脉心康干预载脂蛋白E基因敲除小鼠动脉粥样硬化及其巨噬细胞泡沫化的分子机制研究
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摘要
目的：1．探讨动脉粥样硬化(As)中医病因病机治则新认识，分析整理脉心康胶囊创制的理论基础及前期成果。2．通过载脂蛋白E基因敲除[ApoE(-／-)]小鼠整体体内实验及其腹腔巨噬细胞体外细胞培养实验，多层次、多靶点探讨脉心康抗As的作用原理特别是分子机制。
方法：1．结合中医药文献、基础理论和临床实际，在对As中医病因病机治则传统认识回顾的基础上，进行创新性探讨；对脉心康的方药组成特色进行中西医结合分析，对脉心康的临床应用与基础研究成果进行分析整理。2．实验研究：(1)整体体内实验研究：ApoE(-／-)小鼠按随机数字表法随机分组，各组分别给予脉心康、洛伐他汀、罗格列酮、生理盐水灌胃，正常对照组(正常C57BL／6J小鼠)给予生理盐水灌胃，各组与正常对照组分别于给药后第8周、第12周各处死一半，静脉取血，取主动脉标本固定、染色及相应处理。(2)细胞学实验研究：ApoE(-／-)小鼠腹腔巨噬细胞培养，各组分别给予脉心康、洛伐他汀、罗格列酮无菌含药血清，并与ox-LDL共孵育(泡沫化)，分别观察0—72小时不同时相的指标变化。光镜及电镜下观察主动脉As病变及超微结构；激光共聚焦扫描显微镜检测细胞内钙离子(Ca~(2+))；高效液相色谱法检测细胞内胆固醇及胆固醇酯；免疫组化法检测细胞、主动脉PPARγ、ABCA1、CD36蛋白表达；流式细胞仪检测CD36；原位杂交法检测细胞、主动脉PPARγ、CD36、ABCA1 mRNA表达；ELISA法检测血清、巨噬细胞培养液TNF-α、IL-1β。
结果：1．明确了As及其易损斑块的气虚血瘀，毒损脉络病机和益气活血解毒治则创新思路，体现此治则的脉心康对As与高脂血症疗效显著，具有降脂、抗炎、抗氧化、保护血管内皮、抗As、抑制细胞外基质降解、稳定斑块等作用。2．实验研究：(1)整体体内实验研究：脉心康能使ApoE(-／-)小鼠As病理形态学及超微结构改变减轻，有助于斑块缩小稳定；脉心康组、罗格列酮组血管壁PPARγ、ABCA1 mRNA的表达显著增加，PPARγ、ABCA1蛋白的表达显著增加；脉心康组、洛伐他汀组血管壁CD36 mRNA表达及CD36蛋白的表达显著降低；脉心康组、洛伐他汀组、罗格列酮组血清TNF-a、IL-1水平显著降低。(2)细胞学实验研究：用含药血清干预ApoE(-／-)小鼠泡沫化腹腔巨噬细胞后，巨噬细胞内Ca~(2+)浓度各组都有升高，脉心康、洛伐他汀、罗格列酮含药血清干预组Ca~(2+)浓度显著低于生理盐水组和空白对照组；脉心康、罗格列酮组PPARγ及ABCA1mRNA表达和PPARγ及ABCA1蛋白表达较洛伐他汀、空白对照组和生理盐水组均显著增加；脉心康、洛伐他汀组CD36 mRNA表达与CD36蛋白表达均显著低于罗格列酮组、生理盐水组和空白对照组。脉心康组、洛伐他汀组及罗格列酮组细胞内总胆固醇、游离胆固醇及胆固醇酯含量显著低于生理盐水组和空白对照组。脉心康组、洛伐他汀组及罗格列酮组培养液TNFα、IL-1β较生理盐水组和空白对照组显著降低。
结论：1．益气解毒活血方脉心康具有确切的降脂、抗炎、抗As与稳定易损斑块等作用。2．脉心康通过增加PPARγ、ABCA1mRNA表达，增加PPARγ、ABCA1蛋白表达，降低CD36 mRNA表达和蛋白表达，减少巨噬细胞内胆固醇及胆固醇酯的含量，降低巨噬细胞钙超载，减少巨噬细胞释放TNFα、IL-1β，达到抗炎、降低巨噬细胞的趋化性、抗细胞泡沫化，从而保护动脉、保护超微结构、抗As及稳定斑块，对防治As和预防急性冠脉综合征等心脑血管事件有重要意义。
Objective:To study the etiological factor,pathogenesis and new therapeutics ofatherosclerosis by means of benefiting vital energy to activate blood,remove stasis,anddiscuss the mechanism of atherosclerosis and the theoretical basis of the intervention innew therapeutics of benefiting vital energy,toxin-resolving and blood-activating.Toexplore the pharmacologic action and effect of Capsule Maixinkang on Atherosclerosis andinvestigate the mechanism of maixinkang to prevent macrophages transforming into foamcell.
