TAFI在大鼠动脉粥样硬化形成过程中的变化及作用机制研究
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摘要
背景：冠状动脉粥样硬化性疾病(Coronaryatheros clerotic heart disease，CHD)是动脉粥样硬化导致器官病变的最常见类型，是严重危害人类健康的一种全球性疾病，不仅是发达国家威胁人类健康与生命的头号杀手，而且在发展中国家也面临着严峻挑战。冠状动脉粥样硬化性疾病的主要病理、生理基础是动脉粥样硬化，因此动脉粥样硬化的发生、发展、预防、治疗就成为该领域研究的热点，并且时时都有新的发现和新的突破。近年来研究表明，在心脑血管缺血性疾病患者中凝血和纤溶的调节可能与新的分子生物活性物质—凝血酶激活的纤溶抑制物有关，凝血酶激活的纤溶抑制物(thrombin-activatable fibrinolysis Inhibitor，TAFI)作为凝血纤溶活性的调节因子，在心脑血管血栓性疾病发生、发展中可能起重要作用。但是，TAFI是否与参与了动脉粥样硬化(atherosclerosis，AS)的发生和发展，它在AS的发生、发展中起到什么作用，国内外报道不多。本研究拟采取条件控制科学、严格的动物实验，明确TAFI对动脉粥样硬化发生、发展中凝血—纤溶活性的调节作用，为动脉粥样硬化疾病血栓事件的防治提供新的理论依据，为通过降低TAFI活性以及应用TAFI拮抗剂促进溶栓来防治动脉粥样硬化性疾病及促进有效、安全、促纤溶药物的开发提供思路。
目的：通过建立大鼠动脉粥样硬化形成过程中不同阶段的模型(即高脂血症期、纤维增生性动脉硬化期、较成熟的AS斑块病变期动脉粥样硬化模型)，测定大鼠动脉粥样硬化形成过程中不同阶段的血浆凝血酶激活的纤溶抑制物、血脂、凝血指标的水平，分析TAFI水平的变化及TAFI与血脂、凝血指标的相关性，探讨TAFI在大鼠动脉粥样硬化发生发展中的作用机制。
方法：40只健康雄性的Wistar大鼠随机分为4组(每组10只)，包括正常对照组、高脂组、高脂维生素D3组和内皮损伤组。分别以普通饲料、高脂饲料、高脂饲料+维生素D3、高脂饲料+维生素D3+内皮球囊损伤处理4个多月，复制大鼠动脉粥样硬化形成过程中三个阶段的模型，即高脂血症期、纤维增生性动脉硬化期、较成熟的AS斑块病变期。建模前，颈静脉取血，模型制造成功后，下腔静脉取血，用全自动生化仪测定血脂系列，用全自动血凝仪测定凝血系列，发色底物法测定血浆TAFI的活性。
结果：①用高脂饲料、高脂饲料+维生素D3、高脂饲料+维生素D3+内皮球囊损伤处理4个月可成功地建造大鼠动脉粥样硬化形成过程中三个阶段(即高脂血症、纤维增生性动脉硬化、较成熟的AS斑块病变)的模型。②模型制造成功后，高脂组、高脂维生素D3组和内皮损伤组的血浆总胆固醇(TC)、总甘油三脂(TG)、低密度脂蛋白(LDL-C)、纤维蛋白原(Fib)水平和TAFI活性均明显高于正常对照组(P＜0.01)，有递增趋势，以内膜损伤组升高最为明显；高脂组、高脂维生素D3组和内皮损伤组的血浆高密度脂蛋白(HDL-C)、血浆凝血酶原时间(PT)、部分活化凝血活酶时间(APTT)水平明显低于正常对照组(P＜0.01或P＜0.05)，有递减趋势，以内膜损伤组降低最为明显。③血浆TAFI活性与TC、TG和Fib水平呈正相关。
结论：1．用高脂饲料、高脂饲料+维生素D3、高脂饲料+维生素D3+内皮球囊损伤处理4个月可成功地建造大鼠动脉粥样硬化形成过程中三个阶段(即高脂血症、纤维增生性动脉硬化、较成熟的AS斑块病变)的模型。2．血浆TAFI水平与AS的病变程度密切相关，说明TAFI参与了大鼠AS形成过程中的凝血纤溶活性的调节，TAFI活性升高可能是动脉粥样硬化的致病因素之一。
Background: Coronary atherosclerotic heart disease(CHD) is a kind of global disease. and it does harm to mankind severity, which because of atherosclerosis induce organ deformed . Now not only it theats life and health of mankind in the developed contries, but also in our contry it is a severity challenge. Atherosclerosis is capital pathological and physiological foundation of CHD, then genesis development prevention and therapy of atherosclerosis have become a hot spot of research. And in the domain new discovery and new breakthrough uauslly appear . recently, in the cardiovascular and cerebrovascular diseases, ajustment of thrombosis and fibrinolysis may correlate with new biological factor, thrombin-activatable fibrinolysis Inhibitor (TAFI) has attached more importance as a factor regulatory to activity of thrombosis and fibrinolysis in cardiovascular and cerebrovascular diseases.
