急性冠脉综合征瘀毒证及解毒活血抗动脉粥样硬化的分子机制研究
|
摘要
目的
1.临床研究：探讨急性冠脉综合征(ACS)标实证与冠状动脉造影指标及炎症指标的相关性,为瘀毒病机探讨及解毒活血治疗方案的设计提供科学依据。2.实验研究：观察解毒活血中药配伍对载脂蛋白E基因敲除[ApoE(-／-)]小鼠腹腔巨噬细胞泡沫化的影响,探讨其机制。
方法
1.临床研究：搜集ACS患者50例,按照中医标实证辨证标准,分为痰浊证、血瘀证、气滞证、寒凝证、热毒证。每例患者均进行冠状动脉造影,记录冠脉病变支数、冠脉最大狭窄程度,并计算冠脉病变积分；检测患者炎症指标血清超敏C反应蛋白(hs-CRP)及肿瘤坏死因子(TNF)。将各标实证与冠脉造影指标、炎症指标进行相关性分析。2.实验研究：收集ApoE(-／-)小鼠腹腔巨噬细胞,分为空白组、解毒组(加入虎杖苷)、活血组(加入山楂提取物)、解毒活血配伍组(加入虎杖苷及山楂提取物)、洛伐他汀组(加入洛伐他汀)、罗格列酮组(加入罗格列酮)、模型组。除空白组外,其他各组均同时加入氧化型低密度脂蛋白(ox-LDL)及脂多糖(LPS)。各组在培养箱内共孵育(泡沫化)2天,电镜下观察48小时后空白组、模型组及解毒活血配伍组细胞内超微结构的变化；并分别观察0小时、24小时、48小时三个不同时相各组细胞内游离钙离子浓度的变化,总胆固醇、游离胆固醇及胆固醇酯的变化,过氧化物酶体增殖物激活受体γ(PPARγ)、三磷酸腺苷结合盒转运子Al (ABCAl)、白细胞分化抗原36配体(CD36)的mRNA表达,Toll样受体(TLR4)、核因子-KB(NF-KB)、肿瘤坏死因子-α(TNF-α)及白介素-1β(IL-1β)的表达。
结果
1.临床研究：ACS标实证中以血瘀证及热毒证最多,且血瘀证与热毒证冠脉病变程度及范围均较重,其病变积分明显高于痰浊证、气滞证及寒凝证；与其它证相比,血瘀证和热毒证的hs-CRP、TNF均明显增高；随着冠脉病变最大狭窄程度加重、病变支数增加,hs-CRP、TNF呈升高趋势；hs-CRP、TNF与冠脉病变积分均呈正相关。2.实验研究：解毒活血中药配伍能够减轻ox-LDL、LPS对细胞内部超微结构的损害；拮抗巨噬细胞内钙离子水平的增高；显著降低巨噬细胞内总胆固醇、游离胆固醇及胆固醇酯的浓度；提高巨噬细胞内PPARγ、ABCAl的mRNA表达,降低CD36的mRNA表达；减少TLR4、NF-KB、TNF-α及IL-1β的表达；其综合作用优于单纯解毒或活血中药,相当于或优于洛伐他汀及罗格列酮。
结论
1.临床研究：热毒证是ACS的另一重要标实证,瘀毒互结是ACS的主要病机；解毒活血可望成为ACS的重要治法。2.实验研究：解毒活血中药配伍能够通过保护细胞内超微结构,拮抗钙离子水平的增高,改善细胞内胆固醇及胆固醇酯转移,上调PPARy、ABCAl的mRNA表达,下调CD36的mRNA表达,抑制炎症因子分泌等途径干预巨噬细胞泡沫化过程,延缓动脉粥样硬化的发生与发展。
Objective
1.The clinical research:To discuss the correlation of sthenia syndrome of acute coronary syndrome (ACS) with coronary arteriongraphy and inflammation index, and to provide scientific evidence for pathogenesis of blood stasis and pyretic toxicity and treatment of detoxication and promoting blood flow on ACS.2. The empirical study:To observe the effect of the compatibility of detoxication and promoting blood flow on the peritoneal macrophage foaming of apolipoprotein E gene knock out[ApoE(-/-)] mice, and to discuss its mechanism.
Methods
1. The clinical research:Fifty patients of ACS were divided in the syndrome of phlegm, the syndrome of blood stasis, the syndrome of stagnation of QI, the syndrome of cold coagulation and the syndrome of pyretic toxicity, according to the differentiation of symptoms and signs standard of chinese medical science sthenia syndrome. Everyone was given coronary arteriongraphy, recorded numbers of coronary artery process and greatest narrow degree of coronary artery, and calculated scores of coronary artery process. Everyone was detected the inflammatory indexes such as highsensitivity C reactive protein(hs-CRP) and tumour necrosis factor(TNF). To analyze the correlation of all sthenia syndromes with coronary arteriongraphy and inflammatory indexes.2. The empirical study:The peritoneal macrophage of ApoE(-/-) mice were divided in seven groups:blank group, detoxication group (add polydatin), promoting blood flow group(add hawthorn extractive), detoxication and promoting blood flow group(add polydatin and hawthorn extractive), lovastatin group(add lovastatin), rosiglitazone group(add rosiglitazone), model group. Except for blank group, other groups were added in oxidized-LDL (ox-LDL) and lipopolysaccharide (LPS).All groups were incubated two days in incubator. To observe the ultrastructural changes in cells of the blank group, model group and detoxication and promoting blood flow group with electron microscope after 48 hours. To observe the changes of intracellular calcium concentration, the changes of intracellular total cholesterol, free cholesterol and cholesteryl esters, the mRNA express of intracellular peroxisome proliferators-activated receptor gamma (PPARγ), ATP-binding cassette transporter Al (ABCA1), cluster of differentiation antigen 36 (CD36), toll-like receptor4 (TLR4), neuclear factor kappa B(NF-κB), tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in all groups after 0 hour,24 hours and 48 hours respectively.
Results
1. The clinical research:The syndrome of blood stasis and the syndrome of pyretic toxicity were more than other sthenia syndromes of ACS, their coronary artery process and scope were severer, and their scores of coronary artery process were obviously higher than the syndrome of phlegm, the syndrome of stagnation of QI and the syndrome of cold coagulation. Compared with other sthenia syndromes, the hs-CRP and the TNF of the syndrome of blood stasis and the syndrome of pyretic toxicity all raised up obviously. The hs-CRP and the TNF had a tendency of raise along with the increase of coronary artery process greatest narrow degree and process numbers. The hs-CRP and the TNF had a positive correlation with the scores of coronary artery process.2. The empirical study:The compatibility of detoxication and promoting blood flow could relieve the damage of ox-LDL and LPS on intra-cellular ultrastructure, rivalry the levels of calciumion in macrophage, degrade the concentration of total cholesterol, free cholesterol and cholesteryl esters obviously, elevate the express of PPARγmRNA and ABCA1mRNA, degrade the express of CD36mRNA and decrease the express of TLR4, NF-κB, TNF-αand IL-1β. Its synthetic effect was superior to the simple detoxication medicine or the simple promoting blood flow medicine, and was equal to or superior to the lovastatin and the rosiglitazone.
Conclusion
1. The clinical research:The syndrome of pyretic toxicity is another significant sthenia syndrome of ACS, the combination of blood stasis and pyretic toxicity is its major pathogenesis, the detoxication and promoting blood flow is hope to become its important treament.2.The empirical study: The compatibility of detoxication and promoting blood flow can obviously interfere in macrophage foaming and delay generation and development of atherosclerosis, which may be because it can protect the intra-cellular ultrastructure, rivalry the rise of calciumion, improve the outflow of cholesterol and cholesterol esters in macrophage, up-regulate the express of PPARymRNA and ABCA1mRNA, down-regulate the express of CD36mRNA and inhibt the secretion of inflammatory factor.
