基于蛋白质组学技术的大鼠心肌缺血气虚血瘀证相关生物学标志分子研究
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摘要
目的：
建立稳定、可重复并能用于中药药效评价的心肌缺血大鼠病证结合动物模型,并应用非标记定量蛋白质组学研究策略对病证结合模型动物证候生物标志分子进行研究。
通过心肌缺血气虚血瘀证证候特征性蛋白质或蛋白质群的发现,探究“气虚-气虚血瘀-气虚”证候及证候转化过程中,心肌蛋白质表达的变化规律,为心肌缺血气虚血瘀证证候的生物学基础研究提供新的证据；为疾病证候的诊断提供新的标志物；为对证治疗提供新的靶标。
通过对心肌缺血病证结合模型动物心肌蛋白质组的动态检测、鉴定和后续的生物信息学处理,将检出的蛋白质根据功能和表达水平发生改变的时间进行分类,为中药对证治疗策略的形成和治疗靶点的确定提供依据。
方法：
1.采用基于Shannon熵互信息的方法对证候相关理化指标进行文献研究,筛选出与缺血性心脏病证候关系最为密切的理化指标；
2.采用左冠状动脉结扎法造成大鼠急性心肌缺血动物模型,运用病证结合的思路,对术后4、7、14、21、28、45、60d模型组和假手术组动物的宏观指标进行全面采集的同时进行理化指标跟踪检测,将宏观指标与理化指标相结合,对不同时间点模型动物的证候属性进行判定；
3.根据各时间点模型动物心肌组织HE染色和细胞凋亡检测结果选择进行蛋白质组检测的目的心肌组织；
4.采用非标记定量蛋白质组策略对术后4、14、28、45d,即两个气虚证时间点和两个气虚血瘀证时间点的模型组左心室梗死边缘区和假手术组左心室心肌样品进行蛋白质组分析检测；通过GO注释和KEGG信号通路注释对差异蛋白质进行生物学过程、细胞成分、分子功能分类和细胞信号通路注释,对差异蛋白的证候相关性进行初步阐释；
5.采用Western-blot法对部分差异蛋白的动态表达情况进行验证。
结果：
1.现有文献中,有相关理化指标研究的证候要素包括气虚、血瘀、痰浊、阴虚、寒凝、阳虚、气滞等7个,涉及理化指标134个。其中,与气虚证最相关的理化指标为超声心动,血液流变学指标与血瘀证相关系数最高。
2.术后4d,模型组大鼠被毛竖立,懒动,易激惹；与同时间点假手术组大鼠比较,安静状态下呼吸频率明显减慢,应激后呼吸频率显著增快,左心室射血分数显著降低,左室短轴缩短率降低,舌、耳廓、足底色度以及血液流变学指标无显著差异。术后7-28d,模型组大鼠被毛无光泽,活动度明显减低,对外界刺激反应迟钝；与假手术组大鼠比较,模型组大鼠安静状态下呼吸频率明显减慢,应激后呼吸频率显著增快,游泳力竭时间明显缩短,左心室射血分数和左室短轴缩短率均显著降低,舌、耳廓、足底色度值及血液流变学指标与假手术组大鼠相比存在显著差异；术后45-60d,模型组大鼠被毛无光泽,活动度明显降低,对外界刺激反应逐渐迟钝,挣扎无力；与假手术组比较安静状态下呼吸频率明显减慢,应激后呼吸频率显著增快,左心室射血分数和左室短轴缩短率进一步降低,舌、耳廓、足底色度值及血液流变学指标与假手术组大鼠相比无显著差异。
结合临床气虚血瘀证诊断标准,对左冠结扎术后不同时间点模型动物证候属性进行判定,术后4d为气虚证,术后7-28d为气虚血瘀证,术后45-60d为气虚证。Lars回归显示动物各部位色度改变与红细胞压积和血小板聚集率改变有关。
3.心肌组织HE染色和原位细胞凋亡检测可见,术后各时间,点模型组大鼠心肌梗死区以心肌坏死为主要改变,左心室梗死边缘区表现为炎细胞浸润、细胞凋亡、细胞肥大等一系列病理改变。
4.对术后4个时间点模型组大鼠左心室梗死边缘区和同时间点假手术组大鼠左心室心肌进行非标记定量蛋白质组分析检测结果为,在8组样品中共鉴定到526个蛋白。其中467个蛋白在4个时间点均被鉴定到。以蛋白表达量比值0.8～1.2作为阈值对4个时间点的蛋白进行筛选,得到45个差异蛋白可能与“气虚证-气虚血瘀证-气虚证”演变过程相关。通过GO功能注释、模糊聚类和KEGG细胞信号通路注释发现,差异蛋白质主要包括细胞骨架蛋白、代谢相关酶类、氧化应激相关蛋白和物质转运相关蛋白。这些蛋白质在维持细胞结构,增强心肌收缩力、调节细胞能量代谢、诱导细胞凋亡以及细胞内信号转导等方面发挥着重要的作用。
5.经Western-blot法对肌动蛋白、alphaB晶体蛋白、L-乳酸脱氢酶、热休克蛋白8表达的动态变化验证结果与蛋白质组检测分析结果基本一致。
结论：
1.通过左冠状动脉结扎法造成的大鼠急性心肌缺血模型动物在术后不同时间段内表现为不同的证候。该模型能够应用于冠状动脉病变导致的心肌缺血气虚证和气虚血瘀证的生物学基础和中药药理研究。
2.心肌蛋白质组检测结果能够反映心肌缺血疾病的进展和证候演进情况,心肌蛋白质组动态变化与心肌缺血疾病证候的动态演变相关。
Objective:To establish a stable and repeatable disease and syndrome combination animal model on myocardial infarction rats, and to quest the biomarkers through the application of label free quantitative proteomics strategy.
To inquiry the variation of protein expression during the syndrome and syndrome transformation of "Qi deficiency-Qi deficiency and Blood stasis-Qi deficiency", in order to provide the new proof for the biological basis, the new biomarkers, and the new therapeutic target for the syndrome of Qi deficiency and Blood stasis after acute myocardial infarction.
To check against the formation and to provide the basis to the determination of therapeutic targets of Chinese medicine, which based on the proteins cluster according to the expression changes resulted from the detection, identification, and the analysis by the bioinformatics technology on the myocardium proteomics of the model animals.
Methods:
