Oxidized low-density lipoprotein promotes vascular endothelial cell dysfunction by stimulating miR-496 expression and inhibiting the Hippo pathway effector YAP.

Abstract

Oxidized low‐density lipoprotein (ox‐LDL) can damage vascular endothelial cells and cause atherosclerosis, but its epigenetic regulatory mechanism has not been fully elucidated. We show that ox‐LDL induced significant apoptosis and loss of function in human umbilical vascular endothelial cells (HUVECs). At the same time, ox‐LDL significantly decreased the expression of Hippo–YAP/ZAP (Yes‐associated protein/YLP motif–containing 1) pathway proteins as compared to that of the control. The luciferase reporter system confirmed that microRNA (miR)‐496 silenced YAP gene expression by binding to its 3′ untranslated region (3′ UTR). Ox‐LDL–treated miR‐496 overexpression HUVECs had a higher apoptosis rate and more severe dysfunction compared to the control cells. This in‐depth study shows that ox‐LDL inhibits YAP protein expression by inducing miR‐496 expression, leading to its inability to enter the nucleus, thereby losing its function as a transcriptional cofactor for activating the downstream genes. Our findings reveal that, through epigenetic modification, ox‐LDL can inhibit the normal expression of Hippo–YAP/ZAP pathway proteins via miR‐496 expression and induce vascular endothelial cell dysfunction.