Method:To study the etiological factor and pathogenesis of atherosclerosis,to sumup the result of the observation Capsule Maixinkang on atherosclerosis,hyperlipidemiaand the experiments of effect of Maixinkang to high fat diet rat and ApoE(-/-)mice.Analyze the composition of Maixinkang,explore the pharmacologic action and effect ofMaixinkang on atherosclerosis.Summarize the academic experience in treatingatherosclerosis by benefiting vital energy,activating blood to remove stasis,andtoxin-resolving.Six weeks old ApoE(-/-) mice were divided randomly into four groups,inwhich lavaged with maixinkang,lovastatin,rosiglitazone and saline for two weeks,half ofwhich lavaged for eight weeks,while normal control group which is composed of sixweeks old C57BL/6J mice lavaged no medicine.Half of mice in all groups is put to deathrespectively,collect venous blood and arteriae aorta after eight and twelve lavaged.The areaof Aorta atherosclerosis which observed under light microscope and electron microscopewas analyzed by image analysis system.The expression of PPARγ、CD36、ABCA1 mRNA
was detected hybridization in situ.The PPARγ、CD36、ABCA1 protein was evaluatedby immunohistochemistry.The serum concentration of TNF-α,IL-1βwere detected byELISA.2.Peritoneal macrophages derived from ApoE(-/-) mice were incubated withox-LDL and blood serum containing medicine for 72 hours.The peritoneal macrophageswere divided into six groups according to blood serum containing different medicine:Maixinkang,Lovastatin,rosiglitazone,saline and control group.The congcentration ofCa~(2+) intra-cellular was observed and analyzed with Ca~(2+) image analysis system and
confocal laser scanning microscope.Intracellular total cholesterol and free cholesterol(FC) was measured by high performance liquid chromatography (HPLC),ABCA1 andPPAR),protein was detected in immunohistochemistry and semiquantitative analyzed byimage analysis system.CD36 protein was detected by flow cytometry.The expression ofPPAR3,,CD36,ABCA1 mRNA was detected hybridization in situ.
Result:1.Maixinkang,relieve and regress atherosclerosis plaque in ApoE(-/-) miceaorta,even for advanced plaques by reducing blood lipid,anti-inflammation,anti-oxidation,protecting vascular endothelium,inhibiting the degradation of extracellular matrix,whichcertificate the therapeutics effect of benefiting vital energy,toxin-resolving andblood-activating has highly effective to prevent atherosclerosis.2.Maixinkang relieveultramicrostructure pathological changes,prevent atherosclerosis and reduce atheroscleroticplaque in aorte.The expression of ABCA1 and PPARγmRNA increasing obviously inMaixinkang group,Lovastatin,rosiglitazone group,thus,.the expression of ABCA1 andPPARγprotein increasing in Maixinkang,Lovastatin,rosiglitazone group,while CD36mRNA and protein expressed less than control group and saline group.The bood serumconcentration of TNF-a、IL-1 in Maixinkang,Lovastatin,rosiglitazone group lowersignificantly than saline and control group.The concentrition of Ca~(2+) of the activatedmacrophages increased fast in control group and saline group more than Maixinkang,Lovastatin,rosiglitazone group.The expression of ABCA1 and PPARγmRNA increasingobviously in Maixinkang,Lovastatin,rosiglitazone group,thus,the expression of ABCA1and PPARγprotein increasing in Maixinkang,Lovastatin,rosiglitazone group,whileCD36 mRNA and protein expressed less than control group and saline group.The bood
serum concentration of TNF-α、IL-1βin Maixinkang,Lovastatin,rosiglitazone grouplower significantly than saline and control group.The lever of intra-cellular Cholesteroland cholesteryl ester of Maixinkang,Lovastatin,rosiglitazone is lower than saline andcontrol group in 48h and 72h cultrued.
Conclusion:The therapeutic of Combination of benefiting vital energy,toxin-resolving and blood-activating method in anti-atherosclerosis has important clinicaland academic significance.Our research indicated that Maixinkang has the fouction ofinhibit the formation of foam cell,anti-inflammatory,anti-inflammatory,down regulationof macrophages chematropism,anti-atheroscierosis and stabilize atherosclerotic plaque byincreasing the expression of ABCA1 and PPARγmRNA and protein intra-cellular,reducing the level of TNF-αIL-1βin blood serum and culture medium,decreasing theCholesterol and cholesteryl ester and degrading the calcium overload intra-cellular.
