Abstract
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.
Highlights
The two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators.[2]
We found that human umbilical vein endothelial cell (HUVEC) apoptosis induced by oxLDL10 accompanied by Phosphatidylcholinespecific phospholipase C (PC-PLC) activation,[8] whereas ABO could directly target annexin A7 (ANXA7),18 induce autophagy in cultured VECs11 and inhibit vascular endothelial cell (VEC) apoptosis induced by oxidized low-density lipoprotein (oxLDL),[10] suggesting that there may be an interaction between ANXA7 and PC-PLC in VECs
As PC-PLC involved in oxLDL-induced HUVEC apoptosis, which was significantly inhibited by ABO, we first tested the effect of ABO on the protein level of PC-PLC in cultured HUVECs and MS1 cells
Summary
The two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators.[2]. Apoptosis that was induced by deprivation of fibroblast growth factor and serum, and by rattlesnake venom.[5] In addition, our previous studies indicated the roles of PC-PLC in VEC apoptosis and senescence, and found that inhibition of PC-. Based on the relationship of apoptosis and autophagy, recently, we detected decreased PC-PLC activity during HUVEC autophagy induced by Cd2 þ and sphingosylphosphorylcholine.[6,7] Collectively, PC-PLC is a key factor in apoptosis and autophagy of VECs. In addition, our recent in vivo study demonstrated that PCPLC was involved in atherosclerosis in apolipoprotein E À / À (apoE À / À ) mice.[8] PC-PLC is upregulated in the endothelial
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