1.临床研究：探讨急性冠脉综合征(ACS)标实证与冠状动脉造影指标及炎症指标的相关性,为瘀毒病机探讨及解毒活血治疗方案的设计提供科学依据。2.实验研究：观察解毒活血中药配伍对载脂蛋白E基因敲除[ApoE(-／-)]小鼠腹腔巨噬细胞泡沫化的影响,探讨其机制。
方法
1.临床研究：搜集ACS患者50例,按照中医标实证辨证标准,分为痰浊证、血瘀证、气滞证、寒凝证、热毒证。每例患者均进行冠状动脉造影,记录冠脉病变支数、冠脉最大狭窄程度,并计算冠脉病变积分；检测患者炎症指标血清超敏C反应蛋白(hs-CRP)及肿瘤坏死因子(TNF)。将各标实证与冠脉造影指标、炎症指标进行相关性分析。2.实验研究：收集ApoE(-／-)小鼠腹腔巨噬细胞,分为空白组、解毒组(加入虎杖苷)、活血组(加入山楂提取物)、解毒活血配伍组(加入虎杖苷及山楂提取物)、洛伐他汀组(加入洛伐他汀)、罗格列酮组(加入罗格列酮)、模型组。除空白组外,其他各组均同时加入氧化型低密度脂蛋白(ox-LDL)及脂多糖(LPS)。各组在培养箱内共孵育(泡沫化)2天,电镜下观察48小时后空白组、模型组及解毒活血配伍组细胞内超微结构的变化；并分别观察0小时、24小时、48小时三个不同时相各组细胞内游离钙离子浓度的变化,总胆固醇、游离胆固醇及胆固醇酯的变化,过氧化物酶体增殖物激活受体γ(PPARγ)、三磷酸腺苷结合盒转运子Al (ABCAl)、白细胞分化抗原36配体(CD36)的mRNA表达,Toll样受体(TLR4)、核因子-KB(NF-KB)、肿瘤坏死因子-α(TNF-α)及白介素-1β(IL-1β)的表达。
结果
1.临床研究：ACS标实证中以血瘀证及热毒证最多,且血瘀证与热毒证冠脉病变程度及范围均较重,其病变积分明显高于痰浊证、气滞证及寒凝证；与其它证相比,血瘀证和热毒证的hs-CRP、TNF均明显增高；随着冠脉病变最大狭窄程度加重、病变支数增加,hs-CRP、TNF呈升高趋势；hs-CRP、TNF与冠脉病变积分均呈正相关。2.实验研究：解毒活血中药配伍能够减轻ox-LDL、LPS对细胞内部超微结构的损害；拮抗巨噬细胞内钙离子水平的增高；显著降低巨噬细胞内总胆固醇、游离胆固醇及胆固醇酯的浓度；提高巨噬细胞内PPARγ、ABCAl的mRNA表达,降低CD36的mRNA表达；减少TLR4、NF-KB、TNF-α及IL-1β的表达；其综合作用优于单纯解毒或活血中药,相当于或优于洛伐他汀及罗格列酮。
结论
1.临床研究：热毒证是ACS的另一重要标实证,瘀毒互结是ACS的主要病机；解毒活血可望成为ACS的重要治法。2.实验研究：解毒活血中药配伍能够通过保护细胞内超微结构,拮抗钙离子水平的增高,改善细胞内胆固醇及胆固醇酯转移,上调PPARy、ABCAl的mRNA表达,下调CD36的mRNA表达,抑制炎症因子分泌等途径干预巨噬细胞泡沫化过程,延缓动脉粥样硬化的发生与发展。
Objective
1.The clinical research:To discuss the correlation of sthenia syndrome of acute coronary syndrome (ACS) with coronary arteriongraphy and inflammation index, and to provide scientific evidence for pathogenesis of blood stasis and pyretic toxicity and treatment of detoxication and promoting blood flow on ACS.2. The empirical study:To observe the effect of the compatibility of detoxication and promoting blood flow on the peritoneal macrophage foaming of apolipoprotein E gene knock out[ApoE(-/-)] mice, and to discuss its mechanism.
Methods
1. The clinical research:Fifty patients of ACS were divided in the syndrome of phlegm, the syndrome of blood stasis, the syndrome of stagnation of QI, the syndrome of cold coagulation and the syndrome of pyretic toxicity, according to the differentiation of symptoms and signs standard of chinese medical science sthenia syndrome. Everyone was given coronary arteriongraphy, recorded numbers of coronary artery process and greatest narrow degree of coronary artery, and calculated scores of coronary artery process. Everyone was detected the inflammatory indexes such as highsensitivity C reactive protein(hs-CRP) and tumour necrosis factor(TNF). To analyze the correlation of all sthenia syndromes with coronary arteriongraphy and inflammatory indexes.2. The empirical study:The peritoneal macrophage of ApoE(-/-) mice were divided in seven groups:blank group, detoxication group (add polydatin), promoting blood flow group(add hawthorn extractive), detoxication and promoting blood flow group(add polydatin and hawthorn extractive), lovastatin group(add lovastatin), rosiglitazone group(add rosiglitazone), model group. Except for blank group, other groups were added in oxidized-LDL (ox-LDL) and lipopolysaccharide (LPS).All groups were incubated two days in incubator. To observe the ultrastructural changes in cells of the blank group, model group and detoxication and promoting blood flow group with electron microscope after 48 hours. To observe the changes of intracellular calcium concentration, the changes of intracellular total cholesterol, free cholesterol and cholesteryl esters, the mRNA express of intracellular peroxisome proliferators-activated receptor gamma (PPARγ), ATP-binding cassette transporter Al (ABCA1), cluster of differentiation antigen 36 (CD36), toll-like receptor4 (TLR4), neuclear factor kappa B(NF-κB), tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in all groups after 0 hour,24 hours and 48 hours respectively.
Results
1. The clinical research:The syndrome of blood stasis and the syndrome of pyretic toxicity were more than other sthenia syndromes of ACS, their coronary artery process and scope were severer, and their scores of coronary artery process were obviously higher than the syndrome of phlegm, the syndrome of stagnation of QI and the syndrome of cold coagulation. Compared with other sthenia syndromes, the hs-CRP and the TNF of the syndrome of blood stasis and the syndrome of pyretic toxicity all raised up obviously. The hs-CRP and the TNF had a tendency of raise along with the increase of coronary artery process greatest narrow degree and process numbers. The hs-CRP and the TNF had a positive correlation with the scores of coronary artery process.2. The empirical study:The compatibility of detoxication and promoting blood flow could relieve the damage of ox-LDL and LPS on intra-cellular ultrastructure, rivalry the levels of calciumion in macrophage, degrade the concentration of total cholesterol, free cholesterol and cholesteryl esters obviously, elevate the express of PPARγmRNA and ABCA1mRNA, degrade the express of CD36mRNA and decrease the express of TLR4, NF-κB, TNF-αand IL-1β. Its synthetic effect was superior to the simple detoxication medicine or the simple promoting blood flow medicine, and was equal to or superior to the lovastatin and the rosiglitazone.
Conclusion
1. The clinical research:The syndrome of pyretic toxicity is another significant sthenia syndrome of ACS, the combination of blood stasis and pyretic toxicity is its major pathogenesis, the detoxication and promoting blood flow is hope to become its important treament.2.The empirical study: The compatibility of detoxication and promoting blood flow can obviously interfere in macrophage foaming and delay generation and development of atherosclerosis, which may be because it can protect the intra-cellular ultrastructure, rivalry the rise of calciumion, improve the outflow of cholesterol and cholesterol esters in macrophage, up-regulate the express of PPARymRNA and ABCA1mRNA, down-regulate the express of CD36mRNA and inhibt the secretion of inflammatory factor.
