Circulating Toll-like receptor 4-responsive microRNA panel in patients with coronary artery disease: results from prospective and randomized study of treatment with renin-angiotensin system blockade
Circulating Toll-like receptor 4-responsive microRNA panel in patients with coronary artery disease: results from prospective and randomized study of treatment with renin-angiotensin system blockade
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DOI：
10.1042/cs20140417
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发表时间：
2015-04-01
期刊：
影响因子：
6
通讯作者：
Nakamura, Motoyuki
中科院分区：
文献类型：
--
作者：
Satoh, Mamoru;Takahashi, Yuji;Nakamura, Motoyuki
细胞外miRNAs在血流中循环，可以作为新的诊断和治疗生物标志物。本研究的目的是研究冠状动脉疾病（CAD）患者循环Toll样受体4（TLR 4）反应性miRNA表达，并检查肾素-血管紧张素系统（RAS）阻断剂和他汀类药物对miRNA水平的影响。本研究纳入了41例CAD患者和20例无CAD（非CAD）受试者。使用针对1700种人miRNA的微阵列测定来分析血浆TLR 4响应性miRNA样品。通过实时逆转录（RT）-PCR验证候选miRNAs。CAD患者随机接受12个月的替米沙坦和阿托伐他汀[血管紧张素II受体阻滞剂（ARB）]或依那普利和阿托伐他汀[血管紧张素转换酶抑制剂（ACEI）]联合治疗。在基线和12个月后从外周血中获得血浆样品。基因芯片检测结果显示，冠心病组与非冠心病组之间7种TLR 4应答miRNAs的表达差异有统计学意义（P < 0.05）。Real-time PCR检测结果显示，冠心病组miR-31、miR-181 a、miR-16和miR-145的表达水平明显低于非冠心病组（P < 0.01）。冠心病组TLR 4蛋白表达水平高于非冠心病组（P < 0.01），且与TLR 4反应性miRNAs表达水平呈负相关。受试者工作特征（ROC）曲线分析显示，这四种miRNA的一组足够敏感和特异以区分CAD与非CAD [曲线下面积（AUC）= 0.93，95%CI（置信区间）= 0.99-0.87]。ARB组和ACEI组TLR 4反应性miRNAs表达增加，TLR 4蛋白表达减少（P < 0.05）。ARB组miRNAs和TLR 4水平的变化大于ACEI组（P < 0.05）。与对照组相比，冠心病患者外周血中TLR 4反应性miRNAs（包括miR-31、miR-181 a、miR-16和miR-145）水平显著降低，这些miRNAs可能参与了冠心病的发病机制。
The extracellular miRNAs circulate in the bloodstream and may serve as novel diagnostic and therapeutic biomarkers. The aim of the present study was to investigate circulating Toll-like receptor 4 (TLR4)-responsive miRNA expression in patients with coronary artery disease (CAD) and to examine the effects of renin-angiotensin system (RAS) blockade and statins on miRNA levels. This study included 41 patients with CAD and 20 subjects without CAD (non-CAD). Plasma TLR4-responsive miRNA samples were analysed using a microarray assay for 1700 human miRNA. The candidate miRNAs were verified with real-time reverse transcription (RT)-PCR. Patients with CAD were randomized to 12 months of combined treatment with either telmisartan and atorvastatin [angiotensin II receptor blocker (ARB)] or enalapril and atorvastatin [angiotensin-converting enzyme inhibitor (ACEI)]. Plasma samples were obtained from peripheral blood at baseline and after 12 months. The microarray assay showed significant differences in seven TLR4-responsive miRNAs between the CAD and non-CAD groups (P < 0.05). Real-time PCR verified that miR-31, miR-181a, miR-16 and miR-145 were significantly lower in the CAD group than in the non-CAD group (P < 0.01). Levels of TLR4 protein were higher in the CAD group than in the non-CAD group (P < 0.01) and were negatively correlated with levels of TLR4-responsive miRNAs. Receiver operating characteristic (ROC) curve analysis revealed that a panel of these four miRNAs was sensitive and specific enough to distinguish CAD from non-CAD [area under the curve (AUC) = 0.93, 95% CI (confidence interval) = 0.99-0.87]. Both ARB and ACEI groups showed increased TLR4-responsive miRNAs and diminished levels of TLR4 protein (P < 0.05). Changes in miRNAs and TLR4 levels were greater in the ARB group than in the ACEI group (P < 0.05). Circulating TLR4-responsive miRNAs including miR-31, miR-181a, miR-16 and miR-145 were significantly lower in patients with CAD compared with controls and these miRNAs may be involved in the pathogenesis of CAD.