Effects Of FKN In NF-KB Activation And TNF-α Synthesis In Monocytes And The Invention Of Captoril

Background: Recruitment of circulating monocytes to the arterial intima contributes to the formation of atherosclerotic lesions and may participate in their destabilization. Leukocyte emigration from blood into tissues is mediated by multiple adhesion molecules and chemokines, which orchestrate specific steps of emigration and regulate preferential recruitment of different leukocytes depending on their expression patterns of chemokine receptors. Recently chemokines Fractalkine ( FKN ) has been reported implicated in modulation of vascular inflammation and may play an important role in the pathophysiological process of atherosclerosis. Studies by Jin Lee demonstrated that FKN stimulated angiogenesis by activating the MAPK system and PI3K signal pathways via the G protein-coupled receptor CX3CR1, but the underlying mechanism has not been elucidated. Nuclear factor–κappaB (NF-κB), a redox-sensitive transcription factor, has also been indicated to play a critical role in both initiaion and expansion of AS. It is reported that one of the activation of NF-κB may be through PI3K pathway. As a factor of inflammation, TNF-αis always founded in atherosclerotic lesions and not founded in healthy vascular. It can impair vessel endothelium and breakdown the balance between blood coagulation and anticoagulation system. Captopril has been repoted to antiatherosclerosis .We devise this experiment to investigation the relationship of Fractalkine,NF-κB,TNF-αand Captopril.Objective (1) To investigate the sigal transductive mechanism of FKN /CX3CR1 affecting atherosclerosis ; (2)To research the function of NF-κB inthe signal transduction mechanism of FKN /CX3CR1 affecting atherosclerosis; (3)To research the intervention of angiotensin converting enzyme inhibitor captopril in the signal transduction mechanism of Fractalkine/CX3CR1 affecting atherosclerosis.Methods :(1)Peripheral blood monocytes(PBMC) were isolated from fresh blood of healthy volunteers by Ficoll-Paque gradient centrifugation ; (2) PBMC were then diveded into five groups ,they are :control group, FKN group, the inhibitor of PI3K LY294002 group ,inhibitor of NF-κB PDTC group and captopril group;(3) the expressiong of NF-κB in monocytes of each group were detected by western blotting ; (4)culture solution of each group were collected, and detect the concentration of TNF-αby euzyme-linked immunosorbent assay (ELISA)Result: (1) there are much more NF-κB and TNF-αexpression in the monocytes from FKN group compared with control group ;(2) there are less NF-κB and TNF-αexpression in the monocytes from LY294002 group compared with FKN group ;(3) there are less NF-κB and TNF-αexpression in the monocytes from PDTC group compared with FKN group ,but more than control group ; (4) there are less NF-κB and TNF-αexpression in the monocytes from CAP group compared with FKN group ,but more than control group .Conclusion: (1) FKN /CX3CR1 may increase the expression of NF-κB and TNF-αin PBMC as signal tranductive mechanisms which contribute to the progression of atherosclerosis; (2) Protein PI3K play an important role during the process that PBMC synthesize NF-κB and TNF-αinduced by FKN /CX3CR1;(3)NF-κB may promote the expression of TNF-αinduced by FKN /CX3CR1 ;(4)FKN /CX3CR1 may participate in the formation of atherosclerosis through the signal transduction that FKN /CX3CR1 active the protein of PI3K which increase the expression of NF-κB in nuclear and finally promote the synthesis of TNF-α;.(5) Captopril may prevent the progression of atherosclerosis by decreaseing the activity of NF-κB and the synthesis of TNF-αin PBMC .