动脉粥样硬化模型大鼠ADP与炎性因子表达及中药对其调控的机制研究
摘要
目的:通过对动脉粥样硬化模型大鼠治疗,探讨脂联素与炎性因子表达水平的相关性,并观察通脉化浊汤不同剂量对其的影响。
材料与方法:选取SD大鼠216只随机分为六组,空白对照组、模型组、通脉化浊汤二倍剂量组、正常剂量组、1/2剂量组、血脂康对照组,各组大鼠(除正常组大鼠外)在给予维生素D370万IU/kg(3天内灌胃)后,饲喂高脂饮食,以造动脉粥样硬化模型,正常组大鼠在给予同体积生理盐水灌胃后饲喂普通饲料;造模成功后给予改换普通饲料喂养,同时进行药物治疗,通脉化浊汤高、中、低剂量组(分别含生药量2.79g/ml、1.395g/ml、0.6975g/ml)分别给予对应剂量汤剂2ml/200g日一次灌胃给药,中药对照组(含血脂康0.0108g/ml)给予血脂康胶囊水溶液2ml/200g日一次灌胃给药,正常组及模型组给予同等体积的生理盐水,于给药后1、2、4周各组随机抽取12只大鼠,乌拉坦麻醉,腹主动脉取血,检测血脂、ADP、IL-6、CRP,摘取主动脉,备做病理切片,摘取心尖组织,备做RT-PCR。
结果:通过血清学检测血脂指标可见,模型组在各个时间段TC、TG、LDL含量均明显高于空白对照组,HDL含量明显低于空白对照组,通过一周的治疗后各治疗组TC、TG、LDL含量均有所降低,HDL也有一定的升高,继续治疗至第四周后,血脂各项指标已经接近空白对照组,且无显著差异。治疗过程中通脉化浊汤正常剂量组及二倍剂量组与血脂康对照组间血脂水平无显著差异。模型组各个时间段的炎症因子指标IL-6和CRP明显高于空白组,ADP明显低于空白组,通过四周的治疗后各治疗组IL-6和CRP逐渐降低,ADP逐渐升高,于治疗后第二周开始与模型组产生明显差异并继续加深。通过光镜观察病理切片可见,模型组大鼠动脉血管明显增厚,表面纤维帽呈不同程度的玻璃样变;病灶深部可见无定型的坏死崩溃物,其中含有胆固醇结晶(呈针状或梭形空隙),通过中药汤剂通脉化浊汤的治疗后,动脉粥样硬化程度减轻,管壁变薄,胶原纤维增生明显。通过RT-PCR技术检测可见,模型组在各个时间段TNF-α含量均明显高于空白对照组,ADP含量明显低于空白对照组,通过四周的治疗后各治疗组TNF-α逐渐降低,ADP逐渐升高,于治疗后第二周开始与模型组产生明显差异并继续加深。
结论:通脉化浊汤能够明显降低血清TC、TG、LDL含量,升高HDL含量,具有良好的降脂、保护血管内皮、稳定斑块的作用;通脉化浊汤可有效的降低TNF-α、IL-6及CRP,能够良好的对动脉粥样硬化进行抗炎治疗,从而对动脉粥样硬化的发生发展产生重要影响;通脉化浊汤能够明显升高ADP,通过改善血管内皮功能,减少黏附因子的表达,抑制巨噬细胞产生细胞因子并减弱其胞吞作用及抑制血管损伤后平滑肌细胞的增殖从而达到抑制、治疗动脉粥样硬化的作用;通脉化浊汤通过降低血脂含量,抑制炎症因子的表达,提高ADP水平从而达到抗动脉粥样硬化发生机制的作用。
Purpose:To explore the relevance between expression level of adiponectin (ADPN) and tumor necrosis factorα(TNF-α).
Material and method:216 wistar rats were randomly divided into six groups: control group, model group, Tōng Mài HuàZhuóTāng high dose group,Tōng Mài HuàZhuóTāng middle dose group, Tōng Mài HuàZhuóTāng low dose group, and Chinese medicinals control group. The atherosclerosis model was induced by feeding the rats with cholesterol-rich fodder. Then the medicinals were administered on these rats, 12 of which were executed in the fourth, sixth and eighth weeks counted from the day of administration. After the relevant tissues for research were taken, the expression levels of ADP and TNF-αin myocardial cell were tested using the technology of RT-PCR.
Results:
1. There is a positive relevance between expression level of ADPN and TNFα,
2. and also there is an inhibitory effect of ADP on TNF-α. Above all,。
3. recipes of Chinese medicine have clear regulatory effects on the expression of ADP.
Conclusion:
1. Tōng Mài HuàZhuóTāng is very promising both clinically.
2. practically in its effect on controlling.
3. treating atherosclerosis by promoting the level of ADP that inhibits the expression of TNF-α.