引文
[1]Murtagh BM, Anderson HV. Inflammation and atherosclerosis in acute coronary syndromes[J]. The Journal of invasive cardiology,2004; 16(7):377-384.
[2]卢笑晖.论热毒在急性冠脉综合征发病中的作用[J].中国中医急症,2005；14(8)：750-751.
[3]张京春,陈可冀.瘀毒病机与动脉粥样硬化易损斑块相关的理论思考[J].中国中西医结合杂志,2008；28(4)：366-368.
[4]王显刚,张文高,刘建平,等.益气活血解毒法对不稳定性心绞痛患者血管内皮保护与抑制血小板活化作用[J].山东生物医学工程2002；21(1)：24-26.
[5]Zeuk E S, Ulmer A J, Kusumoto S, et al. TLR4-mediated inflammatory activation of human coronary artery endothelial cells by LPS[J]. Cardiovasc Res,2002; 56(1):126-134.
[6]Kazem Zibara, Eric Malaud, John L. McGregor. CD36 Mrna and Protein Expression Levels Are Significantly Increased in the Heart and Testis of apoE Deficient Mice in Comparison to Wild Type (C57BL/6)[J]. J Biomed Biotechnol.2002; 2(1):14-21.
[7]Knight BL. ATP-binding cassette transporter Al:regulation of cholesterol efflux[J]. Biochem Soc Trans.2004; 32(1):124-127.
[8]Wakino S. Anti-atherosclerotic effects of PPAR gamma ligands[J]. Nippon Rinsho.2004; 62(1):180-186.
[9]Rosenfeld ME, Polinsky P, Virmani R, et al. Advanced atherosclerotic lesions in the innominate artery of the apoE knockout mouse [J]. Arterioscler Thromb Vasc Biol.2000; 20:2587-2592.
[10]Williams H, Johnson JL, Carson KG, et al. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice[J]. Arterioscler Thromb Vasc Biol.2002; 22:788-792.
[11]张文高,郑广娟,王显刚.载脂蛋白E基因敲除小鼠及其在心血管病中西医结合研究中的应用[J],全国中西医结合治疗心血管病及血瘀证高级论坛论文汇编149—157页,2004年8月,新疆乌鲁木齐.
[12]中华医学会心血管病学分会.急性心肌梗死诊断和治疗指南[J].中华心血管病杂志,2001；29(12)：710-725.
[13]中华医学会心血管病学分会.不稳定性心绞痛和非ST段抬高心肌梗死诊断与诊疗 指南[J].中华心血管病杂志,2007；35(4)：295-304.
[14]中国中西医结合学会心血管学会.冠心病中医辨证标准[J],中西医结合杂志,1991；11(5)：257-259.
[15]张文高,王显刚,谢庆成,等.益气活血法与益气活血解毒法治疗不稳定性心绞痛及其作用机制研究[J].第三次全国中西医结合养生学与康复医学学术研讨会论文集63-70页,2002年8月,昆明.
[16]张文高,王显刚,谢庆成,等.解毒与益气活血配伍治疗不稳定性心绞痛及其抗炎、抗血小板活化与内皮保护作用研究[J].第六次全国中西医结合心血管会学术会议论文汇编170-174页,2002年9月,北京.
[17]GENSINI GG. A more meaningful scoreing system for determing the severity of coronary heart disease[J]. Am J Cardiol,1983; 51(3):606.
[18]Erkkila AT, Narvanen 0, Lehto S, et al. Autoantibodies against oxidized low density lipoprotein and cardiolipin in patients with coronary heart disease[J].Arterioscler Thromb Vase Biol,2000; 20:204-209.
[19]Shi H, Wei L, She M, et al. Morphometric study of inflammatory cells and smooth muscle cells in coronary plaques and their relation with plaque stability[J].Zhonghua Bing Li Xue Za Zhi,1999; 28(4):256-259.
[20]Libby P. Molecular bases of the acute coronary syndromes[J]. Circulation,1995; 91:2844-2850.
[21]王涛,浦艳华,殷洁,等.易损斑块与急性冠脉综合征[J].心血管病学进展,2007；28(2)：246-248.
[22]胡大一,黄元铸.急性冠状动脉综合征[M].北京：人民卫生出版社,2001；5：37.
[23]郭爱桃,韦立新.基质金属蛋白酶-1与冠状动脉粥样硬化斑块破裂的关系[J].中华病理学杂志,2000；29：263-266.
[24]李崇剑,高润霖,杨跃进,等.易损斑块的病理生理机制及其检测的研究进展[J].中华心血管病杂志,2004；32(6)：570-573.
[25]张文高.中医药干预动脉粥样硬化易损斑块的实验研究与思路[J].中国中西医结合杂志,2008；28(5)：392-393.
[26]Ross R. Atherosclerosis-an inflammatory disease[J].N Engl J Med,1999; 340(2):115-26.
[27]苗阳,雷燕,高铸烨.急性冠脉综合征病理生理研究概况[J].实用心脑肺血管病杂志,2006；14(1)：81-83.
[28]杨顺来.冠状动脉血栓形成的病理生理学-斑块破裂和斑块糜烂的作用[J].中国心血管杂志,2003；8(5)：366-369.
[29]王昀,金晓红,孔令越,等.急性冠脉综合征炎症反应中医药防治切入思路[J].中 国中医药信息杂志,2009；16(5)：7-8.
[30]Van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology [J]. Circulation,1994; 89:361-369.
[31]Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis[J]. Circulation,2002; 105 (9):1135-1143.
[32]杨胜利,何秉贤.C反应蛋白与冠心病[J].中华心血管病杂志,2001；29(3)：187.
[33]张立,焦连亭.C反应蛋白与急性冠状动脉综合征[J].国外医学.临床生物化学与检验学分册,2003；24(5)：260-261.
[34]Sibel Guldiken, Muzaffer Demir, Ender Arikan, et al. The levels of circulating markers of atherosclerosis and inflammation in subjects with different degrees of body mass index:Soluble CD40 ligand andhigh-sensitivity C-reactive protein [J].Thrombosis Research,2007; 119:79-84.
[35]Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease[J]. N Engl J Med,2004; 350(14):1387-1397.
[36]盛春平,杨文东,孙传芳.C反应蛋白浓度与冠心病的关系及氟伐他汀干预治疗的临床研究[J].实用医技杂志,2008；15(9)：1134-1135.
[37]Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention[J]. Circulation,2003; 107(3):363-369.
[38]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture[J]. Arterioscler Thromb Vasc Biol,2007; 27(1):15-26.
[39]王付彬.C-反应蛋白水平与急性心肌梗死预后的关系[J].中国心血管病研究杂志,2005；3(4)：294-295.
[40]R idker PM, Hennekens CK, Buring JE, et al.C-reative protein and other markers of inflammation in the predicition of cardiovascular disease in women Nengl[J]. Med,2000; 34(2):836-843.
[41]Barath P, Fisvvein MC, Cao J, et al. Detection and localization oftumor necro is factor in human atheroma[J]. Am J Cardio,l 1990; 65(5):297-302.
[42]王喜英,吴波,张惠娟.血管内皮细胞生长因子、肿瘤坏死因子与急性冠状动脉综合征的关系及临床意义[J].中国煤炭工业医学杂志,2007；10(9)：1084-1085.
[43]Bidker PM, Rifai N, Pefeffer. Elevation of tumor necrosis and increased risk of recurrent coronary events after myocardial infarction[J]. Circulation, 2000; 101(18):2149-2153.
[44]郝文辉,惠树林,张超英.急性冠脉综合征患者血清肿瘤坏死因子、白介素-6浓度的变化及其临床意义[J].延安大学学报(医学科学版),2008；6(3)：20-22.
