PCSK9 Antagonizes The Anti-inflammatory Effect Of ApoE/ApoER2 By Degrading ApoER2

Atherosclerosis(AS)is a chronic inflammatory disease whose development is mainly manifested by inflammation of the blood vessel wall.Endothelial cells are a single layer of squamous epithelium that is attached to the luminal surface.Endothelial cells damage and dysfunction are not only the initial link of AS,but also play a key role in expanding vascular inflammation.Apolipoprotein E(apoE)is a structural protein of plasma lipoprotein and plays an important role in the metabolism of plasma-rich triglyceride lipoproteins.In addition to affecting the development of AS by participating in lipid metabolism,the anti-inflammatory effect of apoE is also important for inhibiting the development of AS.Apolipoprotein E receptor-2(ApoER2)is a transmembrane endocytic receptor protein widely present on the cell membrane.It acts as a receptor for apoE and has a high affinity for apoE.Studies have shown that binding of apoE to ApoER2 on endothelial cell membranes stimulates endothelial nitric oxide synthase production and endothelial cell migration,and also attenuates monocyte-endothelial cell adhesion.The proprotein convertase subtilisin 9(PCSK9)is a novel protease discovered in recent years that affects plasma low-density lipoprotein cholesterol(LDL-C)levels by regulating the amount of low-density lipoprotein receptor(LDLR)on the liver cell membrane,thus indirectly participate in the progress of AS.In addition to degradation of LDLR,PCSK9 can also degrade other members of the LDLR family,such as ApoER2,low-density lipoprotein receptor-related protein 1(LRP1)and so on.Studies have shown that PCSK9 is associated with inflammation.At the same time,silencing the PCSK9 gene can reduce the production of inflammatory cytokines,but the specific mechanism of PCSK9 and inflammation is not clear.Since it is well-accepted that PCSK9 is able to degrade ApoER2,is there a link between the degradation of ApoER2 by PCSK9 and the anti-inflammatory effect of apoE/ApoER2,which will be the focus of this topic.Objective: The relationship between PCSK9 degradation of ApoER2 and anti-inflammatory effects of apoE/ApoER2.Methods: The effect of LPS on the expression of TLR4,PCSK9,TNF-? and IL-6 was detected by Western blot;Western blot was used to detect the effect of apoE3 on the expression of PCSK9,ApoER2,TNF-? and IL-6 in HUVECs induced by LPS;The effect of PCSK9 on the expression of ApoER2,TNF-? and IL-6 was detected by Western blot.The levels of PCSK9,TNF-? and IL-6 in the supernatant of each experimental group were detected by ELISA.At the same time,Western blot was used to detect the effects of three subtypes of apoE(apoE2,apoE3,apoE4)on the expression of PCSK9 and ApoER2 in HUVECs and HepG2 cells in non-inflammatory state.Results: LPS combined with TLR4 on HUVECs membrane up-regulated the expression of PCSK9,TNF-?,IL-6.apoE3 inhibited the inflammatory state of HUVECs induced by LPS and down-regulated the expression of PCSK9 and up-regulated the expression of ApoER2,but the three subtypes of apoE had no effect on the expression of PCSK9 and ApoER2 in HUVECs and HepG2 cells in non-inflammatory state.PCSK9 down-regulated ApoER2 expression and up-regulated TNF-? and IL-6 expression.Conclusion: PCSK9 antagonizes the anti-inflammatory effects of apoE/ApoER2 by degrading ApoER2.