ACKR3 Upregulation Under Hyperglycemia Associates with Endothelial Dysfunction

Diabetes is a metabolic disorder characterized by chronic hyperglycemia and is associated with cardiovascular complications. Endothelial cell dysfunction is a common feature of both diabetes and its vascular complications. In this study, RNA-seq data from aortic specimens of diabetic patients were analyzed to identify candidate genes that are potentially involved in regulating endothelial cell function under hyperglycemic conditions. Among the identified GPCRs, ACKR3 was singled out as a promising candidate.

Expression of ACKR3 in the vessels of diabetic animals and the HUVEC cell line under hyperglycemia conditions was assessed. Subsequently, the function of the ACKR3 gene was investigated by downregulation of ACKR3 at hyperglycemic conditions in the HUVEC cell line.

Our data showed that expression of Ackr3 in the vessels of diabetic animals was increased. Furthermore, treatment of HUVECs under hyperglycemic conditions (25 mM D-glucose) for 24 h and 48 h resulted in elevated ACKR3 expression at both mRNA and protein levels. Functional analyses revealed that ACKR3 downregulation resulted in significant reductions in oxidative stress levels, inflammation, and the rate of endothelial cell apoptosis under hyperglycemic conditions. Additionally, ACKR3 downregulation reduced the expression of adhesion molecules (ICAM and VCAM), leading to decreased monocyte adhesion under hyperglycemic conditions.

Our findings suggest that hyperglycemia-induced ACKR3 up-regulation may contribute to endothelial cell dysfunction in diabetic vessels. Therefore, targeting ACKR3 could offer valuable insights for developing therapeutic strategies against diabetes-related vascular complications.