Core Concepts
Circular RNA HMGCS1 acts as a sponge for miR-4521, leading to increased expression of arginase 1 (ARG1) and subsequent impairment of vascular endothelial function in type 2 diabetes.
Abstract
The study investigated the role of circular RNA HMGCS1 (circHMGCS1) and microRNA-4521 (miR-4521) in regulating vascular endothelial dysfunction (VED) associated with type 2 diabetes mellitus (T2DM).
Key highlights:
- Screening of circRNAs in human umbilical vein endothelial cells (HUVECs) under high glucose and high palmitate conditions identified circHMGCS1 as significantly upregulated.
- Overexpression of circHMGCS1 promoted the expression of adhesion molecules, reduced nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activity, and increased reactive oxygen species (ROS) generation in endothelial cells, thereby exacerbating VED.
- miR-4521 was identified as a target of circHMGCS1 and was found to be downregulated in the diabetic endothelial environment. Overexpression of miR-4521 attenuated the adverse effects of high glucose and high palmitate on endothelial function.
- Mechanistically, circHMGCS1 acted as a sponge for miR-4521, leading to increased expression of arginase 1 (ARG1), a key regulator of NO production. Inhibition of ARG1 abrogated the regulatory effects of circHMGCS1 and miR-4521 on endothelial function.
- In vivo studies in diabetic mice confirmed the detrimental role of the circHMGCS1/miR-4521/ARG1 axis in diabetes-induced VED, and demonstrated that modulating this axis could be a potential therapeutic strategy.
Stats
Overexpression of circHMGCS1 decreased nitric oxide (NO) content by 30-40% in endothelial cells under high glucose and high palmitate conditions.
Overexpression of circHMGCS1 inhibited endothelial nitric oxide synthase (eNOS) activity by 40-50% in endothelial cells under high glucose and high palmitate conditions.
Overexpression of circHMGCS1 increased reactive oxygen species (ROS) generation by 1.5-2 fold in endothelial cells under high glucose and high palmitate conditions.
Diabetic mice exhibited a 2-3 fold increase in arginase 1 (ARG1) expression in the thoracic aorta compared to control mice.
Quotes
"circHMGCS1 upregulated arginase 1 (ARG1) by sponging miR-4521, leading to decrease in vascular nitric oxide secretion and inhibition of endothelial nitric oxide synthase activity, and an increase in the expression of adhesion molecules and generation of cellular reactive oxygen species, reduced vasodilation and accelerated the impairment of vascular endothelial function."
"Collectively, these findings illuminate the physiological role and interacting mechanisms of circHMGCS1 and miR-4521 in diabetes-induced cardiovascular diseases, suggesting that modulating the expression of circHMGCS1 and miR-4521 could serve as a potential strategy to prevent diabetes-associated cardiovascular diseases."