方法：1．结合中医药文献、基础理论和临床实际，在对As中医病因病机治则传统认识回顾的基础上，进行创新性探讨；对脉心康的方药组成特色进行中西医结合分析，对脉心康的临床应用与基础研究成果进行分析整理。2．实验研究：(1)整体体内实验研究：ApoE(-／-)小鼠按随机数字表法随机分组，各组分别给予脉心康、洛伐他汀、罗格列酮、生理盐水灌胃，正常对照组(正常C57BL／6J小鼠)给予生理盐水灌胃，各组与正常对照组分别于给药后第8周、第12周各处死一半，静脉取血，取主动脉标本固定、染色及相应处理。(2)细胞学实验研究：ApoE(-／-)小鼠腹腔巨噬细胞培养，各组分别给予脉心康、洛伐他汀、罗格列酮无菌含药血清，并与ox-LDL共孵育(泡沫化)，分别观察0—72小时不同时相的指标变化。光镜及电镜下观察主动脉As病变及超微结构；激光共聚焦扫描显微镜检测细胞内钙离子(Ca~(2+))；高效液相色谱法检测细胞内胆固醇及胆固醇酯；免疫组化法检测细胞、主动脉PPARγ、ABCA1、CD36蛋白表达；流式细胞仪检测CD36；原位杂交法检测细胞、主动脉PPARγ、CD36、ABCA1 mRNA表达；ELISA法检测血清、巨噬细胞培养液TNF-α、IL-1β。
结果：1．明确了As及其易损斑块的气虚血瘀，毒损脉络病机和益气活血解毒治则创新思路，体现此治则的脉心康对As与高脂血症疗效显著，具有降脂、抗炎、抗氧化、保护血管内皮、抗As、抑制细胞外基质降解、稳定斑块等作用。2．实验研究：(1)整体体内实验研究：脉心康能使ApoE(-／-)小鼠As病理形态学及超微结构改变减轻，有助于斑块缩小稳定；脉心康组、罗格列酮组血管壁PPARγ、ABCA1 mRNA的表达显著增加，PPARγ、ABCA1蛋白的表达显著增加；脉心康组、洛伐他汀组血管壁CD36 mRNA表达及CD36蛋白的表达显著降低；脉心康组、洛伐他汀组、罗格列酮组血清TNF-a、IL-1水平显著降低。(2)细胞学实验研究：用含药血清干预ApoE(-／-)小鼠泡沫化腹腔巨噬细胞后，巨噬细胞内Ca~(2+)浓度各组都有升高，脉心康、洛伐他汀、罗格列酮含药血清干预组Ca~(2+)浓度显著低于生理盐水组和空白对照组；脉心康、罗格列酮组PPARγ及ABCA1mRNA表达和PPARγ及ABCA1蛋白表达较洛伐他汀、空白对照组和生理盐水组均显著增加；脉心康、洛伐他汀组CD36 mRNA表达与CD36蛋白表达均显著低于罗格列酮组、生理盐水组和空白对照组。脉心康组、洛伐他汀组及罗格列酮组细胞内总胆固醇、游离胆固醇及胆固醇酯含量显著低于生理盐水组和空白对照组。脉心康组、洛伐他汀组及罗格列酮组培养液TNFα、IL-1β较生理盐水组和空白对照组显著降低。
结论：1．益气解毒活血方脉心康具有确切的降脂、抗炎、抗As与稳定易损斑块等作用。2．脉心康通过增加PPARγ、ABCA1mRNA表达，增加PPARγ、ABCA1蛋白表达，降低CD36 mRNA表达和蛋白表达，减少巨噬细胞内胆固醇及胆固醇酯的含量，降低巨噬细胞钙超载，减少巨噬细胞释放TNFα、IL-1β，达到抗炎、降低巨噬细胞的趋化性、抗细胞泡沫化，从而保护动脉、保护超微结构、抗As及稳定斑块，对防治As和预防急性冠脉综合征等心脑血管事件有重要意义。
Objective:To study the etiological factor,pathogenesis and new therapeutics ofatherosclerosis by means of benefiting vital energy to activate blood,remove stasis,anddiscuss the mechanism of atherosclerosis and the theoretical basis of the intervention innew therapeutics of benefiting vital energy,toxin-resolving and blood-activating.Toexplore the pharmacologic action and effect of Capsule Maixinkang on Atherosclerosis andinvestigate the mechanism of maixinkang to prevent macrophages transforming into foamcell.
