Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China; Department of Endocrinology, Nephropathy Clinical Medical Research Center of Sichuan Province, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China; Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China; Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Life Sci. 2019 Dec 15;239:117092. doi: 10.1016/j.lfs.2019.117092. Epub 2019 Nov 21.
Type 2 diabetes mellitus (DM2) is associated with coronary heart disease (CHD) and is characterized by high levels of plasminogen activator inhibitor (PAI)-1. Circulating microRNAs have been reported as potential diagnostic biomarkers for DM2 and CHD. However, the underlying mechanisms have largely remained unclear.
The changes of circulating miR-30c, PAI-1 and vitronetin (VN) in plasma from CHD, noncomplicated (NC) + DM2, CHD + DM2 subjects and control individuals were assessed by quantitative reverse transcription PCR (qRT-PCR) and ELISA assays, respectively. The effects of miR-30c on VN expression by targeting PAI-1 were assessed in vitro SMC and in ex vivo plasma, using bioinformatic analysis, miRNA transfection, luciferase assays, qRT-PCR and western blot, respectively.
We found that decreased circulating miR-30c was negatively correlated with the severity of coronary lesions and the resulting elevated PAI-1 and VN levels. Circulating miR-30c significantly distinguished between patients with CHD + DM2, NC + DM2, CHD and control subjects, and that were significantly associated with certain risk factors for progression from a normal individual to one with CHD + DM2. Furthermore, we also showed that miR-30c plays a previously unrecognized role in regulating the expression of VN levels via regulating PAI-1 levels in vitro SMC and in ex vivo plasma.
These findings provide a novel regulatory mechanism of miR-30c in regulating PAI-1/VN interactions and that may serve as a diagnostic biomarker of DM2 that is complicated with CHD.
2 型糖尿病（DM2）与冠心病（CHD）相关，其特征在于纤溶酶原激活物抑制剂（PAI-1）水平升高。循环 microRNA 已被报道为 DM2 和 CHD 的潜在诊断生物标志物。然而，其潜在机制在很大程度上仍不清楚。
通过定量逆转录 PCR（qRT-PCR）和 ELISA 测定分别评估 CHD、非合并（NC）+DM2、CHD+DM2 患者和对照个体血浆中循环 miR-30c、PAI-1 和 vitronectin（VN）的变化。通过生物信息学分析、miRNA 转染、荧光素酶测定、qRT-PCR 和 Western blot，分别评估 miR-30c 通过靶向 PAI-1 对 VN 表达的影响。
我们发现，循环 miR-30c 的减少与冠状动脉病变的严重程度呈负相关，导致 PAI-1 和 VN 水平升高。循环 miR-30c 可显著区分 CHD+DM2、NC+DM2、CHD 和对照患者，且与从正常个体发展为 CHD+DM2 个体的某些危险因素显著相关。此外，我们还表明，miR-30c 通过调节体外 SMC 和离体血浆中的 PAI-1 水平，在调节 VN 水平方面发挥了以前未被认识的作用。
这些发现提供了 miR-30c 通过调节 PAI-1/VN 相互作用的新的调节机制，可能作为伴有 CHD 的 DM2 的诊断生物标志物。