1. The Data mining technology based on the Shannon entropy mutual information were。used to analysis the complicated correlations of the statistical distribution of coronary heart disease syndromes associated physical and chemical indexes.
2. SD rats were subjected to either proximal LAD ligation or sham operation.20 rats (10 in each group) were subjected to forced swimming test (FST) to measure the exhaustive swimming time in every time point. Echocardiography was used to evaluate the cardiac function in rats at each time point, and the respiratory rate in both peaceful state and post-stress were counted. After the images of ear concha, foot plant and facies lingualis were took, the color indexes were analyzed by Photoshop software, and the hemorheology were measured at the same time. LARS was subjected to calculate the correlation between the color and hemorheology.
3. Label-free nanoscale LC-MS quantitative proteomics was applied in this study to inquiry the variation of protein expression during the syndrome and syndrome transformation of "Qi deficiency-Qi deficiency and Blood stasis-Qi deficiency" on the myocardium of myocardial infarction model animals at 4th,14th,28th,45th after operation. Fuzzy Clustering, GOslimviewer, and KEGG signaling pathway was used to do the annotation of time course expression, molecular function, cellular component, biological process, and the signaling pathway of the differential proteins.
4. Western blotting was used to corroborate the proteomic results.
Results:
1.7 in 13 syndrome factors including qi deficiency,blood stasis,turbid phlegm,yin deficiency,cold coagulation,yang deficiency,qi stagnation which have been most researched are involved in about 134 physical and chemical indexes mentioned in the literature.The top 10 physical and chemical indicators of each syndrome factors were obtained after analysis calculation.Echocardiography is the most relevant indicator of Qi deficiency,and hemorheology and blood stasis has the highest correlation.
2.Compared to sham operation group,the respiratory rate in the peaceful state was slower,but faster post stress,and the cardiac function of rats is significant decreased in model group during the period from 4th day to 60th day.The exhaustive swimming time is much shorter,and both color and hemorheology indexes showed significant differences between the two groups during the period from 7th day to 28th after operation.LARS showed that there was significant correlation between color indexes and results of hematocrit and platelet aggregation rate.
All the results shows that the myocardial infarction rats induced by LAD ligation have Qi-deficiency indications,can be diagnosed as the syndrome of Qi-deficiency at 4th day；have both Qi-deficiency and Blood stasis during the period of 7th day to 28th day after operation, can be diagnosed as Qi-deficiency and Blood stasis syndrome；and only have Qi-deficiency indications,can be diagnosed as Qi-deficiency syndrome during the period of 45th day to 60th day,after operation.