材料与方法:选取SD大鼠216只随机分为六组,空白对照组、模型组、通脉化浊汤二倍剂量组、正常剂量组、1/2剂量组、血脂康对照组,各组大鼠(除正常组大鼠外)在给予维生素D370万IU/kg(3天内灌胃)后,饲喂高脂饮食,以造动脉粥样硬化模型,正常组大鼠在给予同体积生理盐水灌胃后饲喂普通饲料;造模成功后给予改换普通饲料喂养,同时进行药物治疗,通脉化浊汤高、中、低剂量组(分别含生药量2.79g/ml、1.395g/ml、0.6975g/ml)分别给予对应剂量汤剂2ml/200g日一次灌胃给药,中药对照组(含血脂康0.0108g/ml)给予血脂康胶囊水溶液2ml/200g日一次灌胃给药,正常组及模型组给予同等体积的生理盐水,于给药后1、2、4周各组随机抽取12只大鼠,乌拉坦麻醉,腹主动脉取血,检测血脂、ADP、IL-6、CRP,摘取主动脉,备做病理切片,摘取心尖组织,备做RT-PCR。
结果:通过血清学检测血脂指标可见,模型组在各个时间段TC、TG、LDL含量均明显高于空白对照组,HDL含量明显低于空白对照组,通过一周的治疗后各治疗组TC、TG、LDL含量均有所降低,HDL也有一定的升高,继续治疗至第四周后,血脂各项指标已经接近空白对照组,且无显著差异。治疗过程中通脉化浊汤正常剂量组及二倍剂量组与血脂康对照组间血脂水平无显著差异。模型组各个时间段的炎症因子指标IL-6和CRP明显高于空白组,ADP明显低于空白组,通过四周的治疗后各治疗组IL-6和CRP逐渐降低,ADP逐渐升高,于治疗后第二周开始与模型组产生明显差异并继续加深。通过光镜观察病理切片可见,模型组大鼠动脉血管明显增厚,表面纤维帽呈不同程度的玻璃样变;病灶深部可见无定型的坏死崩溃物,其中含有胆固醇结晶(呈针状或梭形空隙),通过中药汤剂通脉化浊汤的治疗后,动脉粥样硬化程度减轻,管壁变薄,胶原纤维增生明显。通过RT-PCR技术检测可见,模型组在各个时间段TNF-α含量均明显高于空白对照组,ADP含量明显低于空白对照组,通过四周的治疗后各治疗组TNF-α逐渐降低,ADP逐渐升高,于治疗后第二周开始与模型组产生明显差异并继续加深。
结论:通脉化浊汤能够明显降低血清TC、TG、LDL含量,升高HDL含量,具有良好的降脂、保护血管内皮、稳定斑块的作用;通脉化浊汤可有效的降低TNF-α、IL-6及CRP,能够良好的对动脉粥样硬化进行抗炎治疗,从而对动脉粥样硬化的发生发展产生重要影响;通脉化浊汤能够明显升高ADP,通过改善血管内皮功能,减少黏附因子的表达,抑制巨噬细胞产生细胞因子并减弱其胞吞作用及抑制血管损伤后平滑肌细胞的增殖从而达到抑制、治疗动脉粥样硬化的作用;通脉化浊汤通过降低血脂含量,抑制炎症因子的表达,提高ADP水平从而达到抗动脉粥样硬化发生机制的作用。
Purpose:To explore the relevance between expression level of adiponectin (ADPN) and tumor necrosis factorα(TNF-α).
Material and method:216 wistar rats were randomly divided into six groups: control group, model group, Tōng Mài HuàZhuóTāng high dose group,Tōng Mài HuàZhuóTāng middle dose group, Tōng Mài HuàZhuóTāng low dose group, and Chinese medicinals control group. The atherosclerosis model was induced by feeding the rats with cholesterol-rich fodder. Then the medicinals were administered on these rats, 12 of which were executed in the fourth, sixth and eighth weeks counted from the day of administration. After the relevant tissues for research were taken, the expression levels of ADP and TNF-αin myocardial cell were tested using the technology of RT-PCR.
Results:
1. There is a positive relevance between expression level of ADPN and TNFα,
2. and also there is an inhibitory effect of ADP on TNF-α. Above all,。
3. recipes of Chinese medicine have clear regulatory effects on the expression of ADP.
Conclusion:
1. Tōng Mài HuàZhuóTāng is very promising both clinically.
2. practically in its effect on controlling.
3. treating atherosclerosis by promoting the level of ADP that inhibits the expression of TNF-α.
引文
[1]刘金波,邓华聪,葛倩,等.脂联素对TNF-α介导的血管炎症反应的影响[J].第四军医大学学报,2006,27(18):1697-1699
[2]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999,340(2):115
[3]Hansson G K. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med, 2005, 352 (16): 1685-1695.
[4]Libby P, Ridker P M, Maseri A. Inflammation and Atherosclerosis. Circulation 2002; 105 (9):1135-1143.