[45]王伟,陈可冀.中西医结合临床研究的思路与方法[J].中国中西医结合杂志,2000；20(2)：136-137.
[46]贾宝善.冠心病患者血小板膜糖蛋白及血小板功能与中医证型分型关系的研究[J].中西医结合杂志,1989；9(12)：717-719.
[47]虞红新,关继华.不稳定心绞痛患者中医证型与冠状动脉Gensini积分、病变支数的相关性研究[J].新疆中医药,2007；25(5)：9-11.
[48]谢淑芸,金章安.C反应蛋白浓度与急性心肌梗死中医证型的关系[J].中华实用中西医杂志,2007；20(3)：212-214.
[49]王强,张双旗.急性冠脉综合征中医证型与IL-18、hs-CRP的相关性临床探讨[J].河南中医学院学报,2007；22(1)：55-56.
[50]缪灿铭,陈翊,麦美琪.急性冠脉综合征中医证型与冠脉病变及C反应蛋白相关性的临床探讨[J].光明中医,2009；8：1423-1424.
[51]郗瑞席,张京春,冯妍.“瘀毒”理论与急性冠脉综合征的相关性探讨[J].中西医结合心脑血管病杂志,2009；7(2)：127-130.
[52]钱卫东.中医药对急性冠状动脉综合征炎症反应干预的研究[J].河南中医学院学报,2005；20(119)：83-84.
[53]王鹂,魏陵博,刘学法等.热毒学说在急性冠脉综合征中的地位[J].中西医结合心脑血管病杂志,2005；12(3)：1080-1081.
[54]Libby P. Fire with inflammations'link to heart attacks[J]. Sci Am,2002; 286:46-55.
[55]于俊生,王砚琳.痰瘀毒相关论[J].山东中医杂志,2000；19(6)：323-325.
[56]朱平.论清热解毒是治疗热毒血瘀证的重要治法[J].中国医药学报,2002；17(3)：171-173.
[57]赵庭勇,黄琴.浅析温病热毒血瘀证病机及其治法[J].甘肃中医,2006；19(11)：4-6.
[58]余蓉,冼绍祥,叶秀琳,等.活血解毒疗法对急性冠脉综合征血清Scd40L影响[J].中医药学刊,2006；24(7)：1375-1376.
[59]耿立梅,陈分乔.解毒活血丸对急性冠脉综合征患者CRP、Fig及预后的影响[J].北京中医药大学学报(中医临床版),2007；14(3)：14-16.
[60]ZHANG Wen-gao. Effect of Removing Toxic Substances Combined with Activating Blood Circulation on Stabilizing the Atherosclerotic Plague and Unstable Angina[J]. Chin J Integr Med,2009; 15(5):325-327.
[61]王建礼,徐兴华,林娜.氧化型低密度脂蛋白与动脉粥样硬化研究进展[J].医学综 述,2009；15(9)：1307-1310.
[62]胡桂才,唐世英,李春华.泡沫细胞与动脉粥样硬化[J].承德医学院学报,2008；25(1)：81-83.
[63]Libby P. Inflammation in atherosclerosis[J]. Nature,2002; 4(20):868-874.
[64]刘美霞,张文高,刘龙涛,等.Toll样受体4在泡沫细胞形成中的作用及中医药干预研究[J].中西医结合心脑血管病杂志,2009；7(4)：466-469.
[65]Wolfgang E, Weber PC, Weber C, et al.Monocytic cell adhesion to endothelial cells stimulated by oxidized low density lipoprotein is mediated by distinct endothelial ligands[J]. Atherosclerosis,1998; 136(2):297-303.
[66]冯翔,凌文华.氧化型低密度脂蛋白及溶血卵磷脂对巨噬泡沫细胞胆固醇外流的影响[J].中国病理生理杂志,2003；19(9)：1246-1249.
[67]Agrawal S, Febbraio M, Podrez E, et al. Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development[J]. Circulation,2007; 115(23):2939-2947.
[68]Cox BE, Griffin EE, Ullery JC, et al. Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification[J]. J-Lipid-Res,2007; 48(5): 1012-1021.
[69]Xu G, Watanabe T,Iso Y,et al. Preventive effects of heregulin-betal on macrophage foam cell formation and atherosclerosis[J]. Circ-Res,2009; 105(5):500-510.
[70]Park DW, Baek K, Kim JR, et al. Resveratrol inhibits foam cell formation via NADPH oxidase 1-mediated reactive oxygen species and monocyte chemotactic protein-1[J]. Exp-Mol-Med,2009; 41(3):171-179.
[71]唐世英,胡桂才,杨凤国,等.U937巨噬细胞源性泡沫细胞模型的建立[J].中国组织工程研究与临床康复,2008；12(15)：2863-2865.
[72]吴鹏,刘映峰,梁东辉,等.人单核源性泡沫细胞疾病模型的建立[J].中国老年学杂志,2008；28(12)：1094-1096.
[73]贺全国,蒋佩,严鹏科,等.胆固醇流出对氧化性低密度脂蛋白诱导的巨噬细胞源性泡沫细胞凋亡的影响[J].中国现代医学杂志,2007；17(22)：2724-2727.
[74]何雪峰,李晓辉,李淑慧,等.三七总皂苷对小鼠巨噬细胞源性泡沫细胞形成的影响[J].中国药房,2007；18(30)：2323-2325.
[75]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠动脉粥样硬化斑块炎症反应的影响[J].中西医结合心脑血管病,2007；5(12)：1202-1205.
[76]张京春,陈可冀,刘剑刚,等.解毒活血配伍方药对载脂蛋白E基因敲除小鼠血清超敏C反应蛋白的影响[J].中国中西医结合杂志,2008；28(4)：330-333.
[77]戴敏,范明霞,余莉,等.兔动脉粥样硬化的动物模型研究[J].公共卫生与预防医学,2004；15(6)：52-53.
[78]叶炳华,管耘园,卢辉和,等.不同大小球囊损伤术加高脂饲料建立兔颈动脉粥样硬化模型的比较[J].南通大学学报(医学版),2006；26(4)：244-246.
[79]刘恩岐,郑华东,赵四海,等.转基因家兔模型制作方法[J].动物学杂志,2006；41(3)：62-69.
[80]张艳平,刘录山,余平.肺炎衣原体感染对巨噬细胞内ox-LDL源性脂质蓄积得影响[J].实用预防医学,2006；13(6)：1496-1473.
[81]A. S. Plum, Jonathan D. Smith, Tony Hayek et al. Severe hypercholesterolemia and atheroslerosis in apolipoprotein E-deficient mice created by homologous recombination in ES Cells[J].Cell,1992; 71(10):343-353.
[82]Sunny H. Zhang, Reddick RL, Piedrahita JA et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking aopolipoprotein E[J]. Science,1992; 258(10): 468-471.
[83]Yutaka Nakashima, Audrew S. Plump, Elaine W. Raines, et al. ApoE-deficient mice develop lesions of all phases of atheroslerosis throughout the arterial tree[J]. Arteriosclerosis and Thrombosis,1994; 14(1):133-140.
[84]Harry BL, Sanders JM, Feaver RE, et al. Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice[J]. Arterioscler-Thromb-Vasc-Biol,2008; 28(11):2003-2008.
[85]Cuaz-Perolin C, Billiet L, Bauge E, et al. Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/-mice[J]. Arterioscler-Thromb-Vasc-Biol,2008; 28(2):272-277.
[86]Schulz C, Konrad I, Sauer S, et al. Effect of chronic treatment with acetylsalicylic acid and clopidogrel on athero progression and athero thrombosis in ApoE-deficient mice in vivo[J]. Thromb-Haemost,2008; 99(1): 190-195.
[87]Nakagami H, Osako MK, Takami Y, et al. Vascular protective effects of ezetimibe in ApoE-deficient mice[J]. Atherosclerosis,2009; 203(1):51-58.
