脂欣康干预动脉粥样硬化易损斑块及平滑肌细胞泡沫化的分子机制研究
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摘要
目的:探讨脂欣康干预载脂蛋白E基因敲除[ApoE(-/-)]小鼠动脉粥样硬化(As)易损斑块及平滑肌细胞泡沫化的分子作用机制,为脂欣康的进一步深入开发及临床应用提供科学依据;探讨脂欣康作为拟过氧化物酶体增殖因子激活受体γ(PPARγ)激动剂的可能性,发现新的中药治疗As靶点,拓宽中医药抗As的研究与应用思路。
方法:通过对脂欣康初步基础研究和临床应用研究的整理分析,结合中西医研究的最新进展,对As易损斑块病机进行探讨。1.整体动物实验6周龄ApoE(-/-)小鼠100只随机分为5组(A-E),每组20只。6周龄具有相同遗传背景的C57BL/6J鼠20只,为C57BL/6J鼠对照组(F)。分组如下:A脂欣康组,B血脂康组,C洛伐他汀,D罗格列酮组,E模型组,F正常对照组。A-E各组分别给予脂欣康、血脂康、洛伐他汀、罗格列酮、生理盐水灌胃,F组给予生理盐水灌胃。连续灌胃给药后12周,腹腔麻醉后下腔静脉取血检测血脂水平(TG、TC、LDL-C、HDL-C、VLDL),酶联免疫吸附法(ELISA)检测肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)等炎症因子;取主动脉,用光镜、电镜观察ApoE(-/-)小鼠主动脉As病变形态,免疫组化法分别检测PPARγ、腺苷三磷酸结合盒转运体A1(ABCA1)蛋白表达。2.体外细胞实验在SD大鼠主动脉血管平滑肌细胞(VSMC)原代培养、传代及鉴定成功的基础上,加入ox-LDL使其泡沫化,分为:A脂欣康组,B血脂康组,C洛伐他汀,D罗格列酮组,E生理盐水组,分别加入脂欣康含药血清、血脂康含药血清、洛伐他汀含药血清、罗格列酮含药血清、生理盐水含药血清,并设F组为不加含药血清的空白对照组。采用高效液相色谱检测VSMC内胆固醇及胆固醇酯含量,激光共聚焦显微镜检测培养平滑肌源性泡沫细胞内Ca2+,原位杂交检测B类清道夫受体CD36 mRNA表达。
结果:1.提出了动脉粥样硬化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的新思路,探讨了体现这一治则的脂欣康胶囊的中医药理论基础,整理分析了脂欣康在调脂、抗As、防治急性冠脉综合征等方面的基础与临床应用研究。2.实验结果:(1)脂欣康能够调节ApoE(-/-)小鼠的血脂水平;(2)脂欣康能显著降低ApoE(-/-)小鼠血清TNF-α和IL-1β等炎症因子的水平;(3)脂欣康具有升高ApoE(-/-)小鼠主动脉的PPARγ与ABCA1的作用,与罗格列酮有相似的PPARγ激动作用,并且优于后者;(4)脂欣康具有与洛伐他汀相似的抑制平滑肌源性泡沫细胞内CD36 mRNA表达的作用,并且优于洛伐他汀;(5)脂欣康可显著降低平滑肌源性泡沫细胞内的Ca2+浓度,优于洛伐他汀及血脂康;(6)脂欣康能抑制VSMC泡沫化、抗SMC增殖、抗As斑块形成,保护主动脉的形态结构特别是超微结构,稳定斑块。
结论:脂欣康能够通过PPARγ活化,从转录水平调节下游靶基因CD36、ABCA1的表达及相关炎症因子TNF-α和IL-1β等的释放,从而抑制平滑肌源性泡沫细胞形成,阻断As的进程。脂欣康有望成为中医药领域中新的、特异性较高的PPARγ激动剂,其作用机制为益气活血与解毒化浊配伍,使平滑肌细胞内蕴藏的痰浊瘀毒得以疏布排泄于外,抑制VSMC增殖和泡沫化细胞形成,起到抗As稳定易损斑块的作用。
Objective: To discuss the molecular mechanism with zhixinkang on atherosclerotic vulnerable plaque and smooth muscle-derived foam cell, and provide scientific evidence for Zhixinkang development and clinical application. To study the opportunity of Zhixinkang as mimic PPARγexcitomotory, and discover the new target of traditional Chinese medicine(TCM) on atherosclerosis(As) treatment,and develop the research and application pathways of TCM on resist As.
