Phosphatidylcholine-specific phospholipase C (
PC-PLC) is a key factor in apoptosis and autophagy of vascular endothelial cells (VECs), and involved in
atherosclerosis in
apolipoprotein E⁻/⁻ (apoE⁻/⁻) mice. But the endogenous regulators of
PC-PLC are not known. We recently found a small chemical molecule (6-amino-2, 3-dihydro-3-hydroxymethyl-1, 4-benzoxazine, ABO) that could inhibit
oxidized low-density lipoprotein (
oxLDL)-induced apoptosis and promote autophagy in VECs, and further identified ABO as an inhibitor of
annexin A7 (ANXA7)
GTPase. Based on these findings, we hypothesize that ANXA7 is an endogenous regulator of
PC-PLC, and targeting ANXA7 by ABO may inhibit
atherosclerosis in apoE⁻/⁻ mice. In this study, we tested our hypothesis. The results showed that ABO suppressed
oxLDL-induced increase of
PC-PLC level and activity and promoted the co-localization of ANXA7 and
PC-PLC in VECs. The experiments of ANXA7 knockdown and overexpression demonstrated that the action of ABO was ANXA7-dependent in cultured VECs. To investigate the relation of ANXA7 with
PC-PLC in
atherosclerosis, apoE⁻/⁻ mice fed with a western diet were treated with 50 or 100 mg/kg/day ABO. The results showed that ABO decreased
PC-PLC levels in the mouse aortic endothelium and
PC-PLC activity in serum, and enhanced the
protein levels of ANXA7 in the mouse aortic endothelium. Furthermore, both dosages of ABO significantly enhanced autophagy and reduced apoptosis in the mouse aortic endothelium. As a result, ABO significantly reduced
atherosclerotic plaque area and effectively preserved a stable plaques phenotype, including reduced
lipid deposition and pro-inflammatory macrophages, increased anti-inflammatory macrophages,
collagen content and smooth muscle cells, and less cell death in the plaques. In conclusion, ANXA7 was an endogenous regulator of
PC-PLC, and targeting ANXA7 by ABO inhibited
atherosclerosis in apoE⁻/⁻ mice.