[88]Ivanovski 0,Nikolov IG,Joki N, et al. The calcimimetic R-568 retards uremia-enhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE-/-) mice[J]. Atherosclerosis,2009; 205(1):55-62.
[89]Wing LY, Chen YC, Shih YY, et al. Effects of oral estrogen on aortic ROS-generating and-scavenging enzymes and atherosclerosis in apoE-deficient mice[J]. Exp-Biol-Med-(Maywood),2009; 234(9):1037-1046.
[90]曹晓娥,李晓波,殷莲华.高脂血症apoE基因敲除小鼠心脏中一氧化氮合酶含量及基因表达[J].复旦学报(医学版),2009；36(4)：403-406.
[91]荆文,尹苗,杜会芹,等.ApoE基因缺失幼龄小鼠动脉粥样硬化相关基因的时序表达研究[J].生物化学与生物物理进展,2008；35(2)：217-223.
[92]叶红燕,尹苗,商允菊,等.脂代谢相关基因在apoE基因缺失幼龄小鼠肝脏中的表达[J].生理学报,2008；60(1)：51-58.
[93]路永刚,张铁忠,程文丽,等.通脉益智胶囊增加ApoE基因敲除小鼠易损动脉粥样硬化斑块稳定性的作用[J].北京中医药大学学报,2007；30(5)：329-333.
[94]刘剑刚,董国菊,史大卓,等.气血并治方提取物对ApoE基因缺陷小鼠动脉粥样硬化病理形态和基质金属蛋白酶-1及其抑制物表达的影响[J].中国药学杂志,2008；43(22)：1700-1705.
[95]杨秀丽,张文高,郑广娟.脂欣康胶囊改善ApoE基因敲除小鼠学习记忆行为障碍的水迷宫观察[J].世界中西医结合杂志,2007；2(5)：274-276.
[96]Russell Ross, Ph.D. Atherosclerosis-an inflammatory disease[J]. The New England Journal of Medicine,1999; 340 (2):115-126.
[97]王辉,郭利平,姜民,等.浅析从毒论治动脉粥样硬化[J].时珍国医国药,2008；19(9)：2305-2306.
[98]徐浩,陈可冀.从对动脉粥样硬化认识转变看中西医结合的优势与切入点[J].中国中西医结合杂志,2007；27(1)：5-7.
[99]王永炎.关于提高脑血管疾病疗效难点的思考[J].中国中西医结合杂志,1997；17(4)：195.
[100]姜良铎,张永生.从“毒”论治初探[J].北京中医药大学学报,1998；21(5)：2.
[101]于俊生.毒邪学说与临床[M].北京：中国中医药出版社,2000：7.
[102]丁书文,李晓,李运伦,等.心系疾病中的热毒学说[J].中国医药学报,2004；19(10)：592.
[103]朱莹,张文高,郑广娟,等.PPARγ与动脉粥样硬化及中医药干预研究[J].中西医结合心脑血管病杂志,2007；5(3)：225-227.
[104]刘煜德,吴辉,吴伟,等.黄连解毒汤对高胆固醇兔血液流变学和动脉粥样硬化干预作用[J].中国中药杂志,2009；34(5)：600-604.
[105]张京春,陈可冀,郑广娟,等.解毒活血中药配伍对载脂蛋白E基因敲除小鼠主动脉NF-κB与MMP-9表达的调控作用[J].中国中西医结合杂志,2007；27(1)：40-44.
[106]葛岚,程晓昱,胡业彬.益气活血解毒汤对实验性动脉粥样硬化家兔炎症细胞因子和血脂的影响[J].中国中西医结合急救杂志,2007；14(5)：306-308.
[107]刘龙涛,吴敏,张文高,等.虎杖苷对颈动脉粥样硬化斑块稳定性的干预研究 [J].北京中医药,2009；28(3)：172-175.
[108]郑刚.他汀类药物多效性研究新进展[J].循证医学,2008；8(5)：301-305.
[109]肖祥彬,程希富,覃数,等.他汀类药物在心血管疾病中应用的研究进展[J].心血管病学进展,2008；29(4)：647-650.
[110]张文礼,马建华.罗格列酮的非降糖作用[J].重庆医学,2008；37(6)：660-662.
[111]王霞,凌世峰.虎杖药理作用研究进展[J].海军医学杂志,2004；25(2)：179-181.
[112]罗玉梅,王贺振.山楂的化学成分及药理研究进展[J].时珍国医国药,2004；15(1)：53-54.
[113]薛洁,夏昌隆.山楂药理研究进展[J].新疆中医药,2002；20(4)：69-71.
[114]沈世林,张子理.中药对胞内钙调节的研究现状评述[J].中医研究,2005；18(7)：57-59.
[115]田乃旭,屠鹏飞.药物学研究与展望[M].1版.北京：科学出版社,1999.
[116]Maor I, Aviram M. Oxidized low density lipoprotern leads to macrophage accumulation of unesterified cholesterol as a result of lysosomal trapping of the lipoprotein hydrolyzed cholesteryl ester[J].J Lipid Res,1994; 35(5):803.
[117]Boyle JJ. Macrophage activation in atherosclerosis:Pathogenesis and Pharmacology of Plaque rupture[J]. Curr Vase Pharmacol,2005; 3(1):63-68.
[118]Fogelman AM, Shechter I, Seager J, et al. Malondialde_hyde Alteration of Low Density Lipoproteins Leads to Cholesteryl Ester Accumulation in Human Monocyte-Macrophages[J].Proc Natl Acad Sci,1980; 77(4):2214.
[119]Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport[J]. Circ Res,2005; 96(12):1221-1232.
[120]Chawla A, Barak Y, Nagy L, et al.PPAR gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation[J].Nat Nbd,2001; 7(1):48-52.
[121]Hiltunen TP, Luoma JS, Mkkari T, et al. Expression of LDL receptor, VLDL Receptor, LDL Receptor related protein, and scavenger Receptor in Rabbit Atherosclerotic lesions[J]. Circulation,1998; 97:1079-1086.
[122]盛富强,程龙献.TLR4信号通路与动脉粥样硬化的研究进展[J].心脏杂志,2009；21(4)：572-574.
[123]敖启林,熊密,郝春荣,等.NF-KB的活性和Inos基因表达在低氧性肺动脉高压中的变化[J].中国病理生理杂志,2002；18(8)：903-906.
[124]李建军,李庚山.核因子-KB与冠心病的关系[J].现代诊断与治疗,2000；11(4)：212-214.
[125]Baeuerle PA, Baltimore D. NF-κB:ten years after[J]. Cell,1996; 87 (1):13-20.
[126]曹建伟,安向光.急性心肌梗死患者炎性细胞因子水平测定[J].中国心血管病研究,2008；6(7)：488-490.
[127]Mouco OM, Nicolau JC, Souza TR, et al. Inflammatory markers of atherosclerotic plaque stabilization after acute coronary event-temporal trends[J]. Arq Bras Cardiol,2006; 87:28-36.
[128]Satoh M, Ishikawa Y, Itoh T, et al. The expression of TNF-alpha converting enzyme at the site of ruptured plaques in patients with acute myocardial infarction[J].Eur J Clin Invest,2008; 38:97-105.
[129]Jiang Jianxia, Tian Kunlun, Diao Youfang, et al. Expression of TNF-α, IL-1β, IL-6 Mrna, release of TNF-ain the vital organs and their relationship with endotoxin translocation following hemorrhagic shock[J]. ClinMed Science J,1997; 12(1):41-46.
[130]Shamash S,Reichert F, Rotshenker S. The cytokine network of Wallerian degeneration:tumor necrosis factor-alpha, interleukin-lalpha, and interleukin-lbeta[J]. J Neurosci,2002; 22:3052-3060.