3.HE staining and myocardium in situ cell death detection showed that myocardial necrosis is the major pathological change in the infarct area at different time points after myocardial infarction, and infarct border zone in left ventricular showed a series of pathological changes as inflammatory cell infiltration,apoptosis,and cell hypertrophy.
4.The myocardium proteome analysis showed that samples were identified in 8 groups of 526 proteins.Among which 467 proteins in the four time points were identified.45 different proteins may be asso-iated with"Qi deficiency-Qi deficiency and Blood stasis-Qi deficiency" evolution-related.The Fuzzy clustering,GO functional annotation,and KEGG cell signaling pathway annotation showed these proteins include cytoskeletal proteins, metabolic enzymes,oxidative stress related proteins and ion channel protein.They might play important roles in maintain cell structure,increase cardiac contractility,regulate intracellular energy metabolism,induce apoptosis and intracellular signal transduction.
5.The dynamic changes of the expression of actin, alphaB crystallin, L-lactate dehydrogenase,and heat shock protein 8 which was tested by the Western blotting assay was concordant with the label-free quantitative proteomic results.
Conclusion:
1.The rats underwent acute myocardial infarction caused by the left coronary artery ligation showed different syndromes in different stages after operation.The animal model can be used in the biological basis research and Pharmacological studies of Chinese medicine on Qi deficiency syndrome or Qi deficiency and blood stasis syndrome in the myocardial ischemia caused by coronary artery disease.
2. Myocardial proteins results reflected the progress of the disease and myocardial ischemia syndrome evolution. The dynamic changes of cardiac proteins related to the syndromes dynamic evolution in myocardial ischemic disease.
建立稳定、可重复并能用于中药药效评价的心肌缺血大鼠病证结合动物模型,并应用非标记定量蛋白质组学研究策略对病证结合模型动物证候生物标志分子进行研究。
通过心肌缺血气虚血瘀证证候特征性蛋白质或蛋白质群的发现,探究“气虚-气虚血瘀-气虚”证候及证候转化过程中,心肌蛋白质表达的变化规律,为心肌缺血气虚血瘀证证候的生物学基础研究提供新的证据；为疾病证候的诊断提供新的标志物；为对证治疗提供新的靶标。
通过对心肌缺血病证结合模型动物心肌蛋白质组的动态检测、鉴定和后续的生物信息学处理,将检出的蛋白质根据功能和表达水平发生改变的时间进行分类,为中药对证治疗策略的形成和治疗靶点的确定提供依据。
方法：
1.采用基于Shannon熵互信息的方法对证候相关理化指标进行文献研究,筛选出与缺血性心脏病证候关系最为密切的理化指标；
2.采用左冠状动脉结扎法造成大鼠急性心肌缺血动物模型,运用病证结合的思路,对术后4、7、14、21、28、45、60d模型组和假手术组动物的宏观指标进行全面采集的同时进行理化指标跟踪检测,将宏观指标与理化指标相结合,对不同时间点模型动物的证候属性进行判定；
3.根据各时间点模型动物心肌组织HE染色和细胞凋亡检测结果选择进行蛋白质组检测的目的心肌组织；
4.采用非标记定量蛋白质组策略对术后4、14、28、45d,即两个气虚证时间点和两个气虚血瘀证时间点的模型组左心室梗死边缘区和假手术组左心室心肌样品进行蛋白质组分析检测；通过GO注释和KEGG信号通路注释对差异蛋白质进行生物学过程、细胞成分、分子功能分类和细胞信号通路注释,对差异蛋白的证候相关性进行初步阐释；
5.采用Western-blot法对部分差异蛋白的动态表达情况进行验证。
结果：
1.现有文献中,有相关理化指标研究的证候要素包括气虚、血瘀、痰浊、阴虚、寒凝、阳虚、气滞等7个,涉及理化指标134个。其中,与气虚证最相关的理化指标为超声心动,血液流变学指标与血瘀证相关系数最高。
