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.

Angiotensin type 1 receptor regulates yes‑associated protein in vascular endothelial cells

“…Notably, phosphorylated YAP (p-YAP) cannot enter the nucleus, and remains in the cytoplasm where it cannot regulate transcription (13). Furthermore, it has been demonstrated that YAP serves an important role in the mediation of the proliferation, migration, apoptosis and phenotypic transition of ECs (14) and vascular smooth muscle cells (15). Additionally, a previous study found that the Hippo-YAP signaling pathway is regulated by Ang II signaling, and that its reactivation induces apoptosis and proliferation in podocytes (16).…”

MicroRNA‑496 suppresses tumor cell proliferation by targeting BDNF in osteosarcoma

“…miR-496 has been identified to participate in various pathobiological processes (15,16). However, the functions of miR-496 in OS have not yet been elucidated.…”

The Association Between Hyperlipidemia and In-Hospital Outcomes in Takotsubo Cardiomyopathy

“…29,30 HLD is known to cause endothelial dysfunction as a result of an elevated oxidized LDL-C (ox-LDL) level. Ox-LDL can damage vascular endothelium by 1) downregulating Hippo Yes-associated protein/YLP motif contain 1 (Hippo-YAP/ZAP) pathway which in turn interferes with cardiovascular remodeling, 31 2) by inducing the apoptosis of vascular endothelial as a result of upregulated expression of autophagy-related protein, 32 and 3) by inhibiting vascular relaxations induced by nitric oxide. 33 In theory, HLD patients are more likely to have endothelial dysfunction, which may facilitate the pathophysiologic basis for the occurrence of TCM.…”