The Effects And Therapeutic Mechanism Of Drugs Of Atherosclerotic Plaque's Regression

ObjectivesTo study the effects of high-cholesterol diet on levels of plasma lipids,IT/MT of the atherosclerotic plaque and the expression of VCAM-1,bFGF and Bcl-2 in the rabbits.To observe the therapeutic effects of drugs-simvastatin,amlodipine,amlodipine+simvastatin,irbesartan and probucol on the these targets.To supply the experimental evidence for the therapeutic effects on antiatherogenic.Methods1.Establishment of the rabbit atherosclerosis model:70 rabbits were divided into control group(n=10) and experimental group(n=60),the control group was fed with normal diet,while the experimental group was fed with cholesterol diet for 12 weeks, then was fed with normal diet and divided into regression control group,simvastatin group,amlodipine group,amlodipine+simvastatin group,irbesartan group and probucol group(n=10),and respectively administrated with simvastatin 2mg/(kg·d), amlodipine 2mg/(kg·d),amlodipine 2mg/(kg·d) + simvastatin 2mg/(kg·d), irbesartan 75mg/(kg·d) and probucol 50mg/(kg·d) for 12 weeks.2.Laboratary examinations:The levels of plasma TC,TG,LDL-C and HDL-C were obtained at the beginning,the 12^th and 24^th respectively.3.Histopathology:The aorta were processed and examined by HE stain and IT and MT were measured.The expressions of VCAM-1,bFGF and Bcl-2 were determined by immunohistochemical stain.And the arteries' ultra-structure was observed by transmission electron microscopy. 4.Statistic analysis:Continuous variables are reported as mean±deciazione standard.The data were analyzed with Excel and SPSS16.0 software:applied with ANOVA,the curative effect of drugs applied with paired T-test,a P value less than 0.05 is considered significant.Results1.Lipid profile:The levels of plasma TC,TG,LDL-C of the regression control group were higher significantly than the normal control group(P＜0.01) and that of HDL-C was no significant change.Compared with the regression control group,the levels of plasma lipids of amlodipine+simvastatin group and simvastatin group lowered the levels of TC,TG,LDL-C(P＜0.01)and HDL-C was no significant change.The levels of TC,HDL-C and LDL-C decreased apparently,TG has no change in probucol group.While there were no significant effects on the levels of plasma lipids in amlodipine group and irbesartan group(P＞0.05).2.Histological evaluation:In the regression control group,IT/MT increased apparently,the expressions of VCAM-1 and bFGF were higher and Bcl-2's was lower. And ultra-structure showed:the endothelium in the earlier injured region was denude, subintima was thicker,macrophage-derived and VSMC aggregated in the intima, these were the constitutive characteristics of AS.VSMC-derived foam cells and apoptotic cells were also found in AP.Compared with the regression control group,①The 5 drug-therapy groups' IT/MT reduced,especially the amlodipine+simvastatin group decreased most markedly(P＜0.01).②The expressions of VCAM-1 and bFGF significantly decreased in drug-therapy groups and that of Bcl-2 was increased prominently(P＜0.01),except the expression of Bcl-2 in amlodipine and probucol groups has no change.There was most statistical significance in amlodipine+simvastatin group.③Electron microscopy:In the 5 drug-therapy groups, EC were intact,less foam cells,less or none of fatty vesicles in or out of the cytoplasm,VSMC were less and showed a contractile phenotype.Collagen hyperplasia was significant in the ECM.Except for the amlodipine and probucol groups,other groups' apoptotic cells reduced.The ultra structure of arteries in 5 drug-therapy groups showed the regression,which suggested that these drugs could reverse the pathologic course of AS,especially the amlodipine+simvastatin group.Conclusions1.The levels of plasma TC,TG,LDL-C of the regression control group were higher significantly and that of HDL-C was no significant change,in the rabbits fed with high-cholesterol diet.IT/MT increased marked.The expressions of VCAM-1 and bFGF significantly increased in the AP and that of Bcl-2 decreased prominently.2.Compared with the regression control group,the levels of plasma lipids of amlodipine+simvastatin group and simvastatin group lowered the levels of TC,TG,LDL-C,while HDL-C was no significant change.The levels of TC,HDL-C and LDL-C decreased apparently,TG has no change in probucol group.While there were no significant effects on the levels of plasma lipids in amlodipine group and irbesartan group.The 5 drug-therapy groups' IT/MT reduced,especially the amlodipine+simvastatin group decreased most markedly(P＜0.01).The expressions of VCAM-1,bFGF were significantly decreased in drug-therapy groups and that of Bcl-2 was increased prominently(P＜0.01),except the expression of Bcl-2 in amlodipine and probucol groups has no change.There was most statistical significance in amlodipine+simvastatin group.3.Electron microscopy:In the regression control group,the endothelium in the earlier injured region was denude,subintima was thicker,macrophage-derived and VSMC aggregated in the intima,these were the constitutive characteristics of AS. VSMC-derived foam cells and apoptotic cells were also found in AP.In the 5 drug-therapy groups,EC were intact,less foam cells,less or none of fatty vesicles in or out of the cytoplasm,VSMC were less and showed a contractile phenotype.Collagen hyperplasia was significant in the ECM.Except for the amlodipine and probucol groups,other groups' apoptotic cells reduced.The ultra structure of arteries in 5 drug-therapy groups showed the regression,which suggested that these drugs could reverse the pathologic course of AS,and the amlodipine+simvastatin group had the best effect.4.All of these four drugs could regress AP,and the effect of amlodipine+simvastatin was better.They may influence the expressions of VCAM-1,bFGF and Bcl-2,therefore the endothelial function was improved,the migration and proliferation of VSMC was inhabited in the early stage and cell apoptosis was also suppressed,furthermore AP was regressed,then the pathologic course of AS was reversed,and they have synergistic effect.