2.术后4d,模型组大鼠被毛竖立,懒动,易激惹；与同时间点假手术组大鼠比较,安静状态下呼吸频率明显减慢,应激后呼吸频率显著增快,左心室射血分数显著降低,左室短轴缩短率降低,舌、耳廓、足底色度以及血液流变学指标无显著差异。术后7-28d,模型组大鼠被毛无光泽,活动度明显减低,对外界刺激反应迟钝；与假手术组大鼠比较,模型组大鼠安静状态下呼吸频率明显减慢,应激后呼吸频率显著增快,游泳力竭时间明显缩短,左心室射血分数和左室短轴缩短率均显著降低,舌、耳廓、足底色度值及血液流变学指标与假手术组大鼠相比存在显著差异；术后45-60d,模型组大鼠被毛无光泽,活动度明显降低,对外界刺激反应逐渐迟钝,挣扎无力；与假手术组比较安静状态下呼吸频率明显减慢,应激后呼吸频率显著增快,左心室射血分数和左室短轴缩短率进一步降低,舌、耳廓、足底色度值及血液流变学指标与假手术组大鼠相比无显著差异。
结合临床气虚血瘀证诊断标准,对左冠结扎术后不同时间点模型动物证候属性进行判定,术后4d为气虚证,术后7-28d为气虚血瘀证,术后45-60d为气虚证。Lars回归显示动物各部位色度改变与红细胞压积和血小板聚集率改变有关。
3.心肌组织HE染色和原位细胞凋亡检测可见,术后各时间,点模型组大鼠心肌梗死区以心肌坏死为主要改变,左心室梗死边缘区表现为炎细胞浸润、细胞凋亡、细胞肥大等一系列病理改变。
4.对术后4个时间点模型组大鼠左心室梗死边缘区和同时间点假手术组大鼠左心室心肌进行非标记定量蛋白质组分析检测结果为,在8组样品中共鉴定到526个蛋白。其中467个蛋白在4个时间点均被鉴定到。以蛋白表达量比值0.8～1.2作为阈值对4个时间点的蛋白进行筛选,得到45个差异蛋白可能与“气虚证-气虚血瘀证-气虚证”演变过程相关。通过GO功能注释、模糊聚类和KEGG细胞信号通路注释发现,差异蛋白质主要包括细胞骨架蛋白、代谢相关酶类、氧化应激相关蛋白和物质转运相关蛋白。这些蛋白质在维持细胞结构,增强心肌收缩力、调节细胞能量代谢、诱导细胞凋亡以及细胞内信号转导等方面发挥着重要的作用。
5.经Western-blot法对肌动蛋白、alphaB晶体蛋白、L-乳酸脱氢酶、热休克蛋白8表达的动态变化验证结果与蛋白质组检测分析结果基本一致。
结论：
1.通过左冠状动脉结扎法造成的大鼠急性心肌缺血模型动物在术后不同时间段内表现为不同的证候。该模型能够应用于冠状动脉病变导致的心肌缺血气虚证和气虚血瘀证的生物学基础和中药药理研究。
2.心肌蛋白质组检测结果能够反映心肌缺血疾病的进展和证候演进情况,心肌蛋白质组动态变化与心肌缺血疾病证候的动态演变相关。
Objective:To establish a stable and repeatable disease and syndrome combination animal model on myocardial infarction rats, and to quest the biomarkers through the application of label free quantitative proteomics strategy.
To inquiry the variation of protein expression during the syndrome and syndrome transformation of "Qi deficiency-Qi deficiency and Blood stasis-Qi deficiency", in order to provide the new proof for the biological basis, the new biomarkers, and the new therapeutic target for the syndrome of Qi deficiency and Blood stasis after acute myocardial infarction.
To check against the formation and to provide the basis to the determination of therapeutic targets of Chinese medicine, which based on the proteins cluster according to the expression changes resulted from the detection, identification, and the analysis by the bioinformatics technology on the myocardium proteomics of the model animals.
Methods:
1. The Data mining technology based on the Shannon entropy mutual information were。used to analysis the complicated correlations of the statistical distribution of coronary heart disease syndromes associated physical and chemical indexes.
2. SD rats were subjected to either proximal LAD ligation or sham operation.20 rats (10 in each group) were subjected to forced swimming test (FST) to measure the exhaustive swimming time in every time point. Echocardiography was used to evaluate the cardiac function in rats at each time point, and the respiratory rate in both peaceful state and post-stress were counted. After the images of ear concha, foot plant and facies lingualis were took, the color indexes were analyzed by Photoshop software, and the hemorheology were measured at the same time. LARS was subjected to calculate the correlation between the color and hemorheology.