[2]卢笑晖.论热毒在急性冠脉综合征发病中的作用[J].中国中医急症,2005；14(8)：750-751.
[3]张京春,陈可冀.瘀毒病机与动脉粥样硬化易损斑块相关的理论思考[J].中国中西医结合杂志,2008；28(4)：366-368.
[4]王显刚,张文高,刘建平,等.益气活血解毒法对不稳定性心绞痛患者血管内皮保护与抑制血小板活化作用[J].山东生物医学工程2002；21(1)：24-26.
[5]Zeuk E S, Ulmer A J, Kusumoto S, et al. TLR4-mediated inflammatory activation of human coronary artery endothelial cells by LPS[J]. Cardiovasc Res,2002; 56(1):126-134.
[6]Kazem Zibara, Eric Malaud, John L. McGregor. CD36 Mrna and Protein Expression Levels Are Significantly Increased in the Heart and Testis of apoE Deficient Mice in Comparison to Wild Type (C57BL/6)[J]. J Biomed Biotechnol.2002; 2(1):14-21.
[7]Knight BL. ATP-binding cassette transporter Al:regulation of cholesterol efflux[J]. Biochem Soc Trans.2004; 32(1):124-127.
[8]Wakino S. Anti-atherosclerotic effects of PPAR gamma ligands[J]. Nippon Rinsho.2004; 62(1):180-186.
[9]Rosenfeld ME, Polinsky P, Virmani R, et al. Advanced atherosclerotic lesions in the innominate artery of the apoE knockout mouse [J]. Arterioscler Thromb Vasc Biol.2000; 20:2587-2592.
[10]Williams H, Johnson JL, Carson KG, et al. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice[J]. Arterioscler Thromb Vasc Biol.2002; 22:788-792.
[11]张文高,郑广娟,王显刚.载脂蛋白E基因敲除小鼠及其在心血管病中西医结合研究中的应用[J],全国中西医结合治疗心血管病及血瘀证高级论坛论文汇编149—157页,2004年8月,新疆乌鲁木齐.
[12]中华医学会心血管病学分会.急性心肌梗死诊断和治疗指南[J].中华心血管病杂志,2001；29(12)：710-725.
[13]中华医学会心血管病学分会.不稳定性心绞痛和非ST段抬高心肌梗死诊断与诊疗 指南[J].中华心血管病杂志,2007；35(4)：295-304.
[14]中国中西医结合学会心血管学会.冠心病中医辨证标准[J],中西医结合杂志,1991；11(5)：257-259.
[15]张文高,王显刚,谢庆成,等.益气活血法与益气活血解毒法治疗不稳定性心绞痛及其作用机制研究[J].第三次全国中西医结合养生学与康复医学学术研讨会论文集63-70页,2002年8月,昆明.
[16]张文高,王显刚,谢庆成,等.解毒与益气活血配伍治疗不稳定性心绞痛及其抗炎、抗血小板活化与内皮保护作用研究[J].第六次全国中西医结合心血管会学术会议论文汇编170-174页,2002年9月,北京.
[17]GENSINI GG. A more meaningful scoreing system for determing the severity of coronary heart disease[J]. Am J Cardiol,1983; 51(3):606.
[18]Erkkila AT, Narvanen 0, Lehto S, et al. Autoantibodies against oxidized low density lipoprotein and cardiolipin in patients with coronary heart disease[J].Arterioscler Thromb Vase Biol,2000; 20:204-209.
[19]Shi H, Wei L, She M, et al. Morphometric study of inflammatory cells and smooth muscle cells in coronary plaques and their relation with plaque stability[J].Zhonghua Bing Li Xue Za Zhi,1999; 28(4):256-259.
[20]Libby P. Molecular bases of the acute coronary syndromes[J]. Circulation,1995; 91:2844-2850.
[21]王涛,浦艳华,殷洁,等.易损斑块与急性冠脉综合征[J].心血管病学进展,2007；28(2)：246-248.
[22]胡大一,黄元铸.急性冠状动脉综合征[M].北京：人民卫生出版社,2001；5：37.
[23]郭爱桃,韦立新.基质金属蛋白酶-1与冠状动脉粥样硬化斑块破裂的关系[J].中华病理学杂志,2000；29：263-266.
[24]李崇剑,高润霖,杨跃进,等.易损斑块的病理生理机制及其检测的研究进展[J].中华心血管病杂志,2004；32(6)：570-573.
[25]张文高.中医药干预动脉粥样硬化易损斑块的实验研究与思路[J].中国中西医结合杂志,2008；28(5)：392-393.
[26]Ross R. Atherosclerosis-an inflammatory disease[J].N Engl J Med,1999; 340(2):115-26.
[27]苗阳,雷燕,高铸烨.急性冠脉综合征病理生理研究概况[J].实用心脑肺血管病杂志,2006；14(1)：81-83.
[28]杨顺来.冠状动脉血栓形成的病理生理学-斑块破裂和斑块糜烂的作用[J].中国心血管杂志,2003；8(5)：366-369.
[29]王昀,金晓红,孔令越,等.急性冠脉综合征炎症反应中医药防治切入思路[J].中 国中医药信息杂志,2009；16(5)：7-8.
[30]Van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology [J]. Circulation,1994; 89:361-369.
[31]Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis[J]. Circulation,2002; 105 (9):1135-1143.
[32]杨胜利,何秉贤.C反应蛋白与冠心病[J].中华心血管病杂志,2001；29(3)：187.
[33]张立,焦连亭.C反应蛋白与急性冠状动脉综合征[J].国外医学.临床生物化学与检验学分册,2003；24(5)：260-261.
[34]Sibel Guldiken, Muzaffer Demir, Ender Arikan, et al. The levels of circulating markers of atherosclerosis and inflammation in subjects with different degrees of body mass index:Soluble CD40 ligand andhigh-sensitivity C-reactive protein [J].Thrombosis Research,2007; 119:79-84.
[35]Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease[J]. N Engl J Med,2004; 350(14):1387-1397.
[36]盛春平,杨文东,孙传芳.C反应蛋白浓度与冠心病的关系及氟伐他汀干预治疗的临床研究[J].实用医技杂志,2008；15(9)：1134-1135.
[37]Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention[J]. Circulation,2003; 107(3):363-369.
[38]Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture[J]. Arterioscler Thromb Vasc Biol,2007; 27(1):15-26.
[39]王付彬.C-反应蛋白水平与急性心肌梗死预后的关系[J].中国心血管病研究杂志,2005；3(4)：294-295.
[40]R idker PM, Hennekens CK, Buring JE, et al.C-reative protein and other markers of inflammation in the predicition of cardiovascular disease in women Nengl[J]. Med,2000; 34(2):836-843.
[41]Barath P, Fisvvein MC, Cao J, et al. Detection and localization oftumor necro is factor in human atheroma[J]. Am J Cardio,l 1990; 65(5):297-302.
[42]王喜英,吴波,张惠娟.血管内皮细胞生长因子、肿瘤坏死因子与急性冠状动脉综合征的关系及临床意义[J].中国煤炭工业医学杂志,2007；10(9)：1084-1085.
[43]Bidker PM, Rifai N, Pefeffer. Elevation of tumor necrosis and increased risk of recurrent coronary events after myocardial infarction[J]. Circulation, 2000; 101(18):2149-2153.
[44]郝文辉,惠树林,张超英.急性冠脉综合征患者血清肿瘤坏死因子、白介素-6浓度的变化及其临床意义[J].延安大学学报(医学科学版),2008；6(3)：20-22.
[45]王伟,陈可冀.中西医结合临床研究的思路与方法[J].中国中西医结合杂志,2000；20(2)：136-137.
[46]贾宝善.冠心病患者血小板膜糖蛋白及血小板功能与中医证型分型关系的研究[J].中西医结合杂志,1989；9(12)：717-719.
