Upregulation of circHMGCS1 Promotes Type 2 Diabetes-induced Vascular Endothelial Dysfunction by Sponging miR-4521

Noncoding RNAs play a pivotal role as novel regulators of endothelial cell function. Type 2 diabetes is recognized as one of the primary contributors to cardiovascular diseases (CVD), wherein vascular endothelial dysfunction (VED) is intricately involved in its pathogenesis. We observed the aberrant expression of Circular RNA HMGCS1 (CircHMGCS1) and microRNA 4521 (miR-4521) in diabetes-induced VED. Overexpression of CircHMGCS1 or silencing of miR-4521 expedited the onset of diabetes and aggravated VED. Mechanistically, CircHMGCS1 upregulated arginase 1 (ARG1) by sponging miR-4521, resulting in the decrease of vascular NO secretion, enhanced expression of adhesion molecules (VCAM1, ICAM1, ET-1), and increased generation of cellular ROS, accelerating the impairment of vascular endothelial function. Collectively, these findings illuminate the physiological role and interacting mechanisms of CircHMGCS1 and miR-4521 in CVD triggered by diabetes, suggesting that modulating the expression of CircHMGCS1 and miR-4521 could serve as a potential strategy for preventing VED and the development of diabetes-associated CVD.

非编码RNA（noncoding RNAs）作为内皮细胞功能的新型调控因子，发挥关键作用。2型糖尿病被认为是心血管疾病（cardiovascular diseases, CVD）的主要致病因素之一，而血管内皮功能障碍（vascular endothelial dysfunction, VED）深度参与其发病进程。我们在糖尿病诱导的血管内皮功能障碍样本中，观察到环状RNA HMGCS1（Circular RNA HMGCS1, CircHMGCS1）与微小RNA 4521（microRNA 4521, miR-4521）的表达异常。过表达CircHMGCS1或沉默miR-4521会加速糖尿病的发生，并加重血管内皮功能障碍。从机制层面来看，CircHMGCS1通过海绵吸附miR-4521，上调精氨酸酶1（arginase 1, ARG1）的表达，进而导致血管一氧化氮（nitric oxide, NO）分泌减少、血管细胞黏附分子1（vascular cell adhesion molecule 1, VCAM1）、细胞间黏附分子1（intercellular adhesion molecule 1, ICAM1）及内皮素1（endothelin 1, ET-1）的表达上调，同时增加细胞活性氧（reactive oxygen species, ROS）的生成，最终加速血管内皮功能的损伤。综上，本研究阐明了CircHMGCS1与miR-4521在糖尿病诱导的心血管疾病中的生理作用及相互调控机制，提示调控CircHMGCS1与miR-4521的表达，或可成为预防血管内皮功能障碍及糖尿病相关心血管疾病发生发展的潜在策略。