[5]Lerman A, Zeiher A M. Endothelial function: Cardiac events. Circulation 2005; 111: 363-368.
[6]Bonetti P O, Lerman L O, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler thromb vasc boil, 2003, 23: 168-175.
[7]Massberg S, Brand K, Gruner S, et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med, 2002, 196: 887-896.
[8]Dandona P, Aljada A, Chaudhuri A, et al. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes,and inflammation. Circulation, 2005, 111: 1448-1454.
[9]Tamakoshi K, Yatsuya H, Kondo T, et al. The metabolic syndrome is associated with elevated circulating C-reactive protein in healthy reference range, a systemic low-grade inflammatory state. Int J Obes Relat Metab Disord, 2003, 27: 443-449.
[10]Jongeneet C V, Briant L, Udatova IA, et al. Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended H L A halpotypes. Pro Natl Acad Sci, 1991,88:9717-9721.9
[11]Hotamisligil G S,Peraldi P,Budavari A, et al. IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha andobesity-induced insulin resistance. Science,1996,271:665-668.
[12]Munker R, Gasson J, Ogawa M, et al. Recombinant human TNF induces production of granulocyte-monocyte colony-stimulating factor. Nature, 1986,323:79-82.
[13]Paleolog EM, Delasalle SA, Buurman WA, et al. Functional activities of receptors for tumor necrosis facor-alpha on human vascular endothelial cells. Blood, 1994,84:2578-2590.
[14]Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J of Exp Med, 1986,163:740-745.
[15]Barath P, Fishbein MC, Cao J. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol, 1990,65:297-302.
[16]Yasojima K,Schwab C,McGeer EG,McGeer PL.Generation of Creactive protein and complement components in atherosclerotic plaques[J].Am J Pathol,2001,158(3):1 0392051
[17]Jialal I, Devaraj S, Venugopal SK. C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis? Hypertension, 2004, 44 (1): 6-11.
[18]Yudkin JS, Stehouwer CD, Emeis JJ, et al. C-reactive protein in healthy subjects-associations with obesity, insulin resistance and endothelial dysfunction. A potential role for cytokines originating from adipose tissue? Art Thromb Vasc Biol 1999,19:972-978.
[19]Romano M, Sironi M, Toniatti C, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997,6:1-20.
[20]Tsao TS,Tomas E,Murrey HE,Hug C,Lee DH,Ruderman NB,et al.Role of disulfide bonds in Acrp30/Adiponectin structure and signaling specificity:Different oligomers activate different signal transduction pathways. J Biol Chem ,2003,278 (50):810-817
[21]A rita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adiposespecific protein,adiponectin in obesity.Biochem Biophys Res Commun, 1999,257(1):79-83
[22]Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose- specific gene dysregulation in obesity. J Biol Ch em, 1996, 271(18):10 697-10703.
[23]Kubota N,Terauchi Y, Yamauchi T,et al .Distributionof adiponectin causes insulin resistance and neointimal formation [J」.Biol Chem,2002 ,277 (29):863一866.
[24]Yamauchi T,Kamon J ,Waki H,et al .Globular adiponectin protected ob/ob mice from diabetes and ApoE deficient mice from atherosclerosis [J」.Biol Chem,2003 ,278 (4) :2461一2468
[25]Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, et al.Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP一dependent pathway. Circulation 2000;102:1296-301
[26]Ouchi N ,Kihara S ,Arita Y, et al .Adipocyte derived plasma protein,adiponectin,suppresses lipid accumulation and class A scavenger receptor expression in human monocyte derived macrophage[J].Circulation 2001 ,103 (8):1057一1063.
[27]Mastsuda M,Shimomura I ,Sata M,et a1.Role of adiponectin in preventin vascular stenosis :The missing link of adipo-vascular axis.J Biol Chem 2002,277(37):487-91
[28]Kumada M,Kihara S,Sumitsuji S , et al Association of hypoadiponectinemia with coronary artery disease in men.Arterioscler Thromb Vasc Biol,2003 ,23:85一89.
[29]裴强,秦永文,吴弘,等血清脂联素水平与冠状动脉病变程度的关系[J]临床心血管病杂志,2004,20 (10) :619-624
[30]Ishikawa Y,Akasaka Y,Ishii T,et al .Changes in the distribution pattern of gelatin binding protein of 28 kDa (adiponectin) in myocardial remodeling after ischaemic injury[J」.Histopathology ,2003 ,42 (1) :43一52.
[31]Nakamura Y,Shimada K,Fukuda D,et al.Implications of plasma concentrations of adiponectin in patients with coronary artery disease.Heart. 2004;90:528-33.
