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.