Method:To study the etiological factor and pathogenesis of atherosclerosis,to sumup the result of the observation Capsule Maixinkang on atherosclerosis,hyperlipidemiaand the experiments of effect of Maixinkang to high fat diet rat and ApoE(-/-)mice.Analyze the composition of Maixinkang,explore the pharmacologic action and effect ofMaixinkang on atherosclerosis.Summarize the academic experience in treatingatherosclerosis by benefiting vital energy,activating blood to remove stasis,andtoxin-resolving.Six weeks old ApoE(-/-) mice were divided randomly into four groups,inwhich lavaged with maixinkang,lovastatin,rosiglitazone and saline for two weeks,half ofwhich lavaged for eight weeks,while normal control group which is composed of sixweeks old C57BL/6J mice lavaged no medicine.Half of mice in all groups is put to deathrespectively,collect venous blood and arteriae aorta after eight and twelve lavaged.The areaof Aorta atherosclerosis which observed under light microscope and electron microscopewas analyzed by image analysis system.The expression of PPARγ、CD36、ABCA1 mRNA
was detected hybridization in situ.The PPARγ、CD36、ABCA1 protein was evaluatedby immunohistochemistry.The serum concentration of TNF-α,IL-1βwere detected byELISA.2.Peritoneal macrophages derived from ApoE(-/-) mice were incubated withox-LDL and blood serum containing medicine for 72 hours.The peritoneal macrophageswere divided into six groups according to blood serum containing different medicine:Maixinkang,Lovastatin,rosiglitazone,saline and control group.The congcentration ofCa~(2+) intra-cellular was observed and analyzed with Ca~(2+) image analysis system and
confocal laser scanning microscope.Intracellular total cholesterol and free cholesterol(FC) was measured by high performance liquid chromatography (HPLC),ABCA1 andPPAR),protein was detected in immunohistochemistry and semiquantitative analyzed byimage analysis system.CD36 protein was detected by flow cytometry.The expression ofPPAR3,,CD36,ABCA1 mRNA was detected hybridization in situ.
Result:1.Maixinkang,relieve and regress atherosclerosis plaque in ApoE(-/-) miceaorta,even for advanced plaques by reducing blood lipid,anti-inflammation,anti-oxidation,protecting vascular endothelium,inhibiting the degradation of extracellular matrix,whichcertificate the therapeutics effect of benefiting vital energy,toxin-resolving andblood-activating has highly effective to prevent atherosclerosis.2.Maixinkang relieveultramicrostructure pathological changes,prevent atherosclerosis and reduce atheroscleroticplaque in aorte.The expression of ABCA1 and PPARγmRNA increasing obviously inMaixinkang group,Lovastatin,rosiglitazone group,thus,.the expression of ABCA1 andPPARγprotein increasing in Maixinkang,Lovastatin,rosiglitazone group,while CD36mRNA and protein expressed less than control group and saline group.The bood serumconcentration of TNF-a、IL-1 in Maixinkang,Lovastatin,rosiglitazone group lowersignificantly than saline and control group.The concentrition of Ca~(2+) of the activatedmacrophages increased fast in control group and saline group more than Maixinkang,Lovastatin,rosiglitazone group.The expression of ABCA1 and PPARγmRNA increasingobviously in Maixinkang,Lovastatin,rosiglitazone group,thus,the expression of ABCA1and PPARγprotein increasing in Maixinkang,Lovastatin,rosiglitazone group,whileCD36 mRNA and protein expressed less than control group and saline group.The bood
serum concentration of TNF-α、IL-1βin Maixinkang,Lovastatin,rosiglitazone grouplower significantly than saline and control group.The lever of intra-cellular Cholesteroland cholesteryl ester of Maixinkang,Lovastatin,rosiglitazone is lower than saline andcontrol group in 48h and 72h cultrued.
Conclusion:The therapeutic of Combination of benefiting vital energy,toxin-resolving and blood-activating method in anti-atherosclerosis has important clinicaland academic significance.Our research indicated that Maixinkang has the fouction ofinhibit the formation of foam cell,anti-inflammatory,anti-inflammatory,down regulationof macrophages chematropism,anti-atheroscierosis and stabilize atherosclerotic plaque byincreasing the expression of ABCA1 and PPARγmRNA and protein intra-cellular,reducing the level of TNF-αIL-1βin blood serum and culture medium,decreasing theCholesterol and cholesteryl ester and degrading the calcium overload intra-cellular.
引文
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