[32]Ouchi N,Kihara S,Funahashi T, Nakamura T, Nishida M, Kumada M, et al.Reciprocal association of C2reactive protein with adiponectin in blood stream and adipose tissue[J].Circulation,2003,107 (5):671-674
[33]Kojima S,Funahashi T, Sakamoto T, Miyamoto S,Soejima H,Hokamaki J,etal. The variation of plasma concentrations of a novel,adipocyte derived protein ,adiponectin , in patients with acute myocardial infarction[J].Heart ,2003,89 (6):667-668
[34]Yasojima K, Schwab C,McGeer EG, McGeer PL. Generation of Creactive protein and complement components in atherosclerotic plaques[J].Am J Pathol,2001,158 (3):1 0392051
[35]袁国强,吴以岭,贾振华,等.过逸气虚大鼠血管内皮功能障碍及通络药物的干预研究.中国中医基础医学杂志,2008,14(1):71
[36]李忠民,于风山,田清友,等.人主要动脉动脉粥样硬化与年龄的关系.中国综合临床,1999,15(2):115
[37]林桂永,王子健.冠心病血瘀证气血辨证与内皮细胞损伤的关系.中西医结合心脑血管病杂志,2005,3(10):856
[38]颜德馨,胡泉林,王平平,等.气虚血瘀是人体衰老的主要机制.中国医药学报,1989,4(2):10
[39]梁煜,林代华,王清.气虚血瘀是冠心病的病机关键释义.中医药学刊,2003,21(4):588
[40]陈启兰,祝光礼.祝光礼治疗高脂血症合并肝功能异常的经验[J].浙江中医杂志,2009,44(1):12213.
[41]王志国,季绍良.高脂血症的病因病机及其证治[J].中医药学刊,2003,21(7):114921150.
[42]胡广芹,陆小左,孟玲.八味茶治疗痰浊阻遏型高脂血症临床观察[J].上海中医药杂志,2008,42(5):22223.
[43]祝世讷.中西医学差异与交融[M].第1版.北京:人民卫生出版社,2000.249
[44]薛源.益寿调脂片抗动脉粥样硬化的实验研究[J].江苏中医,2001,22(8):42244
[45]郑源庞,周振鹤,龚康敏,等.补肾护脉方对家兔实验性动脉粥样硬化各项指标的影响[J].中国实验方剂学杂志,1998,4(5):27229
[46]黄河清,吴伟康,程超.四逆汤抗实验性动脉粥样硬化的作用及其机制[J].中国动脉硬化杂志,2000,8(4):302230
[47]刘彦珠,刘维琴,秦腊梅,等.健脾消痰化瘀法对高脂血症患者脂质过氧化的影响[J].北京中医药大学学报,1997,20(3):50
[48]赵学军,李任先,刘国普,等.理脾化痰方对食饵性动脉粥样硬化症家兔血管平滑肌细胞增殖和凋亡的调控[J].广州中医药大学学报,2001,18(2):1442148
[49]范英昌,朱钧,陆一竹,等.疏肝活血方对家兔实验性动脉粥样硬化发病影响的实验研究[J].中国老年学杂志,1997,17(1):37238
[50]范英昌,陆一竹,胡利明,等.疏肝活血方药对实验性动脉粥样硬化血清钙离子及环核苷酸浓度的影响[J].中草药,1997,28(2):91293
[51]范英昌,朱钧,陆融,等.疏肝活血方对家兔主动脉平滑肌细胞内脂过氧化物歧化酶活性的影响[J].中国动脉硬化杂志,1996,4(1):51253
[52]吴敏,周仲瑛,陈文垲,等.滋肾养肝、化痰消瘀法防治脑动脉粥样硬化症临床研究[J].南京中医药大学学报,1999,15(5):2722275
[53]王学岭,张红霞,陆一竹,等.调肝导浊汤对实验性动脉粥样硬化家兔肝脏脂质含量及体外培养肝细胞脂蛋白受体的影响[J].中国中医药科技,2002,9(4):2082210
[54]冷兴文,刘志华,王磊.动脉粥样硬化中医治疗法则与方药作用机理研究[J].实用中西医结合杂志,1997,10(7):6042606
[55]鲍延熙,郑义,陆惠华,等.冠心病中医辨证分型与冠状动脉及左室造影所见的联系[J].中西医结合杂志,1989,9(2):74275
[56]孙建芝,牛晓亚,韩丽华,等.痰浊证微观辨证指标的实验研究[J].河南中医,1996,16(2):21222.
[57]马晓昌,尹太英,陈可冀,等.冠心病中医辨证分型与冠状动脉造影所见相关性比较研究[J].中国中西医结合杂志,2001,21(9):6542656
[58]史大卓,马晓昌,高修安.活血化瘀方药防治动脉粥样硬化概况[J].中医杂志,1995,36(7):4332435
[59]程小曲.痰浊型冠心病与血脂、脂蛋白、载脂蛋白的关系及痰浊形成机理的探讨[J].新中医.1994,26(3):7-9.
[60]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(2):1952196
[61]宁晓暄,孙世仁.感染、炎症与动脉粥样硬化[J].国外医学·老年医学分册,2000,21(4):1732175
[62]赵慧辉,王伟.不稳定性心绞痛血瘀证的血浆蛋白质组学研究[J].化学学报,2009,67(2):1672173.