[47]虞红新,关继华.不稳定心绞痛患者中医证型与冠状动脉Gensini积分、病变支数的相关性研究[J].新疆中医药,2007；25(5)：9-11.
[48]谢淑芸,金章安.C反应蛋白浓度与急性心肌梗死中医证型的关系[J].中华实用中西医杂志,2007；20(3)：212-214.
[49]王强,张双旗.急性冠脉综合征中医证型与IL-18、hs-CRP的相关性临床探讨[J].河南中医学院学报,2007；22(1)：55-56.
[50]缪灿铭,陈翊,麦美琪.急性冠脉综合征中医证型与冠脉病变及C反应蛋白相关性的临床探讨[J].光明中医,2009；8：1423-1424.
[51]郗瑞席,张京春,冯妍.“瘀毒”理论与急性冠脉综合征的相关性探讨[J].中西医结合心脑血管病杂志,2009；7(2)：127-130.
[52]钱卫东.中医药对急性冠状动脉综合征炎症反应干预的研究[J].河南中医学院学报,2005；20(119)：83-84.
[53]王鹂,魏陵博,刘学法等.热毒学说在急性冠脉综合征中的地位[J].中西医结合心脑血管病杂志,2005；12(3)：1080-1081.
[54]Libby P. Fire with inflammations'link to heart attacks[J]. Sci Am,2002; 286:46-55.
[55]于俊生,王砚琳.痰瘀毒相关论[J].山东中医杂志,2000；19(6)：323-325.
[56]朱平.论清热解毒是治疗热毒血瘀证的重要治法[J].中国医药学报,2002；17(3)：171-173.
[57]赵庭勇,黄琴.浅析温病热毒血瘀证病机及其治法[J].甘肃中医,2006；19(11)：4-6.
[58]余蓉,冼绍祥,叶秀琳,等.活血解毒疗法对急性冠脉综合征血清Scd40L影响[J].中医药学刊,2006；24(7)：1375-1376.
[59]耿立梅,陈分乔.解毒活血丸对急性冠脉综合征患者CRP、Fig及预后的影响[J].北京中医药大学学报(中医临床版),2007；14(3)：14-16.
[60]ZHANG Wen-gao. Effect of Removing Toxic Substances Combined with Activating Blood Circulation on Stabilizing the Atherosclerotic Plague and Unstable Angina[J]. Chin J Integr Med,2009; 15(5):325-327.
[61]王建礼,徐兴华,林娜.氧化型低密度脂蛋白与动脉粥样硬化研究进展[J].医学综 述,2009；15(9)：1307-1310.
[62]胡桂才,唐世英,李春华.泡沫细胞与动脉粥样硬化[J].承德医学院学报,2008；25(1)：81-83.
[63]Libby P. Inflammation in atherosclerosis[J]. Nature,2002; 4(20):868-874.
[64]刘美霞,张文高,刘龙涛,等.Toll样受体4在泡沫细胞形成中的作用及中医药干预研究[J].中西医结合心脑血管病杂志,2009；7(4)：466-469.
[65]Wolfgang E, Weber PC, Weber C, et al.Monocytic cell adhesion to endothelial cells stimulated by oxidized low density lipoprotein is mediated by distinct endothelial ligands[J]. Atherosclerosis,1998; 136(2):297-303.
[66]冯翔,凌文华.氧化型低密度脂蛋白及溶血卵磷脂对巨噬泡沫细胞胆固醇外流的影响[J].中国病理生理杂志,2003；19(9)：1246-1249.
[67]Agrawal S, Febbraio M, Podrez E, et al. Signal transducer and activator of transcription 1 is required for optimal foam cell formation and atherosclerotic lesion development[J]. Circulation,2007; 115(23):2939-2947.
[68]Cox BE, Griffin EE, Ullery JC, et al. Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification[J]. J-Lipid-Res,2007; 48(5): 1012-1021.
[69]Xu G, Watanabe T,Iso Y,et al. Preventive effects of heregulin-betal on macrophage foam cell formation and atherosclerosis[J]. Circ-Res,2009; 105(5):500-510.
[70]Park DW, Baek K, Kim JR, et al. Resveratrol inhibits foam cell formation via NADPH oxidase 1-mediated reactive oxygen species and monocyte chemotactic protein-1[J]. Exp-Mol-Med,2009; 41(3):171-179.
[71]唐世英,胡桂才,杨凤国,等.U937巨噬细胞源性泡沫细胞模型的建立[J].中国组织工程研究与临床康复,2008；12(15)：2863-2865.
[72]吴鹏,刘映峰,梁东辉,等.人单核源性泡沫细胞疾病模型的建立[J].中国老年学杂志,2008；28(12)：1094-1096.
[73]贺全国,蒋佩,严鹏科,等.胆固醇流出对氧化性低密度脂蛋白诱导的巨噬细胞源性泡沫细胞凋亡的影响[J].中国现代医学杂志,2007；17(22)：2724-2727.
[74]何雪峰,李晓辉,李淑慧,等.三七总皂苷对小鼠巨噬细胞源性泡沫细胞形成的影响[J].中国药房,2007；18(30)：2323-2325.
[75]周明学,徐浩,陈可冀,等.活血解毒中药有效部位对ApoE基因敲除小鼠动脉粥样硬化斑块炎症反应的影响[J].中西医结合心脑血管病,2007；5(12)：1202-1205.
[76]张京春,陈可冀,刘剑刚,等.解毒活血配伍方药对载脂蛋白E基因敲除小鼠血清超敏C反应蛋白的影响[J].中国中西医结合杂志,2008；28(4)：330-333.
[77]戴敏,范明霞,余莉,等.兔动脉粥样硬化的动物模型研究[J].公共卫生与预防医学,2004；15(6)：52-53.
[78]叶炳华,管耘园,卢辉和,等.不同大小球囊损伤术加高脂饲料建立兔颈动脉粥样硬化模型的比较[J].南通大学学报(医学版),2006；26(4)：244-246.
[79]刘恩岐,郑华东,赵四海,等.转基因家兔模型制作方法[J].动物学杂志,2006；41(3)：62-69.
[80]张艳平,刘录山,余平.肺炎衣原体感染对巨噬细胞内ox-LDL源性脂质蓄积得影响[J].实用预防医学,2006；13(6)：1496-1473.
[81]A. S. Plum, Jonathan D. Smith, Tony Hayek et al. Severe hypercholesterolemia and atheroslerosis in apolipoprotein E-deficient mice created by homologous recombination in ES Cells[J].Cell,1992; 71(10):343-353.
[82]Sunny H. Zhang, Reddick RL, Piedrahita JA et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking aopolipoprotein E[J]. Science,1992; 258(10): 468-471.
[83]Yutaka Nakashima, Audrew S. Plump, Elaine W. Raines, et al. ApoE-deficient mice develop lesions of all phases of atheroslerosis throughout the arterial tree[J]. Arteriosclerosis and Thrombosis,1994; 14(1):133-140.
[84]Harry BL, Sanders JM, Feaver RE, et al. Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice[J]. Arterioscler-Thromb-Vasc-Biol,2008; 28(11):2003-2008.
[85]Cuaz-Perolin C, Billiet L, Bauge E, et al. Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/-mice[J]. Arterioscler-Thromb-Vasc-Biol,2008; 28(2):272-277.
[86]Schulz C, Konrad I, Sauer S, et al. Effect of chronic treatment with acetylsalicylic acid and clopidogrel on athero progression and athero thrombosis in ApoE-deficient mice in vivo[J]. Thromb-Haemost,2008; 99(1): 190-195.
[87]Nakagami H, Osako MK, Takami Y, et al. Vascular protective effects of ezetimibe in ApoE-deficient mice[J]. Atherosclerosis,2009; 203(1):51-58.