3. Label-free nanoscale LC-MS quantitative proteomics was applied in this study to inquiry the variation of protein expression during the syndrome and syndrome transformation of "Qi deficiency-Qi deficiency and Blood stasis-Qi deficiency" on the myocardium of myocardial infarction model animals at 4th,14th,28th,45th after operation. Fuzzy Clustering, GOslimviewer, and KEGG signaling pathway was used to do the annotation of time course expression, molecular function, cellular component, biological process, and the signaling pathway of the differential proteins.
4. Western blotting was used to corroborate the proteomic results.
Results:
1.7 in 13 syndrome factors including qi deficiency,blood stasis,turbid phlegm,yin deficiency,cold coagulation,yang deficiency,qi stagnation which have been most researched are involved in about 134 physical and chemical indexes mentioned in the literature.The top 10 physical and chemical indicators of each syndrome factors were obtained after analysis calculation.Echocardiography is the most relevant indicator of Qi deficiency,and hemorheology and blood stasis has the highest correlation.
2.Compared to sham operation group,the respiratory rate in the peaceful state was slower,but faster post stress,and the cardiac function of rats is significant decreased in model group during the period from 4th day to 60th day.The exhaustive swimming time is much shorter,and both color and hemorheology indexes showed significant differences between the two groups during the period from 7th day to 28th after operation.LARS showed that there was significant correlation between color indexes and results of hematocrit and platelet aggregation rate.
All the results shows that the myocardial infarction rats induced by LAD ligation have Qi-deficiency indications,can be diagnosed as the syndrome of Qi-deficiency at 4th day；have both Qi-deficiency and Blood stasis during the period of 7th day to 28th day after operation, can be diagnosed as Qi-deficiency and Blood stasis syndrome；and only have Qi-deficiency indications,can be diagnosed as Qi-deficiency syndrome during the period of 45th day to 60th day,after operation.
3.HE staining and myocardium in situ cell death detection showed that myocardial necrosis is the major pathological change in the infarct area at different time points after myocardial infarction, and infarct border zone in left ventricular showed a series of pathological changes as inflammatory cell infiltration,apoptosis,and cell hypertrophy.
4.The myocardium proteome analysis showed that samples were identified in 8 groups of 526 proteins.Among which 467 proteins in the four time points were identified.45 different proteins may be asso-iated with"Qi deficiency-Qi deficiency and Blood stasis-Qi deficiency" evolution-related.The Fuzzy clustering,GO functional annotation,and KEGG cell signaling pathway annotation showed these proteins include cytoskeletal proteins, metabolic enzymes,oxidative stress related proteins and ion channel protein.They might play important roles in maintain cell structure,increase cardiac contractility,regulate intracellular energy metabolism,induce apoptosis and intracellular signal transduction.
5.The dynamic changes of the expression of actin, alphaB crystallin, L-lactate dehydrogenase,and heat shock protein 8 which was tested by the Western blotting assay was concordant with the label-free quantitative proteomic results.
Conclusion:
1.The rats underwent acute myocardial infarction caused by the left coronary artery ligation showed different syndromes in different stages after operation.The animal model can be used in the biological basis research and Pharmacological studies of Chinese medicine on Qi deficiency syndrome or Qi deficiency and blood stasis syndrome in the myocardial ischemia caused by coronary artery disease.
2. Myocardial proteins results reflected the progress of the disease and myocardial ischemia syndrome evolution. The dynamic changes of cardiac proteins related to the syndromes dynamic evolution in myocardial ischemic disease.
引文
[1]McGregor E, Dunn MJ. Proteomics of the heart:unraveling disease. Circ Res.2006.98(3):309-21.
[2]Neuhoff V, Stamm R, Pardowitz I, Arold N, Ehrhardt W, Taube D. Essential problems in quantification of proteins following colloidal staining with coomassie brilliant blue dyes in polyacrylamide gels, and their solution. Electrophoresis.1990.11(2):101-17.
[3]Lilley KS, Friedman DB. All about DIGE:quantification technology for differential-display 2D-gel proteomics. Expert Rev Proteomics.2004.1(4):401-9.
[4]Martin K, Steinberg TH, Goodman T, et al. Strategies and solid-phase formats for the analysis of protein and peptide phosphorylation employing a novel fluorescent phosphorylation sensor dye. Comb Chem High Throughput Screen. 2003.6(4):331-9.
[5]Steinberg TH, Pretty OTK, Berggren KN, et al. Rapid and simple single nanogram detection of glycoproteins in polyacrylamide gels and on electroblots. Proteomics.2001.1(7):841-55.