Methods: Through studying and analyzing the initial foundation and clinical application research of Zhixinkang, to combine with the latest advancement of TCM and Western medicine, and discuss the pathogenesis of As Vulnerable Plaque. 1. Animal experiment: 100 ApoE (-/-) mice of 6-week old were randomly assigned into five groups: A Zhixinkang group, B Xuezhikang group, C Lovastatin group, D Rosiglitazone group, E model group. Besides, a normal control group (Group F) was set up with 20 C57BL/6J mice. A-E groups were fed with Zhixinkang, Xuezhikang, Lovastatin, Rosiglitazone and Normal saline, F group were fed with Normal saline. After 12 weeks of intervention, to observe the effect on TC, TG, LDL-C, HDL-C and VLDL. TNF-αand IL-1βwere detected with ELISA method. To take aorta and observe pathomorphology, the expression of PPARγand ABCA1 were assayed by immunohistochemstry measurement. 2. Cell experiment: Vascular smooth muscle cells (VSMC) in aorta of SD rats were cultured, passaged and accredited. The cultured VSMC were loaded with ox-LDL to make foam cells. To assigned into five groups:A Zhixinkang group, B Xuezhikang group, C Lovastatin group, D Rosiglitazone group, E Normal saline group, and interfered with contain Zhixinkang serum, contain Xuezhikang serum, contain Lovastatin serum, contain Rosiglitazone serum, contain Normal saline serum. Group F was not interfered and as blank group. To detected cholesterin and cholesterl ester with high efficiency liquid chromatography, and Ca2+ of smooth muscle-derived foam cell with laser confocal microscopy, and CD36 mRNA expression with hybridization in situ.
Results: 1. According to the theory integrated TCM and Western Medicine, to bring forward As vulnerable plaque pathogenesis of deficiency of qi, stagnation of blood and toxin, so propose a new therapeutic principle of supplementing qi activating blood and resolving toxin. It manifests that Zhixinkang is superior in treating As on the basis of initial foundation and clinical application research consequence. 2. Experiments shows (1) Zhixinkang could reduce blood lipid level of ApoE (-/-) mice; (2) Zhixinkang could reduce TNF-αand IL-1βlevel in ApoE (-/-) mice serum; (3) Zhixinkang could increace PPARγand ABCA1 level in ApoE (-/-) mice aorta, it is superior to Rosiglitazone; (4) Zhixinkang could restrain CD36 mRNA expression of smooth muscle-derived foam cell, it is superior to Lovastatin; (5) Zhixinkang could restrain Ca2+ concentration of smooth muscle-derived foam cell, it is superior to Lovastatin and Xuezhikang; (6) Zhixinkang has the effects for restraining smooth muscle-derived foam cell, anti-proliferation of VSMC, anti-As plaque formation, protecting configuration structure of aorta, and stabilizing plaque.
Conclusion: Zhixinkang could excite PPARγ, regulate downstream target genes CD36, ABCA1 and correlated inflammatory factors TNF-αand IL-1β, restrain foam cell formation and blockade As course. Zhixinkang were anticipated to become a new and higher specificity PPARγexcitomotory of TCM, it could supplement qi activate blood and resolve toxin, which make toxin and turbidity in VSMC to resolve, restrain VSMC proliferation and foam cell formation. It could be one of the effective TCM in treating and preventing As, stabilizing As plaque.
方法:通过对脂欣康初步基础研究和临床应用研究的整理分析,结合中西医研究的最新进展,对As易损斑块病机进行探讨。1.整体动物实验6周龄ApoE(-/-)小鼠100只随机分为5组(A-E),每组20只。6周龄具有相同遗传背景的C57BL/6J鼠20只,为C57BL/6J鼠对照组(F)。分组如下:A脂欣康组,B血脂康组,C洛伐他汀,D罗格列酮组,E模型组,F正常对照组。A-E各组分别给予脂欣康、血脂康、洛伐他汀、罗格列酮、生理盐水灌胃,F组给予生理盐水灌胃。连续灌胃给药后12周,腹腔麻醉后下腔静脉取血检测血脂水平(TG、TC、LDL-C、HDL-C、VLDL),酶联免疫吸附法(ELISA)检测肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)等炎症因子;取主动脉,用光镜、电镜观察ApoE(-/-)小鼠主动脉As病变形态,免疫组化法分别检测PPARγ、腺苷三磷酸结合盒转运体A1(ABCA1)蛋白表达。2.体外细胞实验在SD大鼠主动脉血管平滑肌细胞(VSMC)原代培养、传代及鉴定成功的基础上,加入ox-LDL使其泡沫化,分为:A脂欣康组,B血脂康组,C洛伐他汀,D罗格列酮组,E生理盐水组,分别加入脂欣康含药血清、血脂康含药血清、洛伐他汀含药血清、罗格列酮含药血清、生理盐水含药血清,并设F组为不加含药血清的空白对照组。采用高效液相色谱检测VSMC内胆固醇及胆固醇酯含量,激光共聚焦显微镜检测培养平滑肌源性泡沫细胞内Ca2+,原位杂交检测B类清道夫受体CD36 mRNA表达。
结果:1.提出了动脉粥样硬化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的新思路,探讨了体现这一治则的脂欣康胶囊的中医药理论基础,整理分析了脂欣康在调脂、抗As、防治急性冠脉综合征等方面的基础与临床应用研究。2.实验结果:(1)脂欣康能够调节ApoE(-/-)小鼠的血脂水平;(2)脂欣康能显著降低ApoE(-/-)小鼠血清TNF-α和IL-1β等炎症因子的水平;(3)脂欣康具有升高ApoE(-/-)小鼠主动脉的PPARγ与ABCA1的作用,与罗格列酮有相似的PPARγ激动作用,并且优于后者;(4)脂欣康具有与洛伐他汀相似的抑制平滑肌源性泡沫细胞内CD36 mRNA表达的作用,并且优于洛伐他汀;(5)脂欣康可显著降低平滑肌源性泡沫细胞内的Ca2+浓度,优于洛伐他汀及血脂康;(6)脂欣康能抑制VSMC泡沫化、抗SMC增殖、抗As斑块形成,保护主动脉的形态结构特别是超微结构,稳定斑块。
