MicroRNA-146a-5p Mediates High Glucose-Induced Endothelial Inflammation via Targeting Interleukin-1 Receptor-Associated Kinase 1 Expression.
MicroRNA-146a-5p Mediates High Glucose-Induced Endothelial Inflammation via Targeting Interleukin-1 Receptor-Associated Kinase 1 Expression.
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DOI：
10.3389/fphys.2017.00551
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发表时间：
2017
影响因子：
4
通讯作者：
Wang HJ
中科院分区：
文献类型：
--
作者：
Lo WY;Peng CT;Wang HJ
背景和目的：白细胞介素-1受体相关激酶-1 （IRAK-1）在介导toll样受体和白细胞介素-1受体信号传导中起关键作用。在这项研究中，我们研究了IRAK-1在高糖（HG）刺激的人主动脉内皮细胞（HAECs）中的表达是否改变，以及microRNAs （miRs）是否靶向IRAK-1调节HG诱导的内皮炎症。方法：用HG处理HAECs 24和48 h，进行实时荧光定量PCR、Western blot、单核细胞粘附试验、生物信息学分析、TaqMan®阵列、microRNA模拟物或抑制剂转染、荧光素酶报告基因检测和siRNA IRAK-1转染。采用免疫组化染色法检测db/db 2型糖尿病小鼠主动脉组织。结果：HG时间依赖性地增加了HAECs中IRAK-1 mRNA和蛋白水平，并与VCAM-1/ICAM-1基因表达和单核细胞粘附增加相关。生物信息学分析、TaqMan®阵列和实时PCR证实，miR-146a-5p、miR-339-5p和miR-874-3p在hg刺激的haec中显著下调，表明通过IRAK-1对hg诱导的内皮炎症的反馈抑制受损。然而，只有miR-146a-5p mimic转染降低了hg诱导的IRAK-1表达、VCAM-1/ICAM-1表达和单核细胞粘附的上调。此外，IRAK-1缺失降低了hg诱导的VCAM-1/ICAM-1基因表达和单核细胞粘附，表明hg诱导的内皮炎症部分通过IRAK-1介导。在体内，静脉注射miR-146a-5p模拟物可阻止db/db小鼠内皮细胞IRAK-1和ICAM-1的表达。结论：这些结果表明，miR-146a-5p通过调节IRAK-1参与hg诱导的内皮细胞炎症的调节；这表明miR-146a-5p可能是治疗糖尿病血管并发症的新靶点。
Background and Aims: Interleukin-1 receptor-associated kinase-1 (IRAK-1) is critical for mediating toll-like receptor and interleukin-1 receptor signaling. In this study, we have examined whether IRAK-1 expression is altered in high glucose (HG)-stimulated human aortic endothelial cells (HAECs), and whether microRNAs (miRs) target IRAK-1 to regulate HG-induced endothelial inflammation. Methods: HAECs were treated with HG for 24 and 48 h. Real-time PCR, Western blot, monocyte adhesion assay, bioinformatics analysis, TaqMan® arrays, microRNA mimic or inhibitor transfection, luciferase reporter assay and siRNA IRAK-1 transfection were performed. The aortic tissues from db/db type 2 diabetic mice were examined by immunohistochemistry staining. Results: HG time-dependently increased IRAK-1 mRNA and protein levels in HAECs, and was associated with increased VCAM-1/ICAM-1 gene expression and monocyte adhesion. Bioinformatic analysis, TaqMan® arrays, and real-time PCR were used to confirm that miR-146a-5p, miR-339-5p, and miR-874-3p were significantly downregulated in HG-stimulated HAECs, suggesting impaired feedback restraints on HG-induced endothelial inflammation via IRAK-1. However, only miR-146a-5p mimic transfection reduced the HG-induced upregulation of IRAK-1 expression, VCAM-1/ICAM-1 expression, and monocyte adhesion. Additionally, IRAK-1 depletion reduced HG-induced VCAM-1/ICAM-1 gene expression, and monocyte adhesion, indicating that HG-induced endothelial inflammation was mediated partially through IRAK-1. In vivo, intravenous injections of miR-146a-5p mimic prevented endothelial IRAK-1 and ICAM-1 expression in db/db mice. Conclusion: These results suggest that miR-146a-5p is involved in the regulation of HG-induced endothelial inflammation via modulation of IRAK-1; indicating that miR-146a-5p may be a novel target for the treatment of diabetic vascular complications.
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影响因子：
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