Then, ICAM-1 was identified as a novel target of miR-141 by Target Scan software and the reporter gene system. Further functional experiments showed that elevated levels of miR-141 inhibited ICAM-1 expression and diminished leukocytes adhesion to ECs in vitro. In an in vivo murine model of MI/R injury, pretreatment with miR-141 mimics through the tail vein downregulated the expression level of ICAM-1 in heart and attenuated MI/R injury as evidenced by decreased infarct size and decline of serum cardial troponin I (cTnI) and lactate dehydrogenase (LDH) concentration. The cardioprotective effects of miR-141 mimics may be attributed to the decreased infiltration of CD11b(+) cells and F4/80(+) macrophages into ischemic myocardium tissue. In conclusion, our results demonstrate that miR-141, as a novel repressor of ICAM-1, is involved in the attenuation of MI/R injury via antithetical regulation of ICAM-1 and inflammatory cells infiltration. Thus miR-141 may constitute a new therapeutic target in the setting of ischemic heart disease.