Department of Interventional & Vascular Surgery, Tenth People's Hospital of Tongji University, Shanghai, China.
Department of Pharmacy, Shanghai Children's Medical Center, Shanghai Jiao Tong University, Shanghai, China.
Endocr Res. 2024 Aug-Nov;49(4):213-222. doi: 10.1080/07435800.2024.2365887. Epub 2024 Jun 13.
Diabetes mellitus (DM) and complications such as chronic kidney disease and cardiovascular symptoms pose a substantial public health burden. Increasing studies have shown that circular RNAs (circRNAs) regulate many gene expressions that are essential in diverse pathological and biological procedures. However, the roles of particular circRNAs in DM are unclear.
In the current investigation, endothelial progenitor cells (EPCs) were used to search for abnormal expression of circRNAs by using high-throughput sequencing under high glucose (HG) conditions. The regulatory mechanisms and targets were then studied through bioinformatics analysis, luciferase reporter analysis, angiogenic differentiation experiments, flow cytometry detection of apoptosis and RT-qPCR analysis.
The circ-Astn1 expression in EPCs decreased after HG treatment. Overexpression or circ-Astn1 suppressed HG induced endothelial cell damage. MicroRNA (miR)-138-5p and SIRT5 were found to be the downstream targets of circ-Astn1 through luciferase reporter analysis. SIRT5 downregulation or miR-138-5p overexpression reversed circ-Astn1's protective effect against HG induced endothelial cell dysfunction, including apoptosis and abnormal vascular differentiation. Furthermore, circ-Astn1 overexpression promoted autophagy activation by increasing SIRT5 expression under HG conditions. Our findings suggest that circ-Astn1 mediated promotion of SIRT5 facilitates autophagy by sponging miR-138-5p.
Together, our findings show that the overexpression of circ-Astn1 suppresses HG induced endothelial cell damage by targeting miR-138-5p/SIRT5 axis.
糖尿病（DM）及其并发症，如慢性肾脏病和心血管症状，给公共健康带来了巨大的负担。越来越多的研究表明，环状 RNA（circRNAs）调控着许多基因表达，这些基因表达在多种病理和生物学过程中至关重要。然而，特定 circRNAs 在 DM 中的作用尚不清楚。
在本研究中，我们使用高通量测序技术在高糖（HG）条件下研究内皮祖细胞（EPCs）中 circRNAs 的异常表达。然后通过生物信息学分析、荧光素酶报告分析、血管生成分化实验、凋亡的流式细胞术检测和 RT-qPCR 分析研究其调控机制和靶标。
HG 处理后 EPCs 中 circ-Astn1 的表达降低。过表达或 circ-Astn1 可抑制 HG 诱导的内皮细胞损伤。荧光素酶报告分析发现 microRNA（miR）-138-5p 和 SIRT5 是 circ-Astn1 的下游靶标。通过荧光素酶报告分析发现 SIRT5 下调或 miR-138-5p 过表达逆转了 circ-Astn1 对 HG 诱导的内皮细胞功能障碍（包括凋亡和异常血管分化）的保护作用。此外，circ-Astn1 过表达通过增加 HG 条件下的 SIRT5 表达促进自噬激活。我们的研究结果表明，circ-Astn1 通过海绵吸附 miR-138-5p 来促进 SIRT5 介导的自噬。
总之，我们的研究结果表明，circ-Astn1 的过表达通过靶向 miR-138-5p/SIRT5 轴抑制 HG 诱导的内皮细胞损伤。
