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The Clinical Observation of PAS Therapy on Carotid Atherosclerosis Plaques and Research on Rabbit Atherosclerotic Model

Author: MengJun
Tutor: MengXiaoPing
School: Jilin University
Course: Clinical
Keywords: PAS therapy carotid atherosclerosis plaques Probucol Statin
CLC: R543
Type: Master's thesis
Year: 2009
Downloads: 68
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Abstract


Background:Atherosclerotic cardiovascular disease is a common one, the latest research results show that atherosclerosis is a chronic inflammatory reaction, IL-1, TNF-a, such as a series of pro-inflammatory cytokines involved in the process, and low-density lipoprotein (LDL) formed by oxidative modification of low-density lipoprotein (ox-LDL) is the key to this process-induced inflammatory factors. Macrophage cells in atherosclerotic plaque formation and the develop- ment process has played an important role. Role of pro-inflammatory cytokines, endothelial cell adhesion molecule expression and secretion, chemical chemokines, monocyte migration to vascular endothelium, and differentiate into macrophages. ox-LDL oxidative stress as a material is to promote atherosclerosis and the development of important factors. ox-LDL can be scavenger receptor macrophage unlimited intake, which leads to macrophage lipid cholesterol in a large number of particle accumulation, finally formation of foam cells, foam cells Atherosclerosis are classic cells, in the whole Atherosclerosis process of foam cells secrete matrix metalloproteinase (MMPs), the degradation of the basement membrane to smooth muscle cell migration, and promote the progress of atherosclerosis.MMPs belong to the Zn2 +dependent protease family, are now known to have 23 family members, specific degradation of extracellular matrix, plaque rupture often occurre in the fibrous cap shoulder, its fibrous cap is the thinnest, collagen content and - glucan less fibrous cap bear the tension, anti-poor rupture,which is one of the important factors of matrix metalloproteinases . (MMPs) expression and activation. MMP main artery in the membrane from the patch of smooth muscle cells and mononuclear macrophages, and by inflammatory cytokines that increase the expression of pressure, secretion and activation.The matrix metallopr- oteinases - 2、9 (MMP– 2、9) with the extracellular matrix degradati- on strong.Ⅳof the basement membrane and collagen fibers atherosclerotic plaque are the important component of the cap, MMP - 2、9 promote degradation of smooth muscle cells in the membrane to the endometrium migration, and accelerate the process of atherosclerosis. ox-LDL can be increased through of matrix metalloproteinases (MMPs) and matrix-degrading enzyme (stromelysins) activity, and promote thrombosis. To sum up, to make the atherosclerotic plaque stable is the key to the treatment of atherosclerosis, while with the hope of the reversing or reducing the plaque. Although there are a variety of factors which can cause plaque instability, while animal experiments and clinical trials have proven that the increased levels of MMPs played an important role in the plaque instability. The clinical researches have proven that probucol has obvious inhibiting role to MMPs, so we consider that when treating atherosclerotic diseases, in addition to the recognized intensive lipid-lowering therapy from the substance reducing to block the formation of lipid nuclear , blocking the LDL oxidized also may be a new therapeutic concept. So we plus having the antioxidant role of the matrix metalloproteinase inhibitor– Probucol. In addition, preventing the thrombosis after athe- rosclerosis plaque rupture or erosion, has no doubt become an important component part to atherosclerosis treatment. Aspirin has been recognized having the roles above in theory and clinical practice, and has been considered as the essential drugs in the treatment of coronary heart disease . Therefore, the PAS therapy has become the necessary treatment of atherosclerosis.Experimental purposes:To discuss the regressive effect of PAS therapy on carotid atherosclerotic plaques and the intervention effect of Probucol combined with Simvastatin in rabbit atherosclerosis, to supply a new clinic and theory evidence for PAS therapy cure atherosclerosis disease.Experimental Methods:The research can be divided into two parts: clinical treatment and animal