[63]郭来,丁书文.复方莶草合剂抗动脉粥样硬化内皮细胞损伤实验研究[J].中医药学刊,2001,19(2):1052106
[64]于俊生,王砚琳.痰瘀毒相关论[J].山东中医杂志,2000,19(6):3232325
[65]吴圣贤,林永康,黄政鑫,等.解毒软脉方防治高胆固醇饮食致兔动脉粥样硬化的实验研究[J].福建中医药,2001,32(2):37238
[66]祝世讷.中西医学差异与交融[M].第1版.北京:人民卫生出版社,2000.249
[67]刘彦珠,刘维琴,秦腊梅,等.健脾消痰化瘀法对高脂血症患者脂质过氧化的影响[J].北京中医药大学学报,1997,20(3):50
[68]郑源庞,周振鹤,龚康敏,等.补肾护脉方对家兔实验性动脉粥样硬化各项指标的影响[J].中国实验方剂学杂志,1998,4(5):27229
[69]刘介眉等.病理组织染色的理论方法和应用[M]北京;人民卫生出版社,1983,22,45-38.
[70]王永炎.中医内科学[M].上海:上海科学技术出社,1994:98-157.
[71]双晓萍,冯辉丹参饮合小陷胸汤加味治疗痰瘀痹阻型冠心病稳定型心绞痛的临床研究[D]武汉:湖北中医学院,2005
[72]熊尚全,林超,郭进建,等化痰活血方对不稳定性心绞痛痰证患者血浆hs-CRP、F IB和血脂水平的影响[J].光明中医,2007,22(7):17-19 [73 ]唐可欣,王金光,王凤斌,等.胸痹通胶囊对高脂血症大鼠肝低密度脂蛋白受体基因表达的影响[ J ] .中西医结合心脑血管病杂志,2004,2 (8):854.
[74]刘萍,张静生,张兴中.冠心康对冠心病患者外周血淋巴细胞低密度脂蛋白受体基因表达的影响[ J ] .中医药学刊,2003,21 (7): 1035-1036.
[75].Farmer J A,Gotto A M Jr.Dyslipidernia and other risk factors for coronary artery disease.In;Braunwald E,ed.Heart disease;A text book of cardiovascular medicine[M].5th ed.Philadelphia;WB Saun-ders,1997;1126-1126.
[76]孙璐,黄水清.动脉粥样硬化动物模型与中医证候相关性研究[A]现代中西医结合杂志, 2009,18(3):337-339
[77]覃秀川.C反应蛋白与冠心病[J].国外医学·老年医学分册,1999,20(3);105
[78]Han SH,Quan MJ,Koh KK1Beneficial vascular and metabolic effects of peroxisome p roliferator-activated recep tor-alpha activators〔J〕1Hy2 pertension,2005,46(5):1086
[79]Bergman MR,Kao RH,MeCuneSA,et al.Myocardial tumor ne-crosis factor-aphasecretion in hypertensive and heart failure-prone rats [J].Am J Physiol,1999,277(2);543-550.
[80]Barath P,Fishbein MC,Cao J,et al.Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected byin situhybridization [J].Am J Pathol,1990,137;503.
[81]Barath P,Fishbein MC,Cao J,et a1.Detection and localization of tumor necrosis factor in human atheroma [J].Am J Cardiol,1990,65;297.
[82]HottaK, FunahashiT,AritaY, et a.l Plasma concentrations of a no-ve,l adipose-specific protein, adiponectin, in type 2 diabetic patients[J].ArteriosclerThromb Vasc Bio,l 2000, 20(6): 1 595-1 599.
[83]WeyerC, FunahashiT,Tanaka S, et a.l Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia[J]. J Clin EndocrinolMetab, 2001, 86(5): 1 930-1 935
[84]Pischon T, Girman CJ, Hotamisligil GS, et a.l Plasma adiponectin levels and risk ofmyocardial infarction in men[ J]. JAMA, 2004, 291(14): 1 730-1 737
[85]QuchiN,Kihara S, FunahashiT, et a.l Reciprocal association ofC-reactive protein with adiponectin in blood stream and adipose tissue [J].Circulation, 2003, 107(5): 671-674
[86]周陵、陈绍良、叶飞等.冠心病患者血清脂联素与C-反应蛋白关系的研究[M]中国综合临床2006,22(5):400-401
[87]周淑娴,雷娟,张玉玲等.高血压患者胰岛素抵抗与血清脂联素及炎症标志物水平[J],中华高血压杂志2008,16(2):166-170
[88]Ouchi N, Ohishi M, Kihara S,et al. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension, 2003; 42∶23
[2]Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med.1999,340(2):115
[3]Hansson G K. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med, 2005, 352 (16): 1685-1695.