结论:脂欣康能够通过PPARγ活化,从转录水平调节下游靶基因CD36、ABCA1的表达及相关炎症因子TNF-α和IL-1β等的释放,从而抑制平滑肌源性泡沫细胞形成,阻断As的进程。脂欣康有望成为中医药领域中新的、特异性较高的PPARγ激动剂,其作用机制为益气活血与解毒化浊配伍,使平滑肌细胞内蕴藏的痰浊瘀毒得以疏布排泄于外,抑制VSMC增殖和泡沫化细胞形成,起到抗As稳定易损斑块的作用。
Objective: To discuss the molecular mechanism with zhixinkang on atherosclerotic vulnerable plaque and smooth muscle-derived foam cell, and provide scientific evidence for Zhixinkang development and clinical application. To study the opportunity of Zhixinkang as mimic PPARγexcitomotory, and discover the new target of traditional Chinese medicine(TCM) on atherosclerosis(As) treatment,and develop the research and application pathways of TCM on resist As.
Methods: Through studying and analyzing the initial foundation and clinical application research of Zhixinkang, to combine with the latest advancement of TCM and Western medicine, and discuss the pathogenesis of As Vulnerable Plaque. 1. Animal experiment: 100 ApoE (-/-) mice of 6-week old were randomly assigned into five groups: A Zhixinkang group, B Xuezhikang group, C Lovastatin group, D Rosiglitazone group, E model group. Besides, a normal control group (Group F) was set up with 20 C57BL/6J mice. A-E groups were fed with Zhixinkang, Xuezhikang, Lovastatin, Rosiglitazone and Normal saline, F group were fed with Normal saline. After 12 weeks of intervention, to observe the effect on TC, TG, LDL-C, HDL-C and VLDL. TNF-αand IL-1βwere detected with ELISA method. To take aorta and observe pathomorphology, the expression of PPARγand ABCA1 were assayed by immunohistochemstry measurement. 2. Cell experiment: Vascular smooth muscle cells (VSMC) in aorta of SD rats were cultured, passaged and accredited. The cultured VSMC were loaded with ox-LDL to make foam cells. To assigned into five groups:A Zhixinkang group, B Xuezhikang group, C Lovastatin group, D Rosiglitazone group, E Normal saline group, and interfered with contain Zhixinkang serum, contain Xuezhikang serum, contain Lovastatin serum, contain Rosiglitazone serum, contain Normal saline serum. Group F was not interfered and as blank group. To detected cholesterin and cholesterl ester with high efficiency liquid chromatography, and Ca2+ of smooth muscle-derived foam cell with laser confocal microscopy, and CD36 mRNA expression with hybridization in situ.
Results: 1. According to the theory integrated TCM and Western Medicine, to bring forward As vulnerable plaque pathogenesis of deficiency of qi, stagnation of blood and toxin, so propose a new therapeutic principle of supplementing qi activating blood and resolving toxin. It manifests that Zhixinkang is superior in treating As on the basis of initial foundation and clinical application research consequence. 2. Experiments shows (1) Zhixinkang could reduce blood lipid level of ApoE (-/-) mice; (2) Zhixinkang could reduce TNF-αand IL-1βlevel in ApoE (-/-) mice serum; (3) Zhixinkang could increace PPARγand ABCA1 level in ApoE (-/-) mice aorta, it is superior to Rosiglitazone; (4) Zhixinkang could restrain CD36 mRNA expression of smooth muscle-derived foam cell, it is superior to Lovastatin; (5) Zhixinkang could restrain Ca2+ concentration of smooth muscle-derived foam cell, it is superior to Lovastatin and Xuezhikang; (6) Zhixinkang has the effects for restraining smooth muscle-derived foam cell, anti-proliferation of VSMC, anti-As plaque formation, protecting configuration structure of aorta, and stabilizing plaque.
Conclusion: Zhixinkang could excite PPARγ, regulate downstream target genes CD36, ABCA1 and correlated inflammatory factors TNF-αand IL-1β, restrain foam cell formation and blockade As course. Zhixinkang were anticipated to become a new and higher specificity PPARγexcitomotory of TCM, it could supplement qi activate blood and resolve toxin, which make toxin and turbidity in VSMC to resolve, restrain VSMC proliferation and foam cell formation. It could be one of the effective TCM in treating and preventing As, stabilizing As plaque.
引文
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