1 型糖尿病（亚临床心血管疾病模型）中上调的抗血管生成 miR-424-5p 与内皮祖细胞、CXCR1/2 及其他血管健康参数相关。

Upregulated anti-angiogenic miR-424-5p in type 1 diabetes (model of subclinical cardiovascular disease) correlates with endothelial progenitor cells, CXCR1/2 and other parameters of vascular health.

机构信息

Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia.

出版信息

Stem Cell Res Ther. 2021 May 14;12(1):249. doi: 10.1186/s13287-021-02332-7.

BACKGROUND

In spite of clinical progress, cardiovascular disease (CVD) remains the predominant cause of mortality worldwide. Overexpression studies in animals have proven miR-424-5p to have anti-angiogenic properties. As type 1 diabetes mellitus (T1DM) without CVD displays endothelial dysfunction and reduced circulating endothelial progenitor cells (cEPCs), it offers a model of subclinical CVD. Therefore, we explored miR-424-5p, cytokines and vascular health in T1DM.

METHODS

Twenty-nine well-controlled T1DM patients with no CVD and 20-matched controls were studied. Cytokines IL8, TNF-α, IL7, VEGF-C, cEPCs/CD45CD34CD133 cells and ex-vivo proangiogenic cells (PACs)/fibronectin adhesion assay (FAA) were measured. MiR-424-5p in plasma and peripheral blood mononuclear cells (PBMC) along with mRNAs in PBMC was evaluated.

RESULTS

We found an elevation of IL7 (p = 0.008), IL8 (p = 0.003), TNF-α (p = 0.041), VEGF-C (p = 0.013), upregulation of mRNA CXCR1 (p = 0.009), CXCR2 (p < 0.001) and reduction of cEPCs (p < 0.001), PACs (p < 0.001) and FAA (p = 0.017) in T1DM. MiR-424-5p was upregulated in T1DM in PBMC (p < 0.001). MiR-424-5p was negatively correlated with cEPCs (p = 0.006), PACs (p = 0.005) and FAA (p < 0.001) and positively with HbA (p < 0.001), IL7 (p = 0.008), IL8 (p = 0.017), VEGF-C (p = 0.007), CXCR1 (p = 0.02) and CXCR2 (p = 0.001). ROC curve analyses showed (1) miR-424-5p to be a biomarker for T1DM (p < 0.001) and (2) significant upregulation of miR-424-5p, defining subclinical CVD, occurred at HbA of 46.5 mmol/mol (p = 0.002).

CONCLUSION

We validated animal research on anti-angiogenic properties of miR-424-5p in T1DM. MiR-424-5p may be a biomarker for onset of subclinical CVD at HbA of 46.5 mmol/mol (pre-diabetes). Thus, miR-424-5p has potential use for CVD monitoring whilst anti-miR-424-5p-based therapies may be used to reduce CVD morbidity/mortality in T1DM.

背景

尽管临床取得了进展，但心血管疾病（CVD）仍然是全球主要的死亡原因。动物的过表达研究证明 miR-424-5p 具有抗血管生成特性。由于没有 CVD 的 1 型糖尿病（T1DM）显示出内皮功能障碍和循环内皮祖细胞（cEPC）减少，因此它提供了亚临床 CVD 的模型。因此，我们在 T1DM 中探索了 miR-424-5p、细胞因子和血管健康。

方法

研究了 29 名控制良好的无 CVD 的 T1DM 患者和 20 名匹配的对照者。测量了细胞因子 IL8、TNF-α、IL7、VEGF-C、cEPC/CD45CD34CD133 细胞和体外促血管生成细胞（PAC）/纤维连接蛋白粘附测定（FAA）。评估了血浆和外周血单核细胞（PBMC）中的 miR-424-5p 以及 PBMC 中的 mRNA。

结果

我们发现 IL7（p=0.008）、IL8（p=0.003）、TNF-α（p=0.041）、VEGF-C（p=0.013）升高，CXCR1（p=0.009）、CXCR2（p<0.001）mRNA 上调，cEPC（p<0.001）、PAC（p<0.001）和 FAA（p=0.017）减少。T1DM 患者 PBMC 中 miR-424-5p 上调（p<0.001）。miR-424-5p 与 cEPC（p=0.006）、PAC（p=0.005）和 FAA（p<0.001）呈负相关，与 HbA（p<0.001）、IL7（p=0.008）、IL8（p=0.017）、VEGF-C（p=0.007）、CXCR1（p=0.02）和 CXCR2（p=0.001）呈正相关。ROC 曲线分析显示（1）miR-424-5p 是 T1DM 的生物标志物（p<0.001），（2）miR-424-5p 的显著上调，定义为亚临床 CVD，发生在 HbA 为 46.5mmol/mol（p=0.002）时。

结论

我们验证了动物研究中 miR-424-5p 在 T1DM 中的抗血管生成特性。miR-424-5p 可能是 HbA 为 46.5mmol/mol（糖尿病前期）时亚临床 CVD 发病的生物标志物。因此，miR-424-5p 可能用于 CVD 监测，而基于抗 miR-424-5p 的治疗可能用于降低 T1DM 的 CVD 发病率/死亡率。