[4]Libby P, Ridker P M, Maseri A. Inflammation and Atherosclerosis. Circulation 2002; 105 (9):1135-1143.
[5]Lerman A, Zeiher A M. Endothelial function: Cardiac events. Circulation 2005; 111: 363-368.
[6]Bonetti P O, Lerman L O, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler thromb vasc boil, 2003, 23: 168-175.
[7]Massberg S, Brand K, Gruner S, et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med, 2002, 196: 887-896.
[8]Dandona P, Aljada A, Chaudhuri A, et al. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes,and inflammation. Circulation, 2005, 111: 1448-1454.
[9]Tamakoshi K, Yatsuya H, Kondo T, et al. The metabolic syndrome is associated with elevated circulating C-reactive protein in healthy reference range, a systemic low-grade inflammatory state. Int J Obes Relat Metab Disord, 2003, 27: 443-449.
[10]Jongeneet C V, Briant L, Udatova IA, et al. Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended H L A halpotypes. Pro Natl Acad Sci, 1991,88:9717-9721.9
[11]Hotamisligil G S,Peraldi P,Budavari A, et al. IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha andobesity-induced insulin resistance. Science,1996,271:665-668.
[12]Munker R, Gasson J, Ogawa M, et al. Recombinant human TNF induces production of granulocyte-monocyte colony-stimulating factor. Nature, 1986,323:79-82.
[13]Paleolog EM, Delasalle SA, Buurman WA, et al. Functional activities of receptors for tumor necrosis facor-alpha on human vascular endothelial cells. Blood, 1994,84:2578-2590.
[14]Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J of Exp Med, 1986,163:740-745.
[15]Barath P, Fishbein MC, Cao J. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol, 1990,65:297-302.
[16]Yasojima K,Schwab C,McGeer EG,McGeer PL.Generation of Creactive protein and complement components in atherosclerotic plaques[J].Am J Pathol,2001,158(3):1 0392051
[17]Jialal I, Devaraj S, Venugopal SK. C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis? Hypertension, 2004, 44 (1): 6-11.
[18]Yudkin JS, Stehouwer CD, Emeis JJ, et al. C-reactive protein in healthy subjects-associations with obesity, insulin resistance and endothelial dysfunction. A potential role for cytokines originating from adipose tissue? Art Thromb Vasc Biol 1999,19:972-978.
[19]Romano M, Sironi M, Toniatti C, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997,6:1-20.
[20]Tsao TS,Tomas E,Murrey HE,Hug C,Lee DH,Ruderman NB,et al.Role of disulfide bonds in Acrp30/Adiponectin structure and signaling specificity:Different oligomers activate different signal transduction pathways. J Biol Chem ,2003,278 (50):810-817
[21]A rita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adiposespecific protein,adiponectin in obesity.Biochem Biophys Res Commun, 1999,257(1):79-83
[22]Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose- specific gene dysregulation in obesity. J Biol Ch em, 1996, 271(18):10 697-10703.
[23]Kubota N,Terauchi Y, Yamauchi T,et al .Distributionof adiponectin causes insulin resistance and neointimal formation [J」.Biol Chem,2002 ,277 (29):863一866.
[24]Yamauchi T,Kamon J ,Waki H,et al .Globular adiponectin protected ob/ob mice from diabetes and ApoE deficient mice from atherosclerosis [J」.Biol Chem,2003 ,278 (4) :2461一2468
[25]Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, et al.Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP一dependent pathway. Circulation 2000;102:1296-301
[26]Ouchi N ,Kihara S ,Arita Y, et al .Adipocyte derived plasma protein,adiponectin,suppresses lipid accumulation and class A scavenger receptor expression in human monocyte derived macrophage[J].Circulation 2001 ,103 (8):1057一1063.
[27]Mastsuda M,Shimomura I ,Sata M,et a1.Role of adiponectin in preventin vascular stenosis :The missing link of adipo-vascular axis.J Biol Chem 2002,277(37):487-91
[28]Kumada M,Kihara S,Sumitsuji S , et al Association of hypoadiponectinemia with coronary artery disease in men.Arterioscler Thromb Vasc Biol,2003 ,23:85一89.
[29]裴强,秦永文,吴弘,等血清脂联素水平与冠状动脉病变程度的关系[J]临床心血管病杂志,2004,20 (10) :619-624
[30]Ishikawa Y,Akasaka Y,Ishii T,et al .Changes in the distribution pattern of gelatin binding protein of 28 kDa (adiponectin) in myocardial remodeling after ischaemic injury[J」.Histopathology ,2003 ,42 (1) :43一52.
[31]Nakamura Y,Shimada K,Fukuda D,et al.Implications of plasma concentrations of adiponectin in patients with coronary artery disease.Heart. 2004;90:528-33.