[88]Ivanovski 0,Nikolov IG,Joki N, et al. The calcimimetic R-568 retards uremia-enhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE-/-) mice[J]. Atherosclerosis,2009; 205(1):55-62.
[89]Wing LY, Chen YC, Shih YY, et al. Effects of oral estrogen on aortic ROS-generating and-scavenging enzymes and atherosclerosis in apoE-deficient mice[J]. Exp-Biol-Med-(Maywood),2009; 234(9):1037-1046.
[90]曹晓娥,李晓波,殷莲华.高脂血症apoE基因敲除小鼠心脏中一氧化氮合酶含量及基因表达[J].复旦学报(医学版),2009；36(4)：403-406.
[91]荆文,尹苗,杜会芹,等.ApoE基因缺失幼龄小鼠动脉粥样硬化相关基因的时序表达研究[J].生物化学与生物物理进展,2008；35(2)：217-223.
[92]叶红燕,尹苗,商允菊,等.脂代谢相关基因在apoE基因缺失幼龄小鼠肝脏中的表达[J].生理学报,2008；60(1)：51-58.
[93]路永刚,张铁忠,程文丽,等.通脉益智胶囊增加ApoE基因敲除小鼠易损动脉粥样硬化斑块稳定性的作用[J].北京中医药大学学报,2007；30(5)：329-333.
[94]刘剑刚,董国菊,史大卓,等.气血并治方提取物对ApoE基因缺陷小鼠动脉粥样硬化病理形态和基质金属蛋白酶-1及其抑制物表达的影响[J].中国药学杂志,2008；43(22)：1700-1705.
[95]杨秀丽,张文高,郑广娟.脂欣康胶囊改善ApoE基因敲除小鼠学习记忆行为障碍的水迷宫观察[J].世界中西医结合杂志,2007；2(5)：274-276.
[96]Russell Ross, Ph.D. Atherosclerosis-an inflammatory disease[J]. The New England Journal of Medicine,1999; 340 (2):115-126.
[97]王辉,郭利平,姜民,等.浅析从毒论治动脉粥样硬化[J].时珍国医国药,2008；19(9)：2305-2306.
[98]徐浩,陈可冀.从对动脉粥样硬化认识转变看中西医结合的优势与切入点[J].中国中西医结合杂志,2007；27(1)：5-7.
[99]王永炎.关于提高脑血管疾病疗效难点的思考[J].中国中西医结合杂志,1997；17(4)：195.
[100]姜良铎,张永生.从“毒”论治初探[J].北京中医药大学学报,1998；21(5)：2.
[101]于俊生.毒邪学说与临床[M].北京：中国中医药出版社,2000：7.
[102]丁书文,李晓,李运伦,等.心系疾病中的热毒学说[J].中国医药学报,2004；19(10)：592.
[103]朱莹,张文高,郑广娟,等.PPARγ与动脉粥样硬化及中医药干预研究[J].中西医结合心脑血管病杂志,2007；5(3)：225-227.
[104]刘煜德,吴辉,吴伟,等.黄连解毒汤对高胆固醇兔血液流变学和动脉粥样硬化干预作用[J].中国中药杂志,2009；34(5)：600-604.
[105]张京春,陈可冀,郑广娟,等.解毒活血中药配伍对载脂蛋白E基因敲除小鼠主动脉NF-κB与MMP-9表达的调控作用[J].中国中西医结合杂志,2007；27(1)：40-44.
[106]葛岚,程晓昱,胡业彬.益气活血解毒汤对实验性动脉粥样硬化家兔炎症细胞因子和血脂的影响[J].中国中西医结合急救杂志,2007；14(5)：306-308.
[107]刘龙涛,吴敏,张文高,等.虎杖苷对颈动脉粥样硬化斑块稳定性的干预研究 [J].北京中医药,2009；28(3)：172-175.
[108]郑刚.他汀类药物多效性研究新进展[J].循证医学,2008；8(5)：301-305.
[109]肖祥彬,程希富,覃数,等.他汀类药物在心血管疾病中应用的研究进展[J].心血管病学进展,2008；29(4)：647-650.
[110]张文礼,马建华.罗格列酮的非降糖作用[J].重庆医学,2008；37(6)：660-662.
[111]王霞,凌世峰.虎杖药理作用研究进展[J].海军医学杂志,2004；25(2)：179-181.
[112]罗玉梅,王贺振.山楂的化学成分及药理研究进展[J].时珍国医国药,2004；15(1)：53-54.
[113]薛洁,夏昌隆.山楂药理研究进展[J].新疆中医药,2002；20(4)：69-71.
[114]沈世林,张子理.中药对胞内钙调节的研究现状评述[J].中医研究,2005；18(7)：57-59.
[115]田乃旭,屠鹏飞.药物学研究与展望[M].1版.北京：科学出版社,1999.
[116]Maor I, Aviram M. Oxidized low density lipoprotern leads to macrophage accumulation of unesterified cholesterol as a result of lysosomal trapping of the lipoprotein hydrolyzed cholesteryl ester[J].J Lipid Res,1994; 35(5):803.
[117]Boyle JJ. Macrophage activation in atherosclerosis:Pathogenesis and Pharmacology of Plaque rupture[J]. Curr Vase Pharmacol,2005; 3(1):63-68.
[118]Fogelman AM, Shechter I, Seager J, et al. Malondialde_hyde Alteration of Low Density Lipoproteins Leads to Cholesteryl Ester Accumulation in Human Monocyte-Macrophages[J].Proc Natl Acad Sci,1980; 77(4):2214.
[119]Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport[J]. Circ Res,2005; 96(12):1221-1232.
[120]Chawla A, Barak Y, Nagy L, et al.PPAR gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation[J].Nat Nbd,2001; 7(1):48-52.
[121]Hiltunen TP, Luoma JS, Mkkari T, et al. Expression of LDL receptor, VLDL Receptor, LDL Receptor related protein, and scavenger Receptor in Rabbit Atherosclerotic lesions[J]. Circulation,1998; 97:1079-1086.
[122]盛富强,程龙献.TLR4信号通路与动脉粥样硬化的研究进展[J].心脏杂志,2009；21(4)：572-574.
[123]敖启林,熊密,郝春荣,等.NF-KB的活性和Inos基因表达在低氧性肺动脉高压中的变化[J].中国病理生理杂志,2002；18(8)：903-906.
[124]李建军,李庚山.核因子-KB与冠心病的关系[J].现代诊断与治疗,2000；11(4)：212-214.
[125]Baeuerle PA, Baltimore D. NF-κB:ten years after[J]. Cell,1996; 87 (1):13-20.
[126]曹建伟,安向光.急性心肌梗死患者炎性细胞因子水平测定[J].中国心血管病研究,2008；6(7)：488-490.
[127]Mouco OM, Nicolau JC, Souza TR, et al. Inflammatory markers of atherosclerotic plaque stabilization after acute coronary event-temporal trends[J]. Arq Bras Cardiol,2006; 87:28-36.
[128]Satoh M, Ishikawa Y, Itoh T, et al. The expression of TNF-alpha converting enzyme at the site of ruptured plaques in patients with acute myocardial infarction[J].Eur J Clin Invest,2008; 38:97-105.
[129]Jiang Jianxia, Tian Kunlun, Diao Youfang, et al. Expression of TNF-α, IL-1β, IL-6 Mrna, release of TNF-ain the vital organs and their relationship with endotoxin translocation following hemorrhagic shock[J]. ClinMed Science J,1997; 12(1):41-46.
[130]Shamash S,Reichert F, Rotshenker S. The cytokine network of Wallerian degeneration:tumor necrosis factor-alpha, interleukin-lalpha, and interleukin-lbeta[J]. J Neurosci,2002; 22:3052-3060.