experiment.1、Choose Thirty-six patients with carotid atherosclerotic plaques detected by carotid color Doppler ultrasonography , they were randomly divided into two groups : PAS group was fed with Probucol 250mg, twice a day base on the treatment of control group, for one year, Control group was fed with Baiaspirin 100mg, once a day, Atorvastatin 20mg, once a day, for one year. The two groups patients’serum lipid including TC、TG、LDL-C and HDL-C and the changes of carotid intima-media thickness ( IMT) were detected by carotid color Doppler ultrasonography before and after the treatment.2、24 male New Zealand rabbits were randomly divided into four groups : the high cholesterol control group was fed with cholesterol-enriched diet containing 1% cholestero+6% yolk powder+8% tallow ; the Probucol group was fed with 125mg/kg/d of Probucol based on the cholesterol-enriched diet; the Simvastatin group was fed with 5.0mg/kg/d of Simvastatin based on the cholesterol-enriched diet ;and the combined therapeutic group was fed with 125mg/kg/d of Probucol combined with 5.0mg/kg/d of Simvastatin based on the cholesterol-enriched diet.,which were fed for 14 weeks. On the 14th weekend , phlebotomized and separated serum, then all the rabbits were killed , at the same time cut the thoracic aorta and observed forming of the atherosclerotic plaques. Serum TC、TG、LDL-C and HDL-C were measured, the levels of MMP-9、ox-LDL、TXB2 and CRP in the serum were detected by ELISA method. Plaque samples were in HE coloration and pathological changes were observed in microscope, MMP-9 expression in plaques were detected by immunohistochemical coloration methods, using HPIAS—1000 High Definition Color Pathologic Picture Analyse System measured thoracic aorta intima thickness、intima∕media thickness ratio and average gray level of MMP-9 immune sediment.The results:1、After the treatment , the levels of TC、TG、LDL-C and HDL-C in the serum were obviously decreased in PAS group(P<0.01), the levels of TC、TG、and LDL-C in the serum were also decreased in control group(P<0.01), the level of HDL-C were increased in control group(P<0.01). And the extent of TC and LDL-C decreased in PAS group was greater than in control group(P<0.01),comparing the changes of TG level after the treatment between the two groups , the differences don’t have statistical significance(P>0.05). Table 2.2—2.5 shows the numerical change of indicators above.2、Both PAS therapy and the treatment of control group all regressed carotid atherosclerotic plaques obviously. After the treatment, carotid intima-media thickness in the two groups all decreased than before the treatment(P<0.01),but the extent of PAS group decreased was greater than control group, and the differences have statistical significance(P<0.05).Table 2.6 shows the numerical change of indicators above.3、Probucol can decrease the levels of TC、LDL-C and HDL-C in the serum of rabbits , but have no effect on TG expression level. Simvastatin can decrease the levels of TC and LDL-C in the serum ,increase the level of HDL-C and decrease the level of TG. Probucol combined with Simvastatin can decrease the levels of TC and LDL-C in the serum significantly, they were (14.15±0.57)mmol/L and (7.30±0.54)mmol/L,the differences have statistical significance(P<0.01 ,P<0.05).The results indicate combined application have cooperate effect on decreasing the levels of TC and LDL-C in the serum.Table 3.1-3.4 shows the numerical change of indicators above.4、Both Probucol and Simvastatin can significantly decrease the levels of MMP-9、 ox-LDL and CRP in the serum of rabbits. Among the two drugs, Probucol has the distinct effect on decreasing the level of ox-LDL compared to Simvastatin ,while Simvastatin has the distinct effect on decreasing the level of CRP compared to Probucol. Probucol combined with Simvastatin can decrease the levels of MMP-9 and ox-LDL in the serum even more significantly, they were(3.33±0.31 ) ng/ml and (9.33±0.84) u/ml,the differences have statistical significance(P<0.01,P<0.01), The results indicate combined application have cooperate effect on decreasing the levels of MMP-9 and ox-LDL in the serum, but have no cooperate effect on decreasing CRP expression level in the serum. Both Probucol and Simvastatin have no influence on the level of TXB2. Table 3.5-3.8 shows the numerical change of indicators above.5、Plaque samples results: Inside the thoracic aorta vessel wall of the high