[32]Ouchi N,Kihara S,Funahashi T, Nakamura T, Nishida M, Kumada M, et al.Reciprocal association of C2reactive protein with adiponectin in blood stream and adipose tissue[J].Circulation,2003,107 (5):671-674
[33]Kojima S,Funahashi T, Sakamoto T, Miyamoto S,Soejima H,Hokamaki J,etal. The variation of plasma concentrations of a novel,adipocyte derived protein ,adiponectin , in patients with acute myocardial infarction[J].Heart ,2003,89 (6):667-668
[34]Yasojima K, Schwab C,McGeer EG, McGeer PL. Generation of Creactive protein and complement components in atherosclerotic plaques[J].Am J Pathol,2001,158 (3):1 0392051
[35]袁国强,吴以岭,贾振华,等.过逸气虚大鼠血管内皮功能障碍及通络药物的干预研究.中国中医基础医学杂志,2008,14(1):71
[36]李忠民,于风山,田清友,等.人主要动脉动脉粥样硬化与年龄的关系.中国综合临床,1999,15(2):115
[37]林桂永,王子健.冠心病血瘀证气血辨证与内皮细胞损伤的关系.中西医结合心脑血管病杂志,2005,3(10):856
[38]颜德馨,胡泉林,王平平,等.气虚血瘀是人体衰老的主要机制.中国医药学报,1989,4(2):10
[39]梁煜,林代华,王清.气虚血瘀是冠心病的病机关键释义.中医药学刊,2003,21(4):588
[40]陈启兰,祝光礼.祝光礼治疗高脂血症合并肝功能异常的经验[J].浙江中医杂志,2009,44(1):12213.
[41]王志国,季绍良.高脂血症的病因病机及其证治[J].中医药学刊,2003,21(7):114921150.
[42]胡广芹,陆小左,孟玲.八味茶治疗痰浊阻遏型高脂血症临床观察[J].上海中医药杂志,2008,42(5):22223.
[43]祝世讷.中西医学差异与交融[M].第1版.北京:人民卫生出版社,2000.249
[44]薛源.益寿调脂片抗动脉粥样硬化的实验研究[J].江苏中医,2001,22(8):42244
[45]郑源庞,周振鹤,龚康敏,等.补肾护脉方对家兔实验性动脉粥样硬化各项指标的影响[J].中国实验方剂学杂志,1998,4(5):27229
[46]黄河清,吴伟康,程超.四逆汤抗实验性动脉粥样硬化的作用及其机制[J].中国动脉硬化杂志,2000,8(4):302230
[47]刘彦珠,刘维琴,秦腊梅,等.健脾消痰化瘀法对高脂血症患者脂质过氧化的影响[J].北京中医药大学学报,1997,20(3):50
[48]赵学军,李任先,刘国普,等.理脾化痰方对食饵性动脉粥样硬化症家兔血管平滑肌细胞增殖和凋亡的调控[J].广州中医药大学学报,2001,18(2):1442148
[49]范英昌,朱钧,陆一竹,等.疏肝活血方对家兔实验性动脉粥样硬化发病影响的实验研究[J].中国老年学杂志,1997,17(1):37238
[50]范英昌,陆一竹,胡利明,等.疏肝活血方药对实验性动脉粥样硬化血清钙离子及环核苷酸浓度的影响[J].中草药,1997,28(2):91293
[51]范英昌,朱钧,陆融,等.疏肝活血方对家兔主动脉平滑肌细胞内脂过氧化物歧化酶活性的影响[J].中国动脉硬化杂志,1996,4(1):51253
[52]吴敏,周仲瑛,陈文垲,等.滋肾养肝、化痰消瘀法防治脑动脉粥样硬化症临床研究[J].南京中医药大学学报,1999,15(5):2722275
[53]王学岭,张红霞,陆一竹,等.调肝导浊汤对实验性动脉粥样硬化家兔肝脏脂质含量及体外培养肝细胞脂蛋白受体的影响[J].中国中医药科技,2002,9(4):2082210
[54]冷兴文,刘志华,王磊.动脉粥样硬化中医治疗法则与方药作用机理研究[J].实用中西医结合杂志,1997,10(7):6042606
[55]鲍延熙,郑义,陆惠华,等.冠心病中医辨证分型与冠状动脉及左室造影所见的联系[J].中西医结合杂志,1989,9(2):74275
[56]孙建芝,牛晓亚,韩丽华,等.痰浊证微观辨证指标的实验研究[J].河南中医,1996,16(2):21222.
[57]马晓昌,尹太英,陈可冀,等.冠心病中医辨证分型与冠状动脉造影所见相关性比较研究[J].中国中西医结合杂志,2001,21(9):6542656
[58]史大卓,马晓昌,高修安.活血化瘀方药防治动脉粥样硬化概况[J].中医杂志,1995,36(7):4332435
[59]程小曲.痰浊型冠心病与血脂、脂蛋白、载脂蛋白的关系及痰浊形成机理的探讨[J].新中医.1994,26(3):7-9.