Therefore, we propose to adopt conditions controlled scientific and severe animal experiment to identify the adjustment of thrombin-activatable fibrinolysis Inhibitor in the system of thrombosis and fibrinolysis. The breakthrough in the domain will provide new pathway and theroy foundation in the prevention and cure of atherosclerosis. Degrading TAFI level and using TAFI antagon will new methods in the prevention and cure of atherosclerosis, and advance to develop fibrinolysis drugs. These can generate great econimic and social efficiency to prevente and cure atherosclerosis. All mentioned above formed the objectives. Objective: The aim of this study is to investigate the level of TAFI and
mechanism of action in the atherosclerosis.
Methods: Totally 40 healthy male Wistar rats were randomly divided into 4 groups(n=10) ,controls group, high lipid group, high lipid +vitamin D overload group, endothelium injure group .four different feeding methods, including normal diet, hign lipid, hign lipid+vitamin D overload, and high lipid + vitamin D overload + endothelium injury, were used for inducing three stages of AS in rats. Then we measured PT APTT Fib, measured the activity of TAFI by a chromogenic assay.
Results: (1) We use three means to copied three stages including high lipid,, hign lipid+vitamin D overload, and high lipid + vitamin D overload + endothelium injury, and the atherosclerosis model of the rats can be copied after four months. (2)TC TG LDL-C Fib and the activity level of TAFI in plasma of three model groups increased gradually compared with the controls (P<0.01) . HDL-C PT 和 APTT in plasma of three model groups decreased gradually compared with the controls (P <0.01or P<0.05) .(3)And the activity level of TAFI in plasma had positive relation with TG TC and Fib.
Conclusions :1. We use three means to copied three stages including high lipid,, hign lipid+vitamin D overload, and high lipid + vitamin D overload + endothelium injury, and the atherosclerosis model of the rats can be copied after four months. 2.the activity level of TAFI in plasma has close relation with atherosclerosis severity, which indicates that TAFI is one of etiological factors of atherosclerosis.
目的：通过建立大鼠动脉粥样硬化形成过程中不同阶段的模型(即高脂血症期、纤维增生性动脉硬化期、较成熟的AS斑块病变期动脉粥样硬化模型)，测定大鼠动脉粥样硬化形成过程中不同阶段的血浆凝血酶激活的纤溶抑制物、血脂、凝血指标的水平，分析TAFI水平的变化及TAFI与血脂、凝血指标的相关性，探讨TAFI在大鼠动脉粥样硬化发生发展中的作用机制。
方法：40只健康雄性的Wistar大鼠随机分为4组(每组10只)，包括正常对照组、高脂组、高脂维生素D3组和内皮损伤组。分别以普通饲料、高脂饲料、高脂饲料+维生素D3、高脂饲料+维生素D3+内皮球囊损伤处理4个多月，复制大鼠动脉粥样硬化形成过程中三个阶段的模型，即高脂血症期、纤维增生性动脉硬化期、较成熟的AS斑块病变期。建模前，颈静脉取血，模型制造成功后，下腔静脉取血，用全自动生化仪测定血脂系列，用全自动血凝仪测定凝血系列，发色底物法测定血浆TAFI的活性。
结果：①用高脂饲料、高脂饲料+维生素D3、高脂饲料+维生素D3+内皮球囊损伤处理4个月可成功地建造大鼠动脉粥样硬化形成过程中三个阶段(即高脂血症、纤维增生性动脉硬化、较成熟的AS斑块病变)的模型。②模型制造成功后，高脂组、高脂维生素D3组和内皮损伤组的血浆总胆固醇(TC)、总甘油三脂(TG)、低密度脂蛋白(LDL-C)、纤维蛋白原(Fib)水平和TAFI活性均明显高于正常对照组(P＜0.01)，有递增趋势，以内膜损伤组升高最为明显；高脂组、高脂维生素D3组和内皮损伤组的血浆高密度脂蛋白(HDL-C)、血浆凝血酶原时间(PT)、部分活化凝血活酶时间(APTT)水平明显低于正常对照组(P＜0.01或P＜0.05)，有递减趋势，以内膜损伤组降低最为明显。③血浆TAFI活性与TC、TG和Fib水平呈正相关。
结论：1．用高脂饲料、高脂饲料+维生素D3、高脂饲料+维生素D3+内皮球囊损伤处理4个月可成功地建造大鼠动脉粥样硬化形成过程中三个阶段(即高脂血症、纤维增生性动脉硬化、较成熟的AS斑块病变)的模型。2．血浆TAFI水平与AS的病变程度密切相关，说明TAFI参与了大鼠AS形成过程中的凝血纤溶活性的调节，TAFI活性升高可能是动脉粥样硬化的致病因素之一。
