| [Background] Atherosclerosis(AS)is a chronic inflammatory disease associated with lipid disorders.It is the pathological basis of cardio-cerebral vascular disease and the main cause of coronary heart disease,cerebral infarction,and peripheral vascular disease.A large number of studies have shown that the damage of vascular endothelial cells(VECs)is the initiating factor in the development of AS.It is very important to maintain the integrity of the structure and function of VECs in the prevention of AS.The clinical anatomy study found that AS occurs in vascular bifurcation,vascular bend and blood disorder,which is related to changes in hemodynamics and abnormal shear stress.Abnormal shear stress includes high shear stress(HSS)and low shear stress(LSS),which can activate or inhibit the expression of related genes,resulting in AS.Endothelial-to-mesenchymal transition(End MT)is the process of endothelial cell losing or reducing its specific antigen phenotype,transforming the phenotype into the mesenchymal cells and the corresponding migration,proliferation functions was enhanced,under certain physiological and pathological conditions(eg,hypoxia,oxidative stress,inflammation,or toxic substances,etc.).It is related to the occurrence and development of tissue fibrosis,malignant tumor,inflammatory reaction and atherosclerosis.Studies have found that low shear stress induces End MT,leading to the development of AS.In our previous experiment,a water-soluble protein with molecular weight of 28 KD was isolated from the flesh of bitter melon and named as Monordicin(MD).It was found to have anti-inflammatory,antiviral,lipid-lowering and anti-AS effects.[Objective] The influence of Momordicin on End MT induced by low shear stress was investigated via constructing animal models,and to explore its mechanism.[Method] 1.To construct a low-shear stress model of carotid artery in apo E-/-mice: After 10% pentobarbital anesthesia,ligation of the left carotid artery was performed,and the left cervix,the external carotid artery,and the posterior left occipital artery were ligated with silk thread.The blood flow of the superior thyroid artery was maintained,resulting in a slow shear stress model of local blood flow.The right side was a physiological shear stress model;2.Twenty apo E-/-mice were randomly assigned to a bitter melon protein group and model group.The rats were fed with high-fat diet,and the Momordicin group was intraperitoneally injected with Momordicin 5 mg/kg/d.The model group was injected with an equal volume of normal saline to observe the effect of Momordicin on atherosclerosis induced by low shear stress.3.ELISA detection Plasma levels of inflammatory cytokines in apo E-/-mice;4.Plasma lipid levels in mice analyzed by automatic biochemistry analyzer;5.Expression of endothelial and interstitial antigen markers in common carotid arteries detected by Western blotting and immunofluorescence and co-localization,NF-?B nuclear translocation,ICAM-1 and VCAM-1 protein expression levels.[Result] 1.low shear stress damages structural integrity of vascular endothelial cells;2.Momordicin inhibits low shear stress-induced endothelial-to-mesenchymal transition;3.Momordicin improves atherosclerotic lesions;4.Momordicin down-regulates blood lipid levels and body weight in apo E-/-mice;5.Momordicin inhibits the expression of serum inflammatory factors;6.Momordicin inhibited the expression of ICAM-1 and VCAM-1;7.Momordicin inhibited the low shear stress-induced endothelial interstitial transformation via inhibiting the activity of NF-?B.[Conclusion] In high-fat fed apo E-/-mice models,Momordicin inhibits low shear stress-induced endothelial interstitial transformation and reduces atherosclerotic lesions by inhibiting nuclear translocation of NF-?B. |
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