Phowira Jason, Ahmed Fahad W, Bakhashab Sherin, Weaver Jolanta U
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia.
Biomedicines. 2022 Aug 31;10(9):2136. doi: 10.3390/biomedicines10092136.
Colony forming unit-Hill's (CFU-Hill's) colonies are hematopoietic-derived cells that participate in neovasculogenesis and serve as a biomarker for vascular health. In animals, overexpression of miR-18a-5p was shown to be pro-atherogenic. We had shown that well-controlled type 1 diabetes mellitus (T1DM) is characterized by an inflammatory state, endothelial dysfunction, and reduced number of CFU-Hill's, a model of subclinical cardiovascular disease (CVD). MERIT study explored the role of miR-18a-5p expression in CFU-Hill's colonies in T1DM, and the cardioprotective effect of metformin in subclinical CVD. In T1DM, miR-18a-5p was significantly upregulated whereas metformin reduced it to HC levels. MiR-18a-5p was inversely correlated with CFU-Hill's colonies, CD34+, CD34+CD133+ cells, and positively with IL-10, C-reactive protein, vascular endothelial growth factor-D (VEGF-D), and thrombomodulin. The receiver operating characteristic curve demonstrated, miR-18a-5p as a biomarker of T1DM, and upregulated miR-18a-5p defining subclinical CVD at HbA1c of 44.5 mmol/mol (pre-diabetes). Ingenuity pathway analysis documented miR-18a-5p inhibiting mRNA expression of insulin-like growth factor-1, estrogen receptor-1, hypoxia-inducible factor-1α cellular communication network factor-2, and protein inhibitor of activated STAT 3, whilst metformin upregulated these mRNAs via transforming growth factor beta-1 and VEGF. We confirmed the pro-atherogenic effect of miR-18a-5p in subclinical CVD and identified several target genes for future CVD therapies.
集落形成单位-希尔氏（CFU-希尔氏）集落是造血来源的细胞，参与新生血管形成，并作为血管健康的生物标志物。在动物中，miR-18a-5p的过表达被证明具有促动脉粥样硬化作用。我们已经表明，控制良好的1型糖尿病（T1DM）的特征是炎症状态、内皮功能障碍以及CFU-希尔氏数量减少，这是亚临床心血管疾病（CVD）的一种模型。MERIT研究探讨了miR-18a-5p在T1DM的CFU-希尔氏集落中的表达作用，以及二甲双胍在亚临床CVD中的心脏保护作用。在T1DM中，miR-18a-5p显著上调，而二甲双胍将其降低至健康对照水平。miR-18a-5p与CFU-希尔氏集落、CD34+、CD34+CD133+细胞呈负相关，与白细胞介素-10、C反应蛋白、血管内皮生长因子-D（VEGF-D）和凝血调节蛋白呈正相关。受试者工作特征曲线表明，miR-18a-5p作为T1DM的生物标志物，在糖化血红蛋白为44.5 mmol/mol（糖尿病前期）时，miR-18a-5p上调定义了亚临床CVD。 Ingenuity通路分析记录了miR-18a-5p抑制胰岛素样生长因子-1、雌激素受体-1、缺氧诱导因子-1α细胞通讯网络因子-2和信号转导与转录激活因子3的蛋白抑制剂的mRNA表达，而二甲双胍通过转化生长因子β-1和VEGF上调这些mRNA。我们证实了miR-18a-5p在亚临床CVD中的促动脉粥样硬化作用，并确定了几个未来用于CVD治疗的靶基因。