Background: Coronary atherosclerotic heart disease(CHD) is a kind of global disease. and it does harm to mankind severity, which because of atherosclerosis induce organ deformed . Now not only it theats life and health of mankind in the developed contries, but also in our contry it is a severity challenge. Atherosclerosis is capital pathological and physiological foundation of CHD, then genesis development prevention and therapy of atherosclerosis have become a hot spot of research. And in the domain new discovery and new breakthrough uauslly appear . recently, in the cardiovascular and cerebrovascular diseases, ajustment of thrombosis and fibrinolysis may correlate with new biological factor, thrombin-activatable fibrinolysis Inhibitor (TAFI) has attached more importance as a factor regulatory to activity of thrombosis and fibrinolysis in cardiovascular and cerebrovascular diseases.
Therefore, we propose to adopt conditions controlled scientific and severe animal experiment to identify the adjustment of thrombin-activatable fibrinolysis Inhibitor in the system of thrombosis and fibrinolysis. The breakthrough in the domain will provide new pathway and theroy foundation in the prevention and cure of atherosclerosis. Degrading TAFI level and using TAFI antagon will new methods in the prevention and cure of atherosclerosis, and advance to develop fibrinolysis drugs. These can generate great econimic and social efficiency to prevente and cure atherosclerosis. All mentioned above formed the objectives. Objective: The aim of this study is to investigate the level of TAFI and
mechanism of action in the atherosclerosis.
Methods: Totally 40 healthy male Wistar rats were randomly divided into 4 groups(n=10) ,controls group, high lipid group, high lipid +vitamin D overload group, endothelium injure group .four different feeding methods, including normal diet, hign lipid, hign lipid+vitamin D overload, and high lipid + vitamin D overload + endothelium injury, were used for inducing three stages of AS in rats. Then we measured PT APTT Fib, measured the activity of TAFI by a chromogenic assay.
Results: (1) We use three means to copied three stages including high lipid,, hign lipid+vitamin D overload, and high lipid + vitamin D overload + endothelium injury, and the atherosclerosis model of the rats can be copied after four months. (2)TC TG LDL-C Fib and the activity level of TAFI in plasma of three model groups increased gradually compared with the controls (P<0.01) . HDL-C PT 和 APTT in plasma of three model groups decreased gradually compared with the controls (P <0.01or P<0.05) .(3)And the activity level of TAFI in plasma had positive relation with TG TC and Fib.
Conclusions :1. We use three means to copied three stages including high lipid,, hign lipid+vitamin D overload, and high lipid + vitamin D overload + endothelium injury, and the atherosclerosis model of the rats can be copied after four months. 2.the activity level of TAFI in plasma has close relation with atherosclerosis severity, which indicates that TAFI is one of etiological factors of atherosclerosis.
引文
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