A high level of low-density lipoprotein cholesterol (LDL) is one of the most important risk factors for coronary artery disease (CAD), the leading cause of death worldwide. However, a low concentration of LDL may be protective. Genome-wide association studies revealed that variation in
ADTRP gene increased the risk of CAD. In this study, we found that a low concentration of oxidized-LDL induced the expression of
ADTRP. Further analyses showed that knockdown of the expression of LDL receptor genes
LDLR,
CD36, or
LOX-1 significantly downregulated
ADTRP expression, whereas overexpression of
LDLR/
CD36/
LOX-1 markedly increased
ADTRP expression through the NF-κB pathway. Like
ADTRP,
LDLR,
CD36 and
LOX-1 were all involved in endothelial cell (EC) functions relevant to the initiation of atherosclerosis. Downregulation of
LDLR/
CD36/
LOX-1 promoted monocyte adhesion to ECs and transendothelial migration of monocytes by increasing expression of ICAM-1, VCAM-1, E-selectin and P-selectin, decreased EC proliferation and migration, and increased EC apoptosis, thereby promoting the initiation of atherosclerosis. Opposite effects were observed with the overexpression of
ADTRP and
LDLR/
CD36/
LOX-1 in ECs. Interestingly, through the NF-κB and AKT pathways, overexpression of
ADTRP significantly upregulated the expression of
LDLR,
CD36, and
LOX-1, and knockdown of
ADTRP expression significantly downregulated the expression of
LDLR,
CD36, and
LOX-1. These data suggest that ADTRP and LDL receptors LDLR/CD36/LOX-1 positively regulate each other, and form a positive regulatory loop that regulates endothelial cell functions, thereby providing a potential protective mechanism against atherosclerosis. Our findings provide a new molecular mechanism by which deregulation of ADTRP and LDLR/CD36/LOX-1 promote the development of atherosclerosis and CAD.
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