Effects Of Atorvastatin And Ezetimibe On The Expression Of CD147,HIF-1?,VEGF And MMP-2 In Atherosclerotic Plaques

BackgroundAtherosclerosis(atherosclerosis,AS)is a pathological physiological basis of atherosclerotic disease,can occur to the body of the small arteries,which cause serious damage to human health of body and mind its pathogenesis is complicated,including lipid infiltration theory and theory of endothelial injury and so on,but at present most of scholars believe that atherosclerosis is a chronic inflammation mediated by the lipoprotein disease,which a variety of inflammatory cells and inflammatory factors are involved.Extracellular matrix metalloproteinases inducing factor(CD 147)increases the expression and activity of a variety of matrix metalloproteinases(MMPs)such as MMP-2,MMP-9 within the plaques,which may degrade the main components of the fibrous cap such as matrix collagen,accelerating the progress of the AS.As the abscence of oxygen,hypoxia inducing factor(HIF)and its downstream factor vascular endothelial growth factor(VEGF)can be induced,resulting in the formation of new blood vessels and persistent inflammation in plaque,eventually leading to the acute thrombotic events and plaque rupture.It has been found that CD 147 can increase the expression of HIF and VEGF in tumor and rheumatoid arthritis tissues,yet the study on atherosclerotic plaque has not been reported.Statins and ezetimibe are the most commonly used lipid-lowering drugs in clinical practice.Except its lipid-lowering effects,statins also has the abilities to improve endothelial function,inhibit inflammatory reaction and so on.A study found that it inhibited the expression of CD147/MMPs subsequently stable plaques,whether to inhibit HIF/VEGF expression has not been researched.As a nonstatin-type of lipid-lowering drug,ezetimibe has rarely been reported as a pleiotropic drug in addition to lipid-lowering effect,and its ability to inhibit the expression of CD147 HIF-la,VEGF and MMP-2 in plaques has not been reported in relevant literatures.ObjectiveTo observe the effect of atorvastatin and ezetimibe on the expression of CD 147,HIF-1?,VEGF and MMP-2 in carotid atherosclerotic plaques in rabbits.Methods32 male New Zealand rabbits were randomly divided into blank control group,model group,atorvastatin group,ezetimibe group,8 rabbits in each group.The blank control group was always given normal diet the other three groups were treated with liquid nitrogen frostbite combined with high-fat diet for 12 weeks to establish the-atherosclerosis model,ezetimibe group was given ezetimibe 2.0 mg/(kg-d),atorvastatin group was given atorvastatin 2.5 mg/(kg·d),the model and the control group was given equal normal saline lavage 4 weeks in a row.Serum levels of TG and LDL-C were detected before high-fat diet and around drug intervention,serum levels of CD147,HIF-la,VEGF and MMP-2 were detected before and after drug intervention.Pathological characteristics of the carotid artery and expressions of CD 147,HIF-1?,VEGF and MMP-2 were detected at the end of experiment,and carotid artery lesions were assessed by OCT and IVUS.ResultsSerum levels of TG,LDL-C and MMP-2 in the model group were significantly higher than those in the control group(p<0.05).Compared with the model group,the serum levels of TG,LDL-C,Hs-CRP and MMP-2 were significantly reduced in the atorvastatin group and ezetimibe group(p<0.05),the serum level of sCD147 in the ezetimibe group was significantly decreased(p<0.05),the serum level of sCD147 in the atorvastatin group was not significantly decreased(p>0.05).The serum levels of HIF-1? and VEGF between various groups had no significant differences(p>0.05).The IHC assay showed the expression of CD147,HIF-1? and MMP-2 in plaque of the model group was significantly higher than the control group(p<0.05).Compared with the model group,expression of HIF-1? was significantly decreased in the atorvastatin group(p<0.05).The expression of VEGF in each group showed no statistical difference(p>0.05).Western Blot results showed that the relative expression of CD147,HIF-1?,VEGF and MMP-2 in the model group was significantly higher than that in the blank control group(p<0.05).Compared with the model group,the relative expression of CD 147 and VEGF in the atorvastatin group was significantly decreased(p<0.05).Pearson correlation analysis showed that the expression of HIF-1?,MMP-2 and VEGF were positively correlated with the expression of CD 147(p<0.05),the expression of VEGF and HIF-1? was positively correlated(p<0.05).IVUS and OCT imaging showed smooth artery intima in the blank control group and no atherosclerotic plaque formation.In the model,atorvastatin and ezetimibe group were found different extents of fibrous plaques and lipid plaques,the carotid artery lumen in the model group showed moderate or severe stenosis,plaque rupture and thrombosis.The carotid artery lumen in the atorvastatin and ezetimibe group showed moderate stenosis,buat no plaque rupture and thrombosis.ConclusionsThe expression of CD 14,HIF-1?,MMP-2 and VEGF in rabbit carotid artery plaques was increased.Atorvastatin not only reduced the serum level of TG,LDL-C MMP-2,Hs-CRP,but also reduced the expression of CD 147,HIF-1?/VTEGF in the plaques,which may relate to the mechanism of plaques stabilization.Ezetimibe not only reduced serum TG,LDL-C level,but also delayed the progression of atherosclerotic plaque by reducing serum sCD147,MMP-2 and Hs-CRP level,the effect of stabilize plaque is not obvious.Both atorvastatin and ezetimibe have the effect of slowing down the progression of atherosclerosis and reduce the stenosis of arterial lumen.