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Autophagy of vascular endothelial cells (VECs) protects against VEC injury, which is a critical step in atherosclerosis.Previously, we found that small molecule 6-amino-2, 3-dihydro-3-hydroxymethyl-1, 4-benzoxazine (ABO) could induce autophagy and had a protective role in VECs.In this study, ABO treatment inhibited the development of atherosclerosis in apoE-/-mice, enhanced autophagy and annexin A7 (ANXA7) levels, and decreased the levels of phosphatidylcholine-specific phospholipase C (PC-PLC) and phosphatidylethanolamine binding protein 1 (PEBP1) in aortic endothelium.Meanwhile, mass spectrometry and immunoprecipitation revealed that PC-PLC interacted with PEBP1.Furthermore, ANXA7 suppressed oxLDL-induced PC-PLC activity and PEBP1 positively regulated PC-PLC activity in human umbilical endothelial cells (HUVECs).ANXA7may negatively and PEBP1 positively regulate PC-PLC activity in VECs, for a novel signaling pathway in atherosclerosis.PEBP1 may be a potential diagnostic indicator for atherosclerosis.