Vaccarin Inhibits The Formation Of Atherosclerosis And Its Underlying Mechanisms

Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality,which is the main cause of hypertension,stroke and cerebral infarction.The pathological mechanism of atherosclerosis is complex,and vascular endothelial injury is one of the main reasons.Under the combined action of various harmful stimuli,the loss of integrity of vascular endothelial cells and the aggravation of intravascular inflammation lead to leukocyte adhesion and migration,endothelial damage and atherosclerosis.Inflammation and apoptosis of vascular endothelium have been accompanied by the formation and development of atherosclerosis.Vaccarin is a flavonoid glycoside from vaccariae semen associated with powerful cardiovascular protective effects,which can inhibit vascular endothelial dysfunction and apoptosis.In order to study the effect of vaccarin on atherosclerosis,apolipoprotein E-deficient mice fed on a high-cholesterol diet to establish atherosclerosis animal models?n=20?.At the16th week,the mice were randomly divided into two groups:one group?n=10? was injected daily with vaccarin at a dose of 1 mg/kg for 4 weeks,the other group?n=10? was injected with saline in the same manner;The C57BL/6J mice were fed on a normal diet?n=20?,At the16th week,the mice were randomly divided into control?n=10? and vaccarin treatment?n=10?.In the vaccarin treatment group,the mice injection vaccarin with 1 mg/kg for 4 weeks;in the control group,the mice was injected with saline in the same manner.The results showed that vaccarin could apply to blood pressure lowering,hypoglycemic effect and losing weight,inhibit the formation in aorta and aortic root plaque and neointima,reduce the levels of TG,TC and LDL-C in serum,increase the level of HDL-C,and inhibit the formation of aortic plaque fibrosis;the results of qRT-PCR,ELISA and WB showed that vaccarin could improved the inflammatory levels of ApoE^-/- knockout mice.The results of caspase 3 activity assay and WB showed that vaccarin could alleviate apoptosis of vascular endothelium in ApoE^-/- knockout mice.The results of DCFH-DA and WB indicated that the reduced the ROS production and inhibited the phosphorylation of p38 MAPK in aorta.These results indicate that the vaccarin can inhibit the formation of atherosclerotic plaque,inhibit the fibrosis,inflammation and apoptosis in the process of atherosclerosis,and block the ROS/p38 MAPK signaling pathway.It was revealed that the vaccarin could be used as a new medicine monomer to inhibit atherosclerosis.Oxidized low-density lipoprotein?ox-LDL?-induced endothelial-mesenchymal transition?EndMT?,inflammation and apoptosis in endothelial cells play crucial roles in the progression of cardiovascular diseases including atherosclerosis.However,the effects of vaccarin on human umbilical vein endothelial cells?HUVEC?injury in response to ox-LDL remain unknown.Herein,we showed that treatment with vaccarin significantly suppressed ox-LDL-induced HUVEC inflammation,EndMT and apoptosis.Mechanistically,the HUVECs exposed to ox-LDL exhibited enlarged reactive oxygen species?ROS?production and p38 MAPK phosphorylation,which was counteracted by vaccarin.Importantly,ROS activator hydrogen peroxide?H₂O₂? and p38 MAPK activator anisomycin pretreatment prevent the protective effect of vaccarin on endothelial injury induced by ox-LDL.Our study suggested that vaccarin impeded ox-LDL-triggered HUVEC inflammation,EndMT and apoptosis via inhibition of ROS/p38 MAPK signaling pathway.Vaccarin may have a therapeutic effect on endothelial injury-related disorders including atherosclerosis.