King's British Heart Foundation Centre, King's College London, United Kingdom.
Circ Res. 2010 Sep 17;107(6):810-7. doi: 10.1161/CIRCRESAHA.110.226357. Epub 2010 Jul 22.
MicroRNAs (miRNAs) have been implicated in the epigenetic regulation of key metabolic, inflammatory, and antiangiogenic pathways in type 2 diabetes (DM) and may contribute to common disease complications.
In this study, we explore plasma miRNA profiles in patients with DM.
Total RNA was extracted from plasma samples of the prospective population-based Bruneck study. A total of 13 candidate miRNAs identified by microarray screening and miRNA network inference were quantified by quantitative PCR in all diabetic patients of the Bruneck study and age- and sex-matched controls (1995 evaluation, n=80 each). Quantitative PCR assessment revealed lower plasma levels of miR-20b, miR-21, miR-24, miR-15a, miR-126, miR-191, miR-197, miR-223, miR-320, and miR-486 in prevalent DM, but a modest increase of miR-28-3p. Findings emerged as robust in multivariable analysis and were independent of the standardization procedure applied. For endothelial miR-126, results were confirmed in the entire Bruneck cohort (n=822) in univariate (odds ratio [95% confidence interval], 0.38 [0.26 to 0.55]; P=2.72 × 10(-7)) and multivariate analyses (0.57 [0.37 to 0.86]; P=0.0082). Importantly, reduced miR-15a, miR-29b, miR-126, miR-223, and elevated miR-28-3p levels antedated the manifestation of disease. Most differences in miRNA levels were replicated in plasma obtained from hyperglycemic Lep(ob) mice. High glucose concentrations reduced the miR-126 content of endothelial apoptotic bodies. Similarly in patients with DM, the reduction of miR-126 was confined to circulating vesicles in plasma.
We reveal a plasma miRNA signature for DM that includes loss of endothelial miR-126. These findings might explain the impaired peripheral angiogenic signaling in patients with DM.
MicroRNAs（miRNAs）已被牵连到 2 型糖尿病（DM）中关键代谢、炎症和抗血管生成途径的表观遗传调控中，并且可能导致常见的疾病并发症。
在这项研究中，我们探索了 DM 患者的血浆 miRNA 谱。
从前瞻性基于人群的 Bruneck 研究的血浆样本中提取总 RNA。通过微阵列筛选和 miRNA 网络推断确定的 13 个候选 miRNA 通过定量 PCR 在 Bruneck 研究中的所有糖尿病患者和年龄及性别匹配的对照者（1995 年评估，每组 80 例）中进行定量。定量 PCR 评估显示，在现患 DM 中，miR-20b、miR-21、miR-24、miR-15a、miR-126、miR-191、miR-197、miR-223、miR-320 和 miR-486 的血浆水平较低，但 miR-28-3p 略有增加。这些发现在多变量分析中仍然很稳健，并且独立于应用的标准化程序。对于内皮细胞 miR-126，结果在整个 Bruneck 队列（n=822）中通过单变量（比值比[95%置信区间]，0.38 [0.26 至 0.55]；P=2.72×10(-7)) 和多变量分析（0.57 [0.37 至 0.86]；P=0.0082）得到证实。重要的是，miR-15a、miR-29b、miR-126、miR-223 的降低和 miR-28-3p 水平的升高先于疾病的表现。miRNA 水平的大多数差异在来自高血糖 Lep(ob)小鼠的血浆中得到了复制。高葡萄糖浓度降低了内皮细胞凋亡小体中的 miR-126 含量。同样在 DM 患者中，miR-126 的减少仅限于血浆中的循环囊泡。
我们揭示了 DM 的血浆 miRNA 特征，其中包括内皮细胞 miR-126 的丢失。这些发现可能解释了 DM 患者外周血管生成信号受损的原因。
