Study Of The Regulation Of Atherosclerosis-associated Foam Cells Formation In Mice By TWEAK/Fn14 Pathway

BACKGROUND:M1 macrophages can accumulate large amounts of lipids and form foam cells in advanced atherosclerosis,they further participate in the formation of lipid core,which is a sign of the progression of atherosclerosis.Tumor necrosis factor-like apoptosis weak inducer（TWEAK）and its functional receptor(TWEAKR,fibroblast growth factor-inducing molecule 14（Fn14）are two proteins belonging to the TNF superfamily.They can activate NF-κB and regulate a variety of cellular functions,such as proliferation,migration,differentiation,apoptosis,inflammation,and angiogenesis through canonical and non-canolical pathways.TWEAK/Fn14 is expressed on many kinds of cell membrane,including macrophages.This study aims to investigate whether TWEAK/Fn14 is involved in the lipids phagocytosis of macrophages,foam cells formation and the mechanisms of TWEAK/Fn14 in the process of atherosclerosis.METHODS:In vivo,apoE^-/-mice and C57B/L6 mice were fed with western and chow diets.Body weights and plasma lipids level（TCH and TG）were collected and measured at different study time points（0week,8week,16week）.Aortic lesion area ratios were determined by oil red O staining.The macrophages and TWEAK/Fn14 in atherosclerotic plaques was detected by immunohistochemical staining.And the protein expression levels of Fn14 in aortas were anaylzed by Western-blot.In vitro,mouse peritoneal macrophages and oxLDL induced foam cells were used to detect the expression levels of TWEAK and Fn14.RESULTS:The aortic lesion existed in apoE^-/-mice with both western and chow diets for 16 weeks,and there was no significant difference of aortic lesion area between each of them.While C57B/L6 mice has the opposite outcome.A large number of macrophage infiltrates in atherosclerotic plaques,and TWEAK/Fn14 were seen in the same area.Fn14 protein level was significantly higher in apoE^-/-mice aortas than in C57B/L6 mice(apoE^-/-mice vs.C57B/L6 mice,P<0.01).In vitro,TWEAK and Fn14expression levels also higher in foam cells than those in macrophages.CONCLUSION:TWEAK and Fn14 expression levels were significantly higher in aortas of apoE^-/-mice with both western and chow diets for 16 weeks and foam cells.Our study provides the evidence that TWEAK/Fn14 plays roles in regulating macrophage lipid phagocytosis and plaque formation in aortas which leads to initiation and deterioration of atherosclerosis.