Department of Vascular Surgery, Multidisciplinary Collaboration Group of Diabetic Foot, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Multidisciplinary Collaboration Group of Diabetic Foot, Shanghai Institute for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Cell Biochem Funct. 2020 Oct;38(7):965-975. doi: 10.1002/cbf.3523. Epub 2020 Mar 20.
To explore the effects of miR-21-3p on diabetic atherosclerosis. Using enzyme-linked immunosorbent assay (ELISA), we also detected the levels of soluble receptor for advanced glycation endproducts RAGE (sRAGE) in the cellular supernatant of vascular endothelial cells after transfecting them with adenovirus vector having miR-21-3p mimic or inhibitor. We found decrease in the expression levels of miR-21-3p in vascular endothelial cells (VECs) induced by high-concentration glucose. We also observed that the introduction of miR-21-3p mimic significantly increased the expression of ADAM10 in the VECs. Similarly, significantly higher levels of sRAGE were found in the cultured supernatant after administration of miR-21-3p mimic in human vein endothelial cells. The production of reactive oxygen species and expression of inflammatory cytokines in VECs induced by LPS and high-concentration glucose were significantly decreased after administration of miR-21-3p. in vivo studies revealed that intravenous injection of miR-21-3p at regular intervals would reduce the area of atherosclerotic lesion and elevate the serum levels of sRAGE in atherosclerotic diabetic mice. miR-21-3p may be beneficial in diabetic atherosclerosis by promoting the cleaved form of sRAGE and inhibition of RAGE/NADPH oxidase signalling depending on the increased expression of ADAM10. SIGNIFICANCE OF THE STUDY: We identified a novel microRNA, miR-21-3p, which is characteristically at elevated levels in serum derived from diabetic patients and responsible for target degradation of ADAM10 mRNA. Further, we show that miR-21-3p aggravates the atherosclerotic lesion via dysfunction of the ectodomain shedding of molecular binding RAGE in the diabetic atherosclerotic mice.
探讨 miR-21-3p 对糖尿病动脉粥样硬化的影响。通过酶联免疫吸附试验（ELISA），我们还检测了转染 miR-21-3p 模拟物或抑制剂的血管内皮细胞细胞上清液中可溶性晚期糖基化终产物受体（sRAGE）的水平。我们发现高浓度葡萄糖诱导的血管内皮细胞（VEC）中 miR-21-3p 的表达水平降低。我们还观察到，miR-21-3p 模拟物的引入显著增加了 VEC 中 ADAM10 的表达。同样，在人静脉内皮细胞中给予 miR-21-3p 模拟物后，培养上清液中的 sRAGE 水平也明显升高。给予 miR-21-3p 后，LPS 和高浓度葡萄糖诱导的 VEC 中活性氧的产生和炎症细胞因子的表达明显减少。体内研究表明，定期静脉注射 miR-21-3p 可减少动脉粥样硬化病变面积，并提高动脉粥样硬化糖尿病小鼠血清中 sRAGE 的水平。miR-21-3p 可能通过促进 sRAGE 的裂解形式和抑制 RAGE/NADPH 氧化酶信号通路，从而增加 ADAM10 的表达，从而有益于糖尿病动脉粥样硬化。研究意义：我们鉴定了一种新型 microRNA，miR-21-3p，它在糖尿病患者血清中表达水平升高，负责 ADAM10 mRNA 的靶标降解。此外，我们表明 miR-21-3p 通过糖尿病动脉粥样硬化小鼠中分子结合 RAGE 的外显子脱落功能障碍加重动脉粥样硬化病变。