cholesterol control group there were a great of white lipid-like atherosclerotic plaques formation, which presented pieces and restis swell towards aorta lumen, joined with flakelike on the section start of thoracic aorta, and intima was rough. Lipid-like atherosclerotic plaques substance were decreased obviously in Probucol group and Simvastatin group, among the two groups, atherosclerotic plaques substance in Simvastatin group were less than in Probucol group. The combined therapeutic group’s lipid-like atherosclerotic plaques were least in four groups, which presented particle distribute, and intima was smooth.6、HE coloration pathological results:The intima was incrassated obviously in high cholesterol control group , and atherosclerosis plaque containing a large number of foam cell , and there was a mass of macrophages and extracellular lipid sediment in intima. Intima thickness was decreased obviously in Probucol group and Simvastatin group compared to high cholesterol control group, and foam cell and extracellular lipid sediment was also decreased obviously.Among the two groups, the extent of pathological in Simvastatin group was alleviated than in Probucol group. The intima incrassation was not obviously in combined therapeutic group, and foam cell was sparse.7、MMP-9 immunohistochemical coloration results:Inside the aorta intima of high cholesterol control group, there were a large number of brown granules positive coloration substance. The brown granules positive coloration substance were reduced in Probucol group and Simvastatin group compared to high cholesterol control group. Among the two groups, the positive coloration substance were less in Simvastatin group than in Probucol group. The combined therapeutic group’s positive coloration substance were least in four groups, only a little brown granules positive coloration substance appeared in intima. 8、Both Probucol and Simvastatin can decrease aorta intima thickness、intima∕media thickness ratio and increase average gray level of MMP-9 immune sediment obviously in atherosclerotic rabbits,the differences have statistical significance(P<0.01). Probucol combined with Simvastatin can decrease aorta intima thickness、intima∕media thickness ratio and increase average gray level of MMP-9 immune sediment more remarkably .And combined application have cooperate effect on decreasing aorta intima thickness、intima∕media thickness ratio, but have no cooperate effect on increase average gray level of MMP-9 immune sediment. Table 3.9-3.11 shows the numerical change of indicators above.Experimental conclusions:1. PAS therapy can regress carotid atherosclerotic plaques obviously , and its effect is more obviously than the effect of treating with Atorvastatin combined with Aspirin, which indicated Probucol can continue regressing carotid atherosclerotic plaques base on the treatment of decrease lipid and anti-platelet aggregation.2. PAS therapy is safe and effective in clinical treatment.3. Probucol combined with Simvastatin can obviously inhibit the formation of rabbit aorta atherosclerotic plaque, and the effect excel single treatment.4. Probucol combined with Simvastatin can obviously decrease the levels of MMP-9、ox-LDL and CRP in the serum of rabbits, and combined application have cooperate effect on decreasing MMP-9 and ox-LDL expression level.5. Both Probucol and Simvastatin have no influence on the level of TXB2 in the serum of rabbits, which indicate that Probucol and Simvastatin don’t have the effect of Anti- blood platelet.6. Probucol combined with Simvastatin can obviously decrease the expression of MMP-9 in rabbit atherosclerotic plaque, and the effect excel single treatment. And combined application can play the effect of stabilizing plaque.7. Probucol combined with Simvastatin can obviously decrease aorta intima thickness、intima∕media thickness ratio , which has the effect of inhibit vascular smooth muscle cell proliferation and transferation.8. In processing of anti-atherosclerosis, Probucol combined with Simvastatin can play more strong anti-oxidation and anti-inflammation effect. And Probucol take anti-oxidation and stabilizing plaque effect as the main aspect of anti-atherosclerosis, however, Simvastatin take anti-inflammation effect as the main aspect of anti-atherosclerosis.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Vascular disease
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