The Mechanisms Of Tnfaip2 Accelerating Atherosclerosis By Regulating Mitochondrial Apoptosis

Atherosclerosis(AS)is a chronic inflammatory disease characterized by lipid deposition in arterial blood walls.Studies have shown that apoptosis plays an important role in different stages of atherosclerosis.In the early stage of atherosclerosis,apoptosis of smooth muscle cells,inflammatory cells(including lymphocytes and macrophages)and endothelial cells may delay the process.However,once plaque is formed,apoptosis of smooth muscle cells and macrophages with lipids may lead to plaque rupture and thrombosis,exacerbate atherosclerosis.Tnfaip2,tumor necrosis factor α-induced protein 2,regulates cell proliferation and migration,and is a multifunctional mediator of angiogenesis and tunneling nanotube formation.Previous studies have found that knocking down Tnfaip2 can reduce the formation of plaques in ApoE-/-mice,and overexpression of Tnfaip2 in 293T cells can upregulate the level of Bcl-2,which is an important anti-apoptotic protein in the Bcl-2 family related to endogenous apoptosis(mitochondrial apoptosis).Mitochondrial apoptosis is an important form of apoptosis.There is no report on the relationship between Tnfaip2 and mitochondrial apoptosis and whether it can regulate atherosclerosis by regulating mitochondrial apoptosis.Therefore,this thesis focused on mitochondrial apoptosis to explore the effects and mechanisms of Tnfaip2 on mitochondrial apoptosis and verified the role of Tnfaip2 in the occurrence and development of atherosclerosis.In this thesis,the role of Tnfaip2 in atherosclerosis was verified through bone marrow transplantion.The results showed that the plaques,blood lipids and inflammatory factors of Ldlr-/-mice transplanted with Tnfaip2-/-mice bone marrow cells were significantly reduced,which further verified the atherogenesis functions of Tnfaip2.In vitro experiments,peritoneal macrophages(PMΦ)or bone marrow derived macrophages(BMDMs)derived from WT and Tnfaip2-/-mice and Tnfaip2 overexpressed 293T cells were used to explore the effects of Tnfaip2 on mitochondrial apoptosis under the oxidative stress condition(stimulation of H2O2 or CCCP).It was found that Tnfaip2 could inhibit apoptosis,resist the decrease of mitochondrial membrane potential(an early marker of mitochondrial apoptosis),and decrease the accumulation of mitochondrial ROS.It was also found that Tnfaip2 could inhibit the oligomerization and binding of Bax and Bak,and reduce the release of Cytochrome C.In conclusion,Tnfaip2 promotes atherosclerosis through inhibiting mitochondrial apoptosis.This thesis systematically studied the effects of Tnfaip2 on atherosclerosis and mitochondrial apoptosis,providing a new potential therapeutic target and theoretical basis for the prevention and treatment of atherosclerosis.