[60]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(2):1952196
[61]宁晓暄,孙世仁.感染、炎症与动脉粥样硬化[J].国外医学·老年医学分册,2000,21(4):1732175
[62]赵慧辉,王伟.不稳定性心绞痛血瘀证的血浆蛋白质组学研究[J].化学学报,2009,67(2):1672173.
[63]郭来,丁书文.复方莶草合剂抗动脉粥样硬化内皮细胞损伤实验研究[J].中医药学刊,2001,19(2):1052106
[64]于俊生,王砚琳.痰瘀毒相关论[J].山东中医杂志,2000,19(6):3232325
[65]吴圣贤,林永康,黄政鑫,等.解毒软脉方防治高胆固醇饮食致兔动脉粥样硬化的实验研究[J].福建中医药,2001,32(2):37238
[66]祝世讷.中西医学差异与交融[M].第1版.北京:人民卫生出版社,2000.249
[67]刘彦珠,刘维琴,秦腊梅,等.健脾消痰化瘀法对高脂血症患者脂质过氧化的影响[J].北京中医药大学学报,1997,20(3):50
[68]郑源庞,周振鹤,龚康敏,等.补肾护脉方对家兔实验性动脉粥样硬化各项指标的影响[J].中国实验方剂学杂志,1998,4(5):27229
[69]刘介眉等.病理组织染色的理论方法和应用[M]北京;人民卫生出版社,1983,22,45-38.
[70]王永炎.中医内科学[M].上海:上海科学技术出社,1994:98-157.
[71]双晓萍,冯辉丹参饮合小陷胸汤加味治疗痰瘀痹阻型冠心病稳定型心绞痛的临床研究[D]武汉:湖北中医学院,2005
[72]熊尚全,林超,郭进建,等化痰活血方对不稳定性心绞痛痰证患者血浆hs-CRP、F IB和血脂水平的影响[J].光明中医,2007,22(7):17-19 [73 ]唐可欣,王金光,王凤斌,等.胸痹通胶囊对高脂血症大鼠肝低密度脂蛋白受体基因表达的影响[ J ] .中西医结合心脑血管病杂志,2004,2 (8):854.
[74]刘萍,张静生,张兴中.冠心康对冠心病患者外周血淋巴细胞低密度脂蛋白受体基因表达的影响[ J ] .中医药学刊,2003,21 (7): 1035-1036.
[75].Farmer J A,Gotto A M Jr.Dyslipidernia and other risk factors for coronary artery disease.In;Braunwald E,ed.Heart disease;A text book of cardiovascular medicine[M].5th ed.Philadelphia;WB Saun-ders,1997;1126-1126.
[76]孙璐,黄水清.动脉粥样硬化动物模型与中医证候相关性研究[A]现代中西医结合杂志, 2009,18(3):337-339
[77]覃秀川.C反应蛋白与冠心病[J].国外医学·老年医学分册,1999,20(3);105
[78]Han SH,Quan MJ,Koh KK1Beneficial vascular and metabolic effects of peroxisome p roliferator-activated recep tor-alpha activators〔J〕1Hy2 pertension,2005,46(5):1086
[79]Bergman MR,Kao RH,MeCuneSA,et al.Myocardial tumor ne-crosis factor-aphasecretion in hypertensive and heart failure-prone rats [J].Am J Physiol,1999,277(2);543-550.
[80]Barath P,Fishbein MC,Cao J,et al.Tumor necrosis factor gene expression in human vascular intimal smooth muscle cells detected byin situhybridization [J].Am J Pathol,1990,137;503.
[81]Barath P,Fishbein MC,Cao J,et a1.Detection and localization of tumor necrosis factor in human atheroma [J].Am J Cardiol,1990,65;297.
[82]HottaK, FunahashiT,AritaY, et a.l Plasma concentrations of a no-ve,l adipose-specific protein, adiponectin, in type 2 diabetic patients[J].ArteriosclerThromb Vasc Bio,l 2000, 20(6): 1 595-1 599.
[83]WeyerC, FunahashiT,Tanaka S, et a.l Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia[J]. J Clin EndocrinolMetab, 2001, 86(5): 1 930-1 935
[84]Pischon T, Girman CJ, Hotamisligil GS, et a.l Plasma adiponectin levels and risk ofmyocardial infarction in men[ J]. JAMA, 2004, 291(14): 1 730-1 737
[85]QuchiN,Kihara S, FunahashiT, et a.l Reciprocal association ofC-reactive protein with adiponectin in blood stream and adipose tissue [J].Circulation, 2003, 107(5): 671-674
[86]周陵、陈绍良、叶飞等.冠心病患者血清脂联素与C-反应蛋白关系的研究[M]中国综合临床2006,22(5):400-401
[87]周淑娴,雷娟,张玉玲等.高血压患者胰岛素抵抗与血清脂联素及炎症标志物水平[J],中华高血压杂志2008,16(2):166-170
[88]Ouchi N, Ohishi M, Kihara S,et al. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension, 2003; 42∶23