[6]于雁灵.比较蛋白质组定量分析及其在疾病研究中的应用.复旦大学博士论文.2004：8-15.
[7]Chen CY, Lee BC, Hsu HC, et al. A proteomic study of the effects of ramipril on post-infarction left ventricular remodelling in the rabbit. Eur J Heart Fail.2008.10(8):740-8.
[8]Cieniewski-Bernard C, Mulder P, Henry JP, et al. Proteomic analysis of left ventricular remodeling in an experimental model of heart failure. J Proteome Res.2008.7(11):5004-16.
[9]Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science.2008.321(5895):1493-5.
[10]Ping P. Getting to the heart of proteomics. N Engl J Med.2009.360(5):532-4.
[11]Gu J, Wang Y, Li J, Wang J, Jin T. Proteomic analysis of left ventricular tissues following intermittent myocardial ischemia during coronary collateralization in rabbits. Int J Cardiol.2009.131(3):326-35.
[12]Julka S, Regnier FE. Recent advancements in differential proteomics based on stable isotope coding. Brief Funct Genomic Proteomic.2005.4(2):158-77.
[13]Kruger M, Moser M, Ussar S, et al. SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function. Cell.2008.134(2):353-64.
[14]Flory MR, Griffin TJ, Martin D, Aebersold R. Advances in quantitative proteomics using stable isotope tags. Trends Biotechnol.2002.20(12 Suppl):S23-9.
[15]Ross PL, Huang YN, Marchese JN, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics.2004.3(12):1154-69.
[16]Hagglund P, Bunkenborg J, Maeda K, Svensson B. Identification of thioredoxin disulfide targets using a quantitative proteomics approach based on isotope-coded affinity tags. J Proteome Res.2008.7(12):5270-6.
[17]Fu C, Hu J, Liu T, Ago T, Sadoshima J, Li H. Quantitative analysis of redox-sensitive proteome with DIGE and ICAT. J Proteome Res.2008.7(9):3789-802.
[18]Zhou H, Ranish JA, Watts JD, Aebersold R. Quantitative proteome analysis by solid-phase isotope tagging and mass spectrometry. Nat Biotechnol.2002.20(5):512-5.
[19]Hansen KC, Schmitt-Ulms G, Chalkley RJ, Hirsch J, Baldwin MA, Burlingame AL. Mass spectrometric analysis of protein mixtures at low levels using cleavable 13C-isotope-coded affinity tag and multidimensional chromatography. Mol Cell Proteomics.2003.2(5):299-314.
[20]Hagglund P, Bunkenborg J, Maeda K, Svensson B. Identification of thioredoxin disulfide targets using a quantitative proteomics approach based on isotope-coded affinity tags. J Proteome Res.2008.7(12):5270-6.
[21]Zhang Y, Wolf-Yadlin A, Ross PL, et al. Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules. Mol Cell Proteomics.2005.4(9): 1240-50.
[22]Hornshoj H, Bendixen E, Conley LN, et al. Transcriptomic and proteomic profiling of two porcine tissues using high-throughput technologies. BMC Genomics.2009.10:30.
[23]Wu WW, Wang G, Baek SJ, Shen RF. Comparative study of three proteomic quantitative methods, DIGE, cICAT, and iTRAQ, using 2D gel-or LC-MALDI TOF/TOF. J Proteome Res.2006.5(3):651-8.
[24]Fu C, Wu C, Liu T, et al. Elucidation of thioredoxin target protein networks in mouse. Mol Cell Proteomics.2009. 8(7):1674-87.
[25]Boja ES, Phillips D, French SA, Harris RA, Balaban RS. Quantitative mitochondrial phosphoproteomics using iTRAQ on an LTQ-Orbitrap with high energy collision dissociation. J Proteome Res.2009.8(10):4665-75.
[26]Wolters DA, Washburn MP,3rd YJR. An automated multidimensional protein identification technology for shotgun proteomics. Anal Chem.2001.73(23):5683-90.
[27]Kislinger T, Gramolini AO, MacLennan DH, Emili A. Multidimensional protein identification technology (MudPIT): technical overview of a profiling method optimized for the comprehensive proteomic investigation of normal and diseased heart tissue. J Am Soc Mass Spectrom.2005.16(8):1207-20.
[28]Bousette N, Kislinger T, Fong V, et al. Large scale characterization and analysis of the murine cardiac proteome. J Proteome Res.2009.8:1887-1901.
[29]Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ. Absolute quantification of proteins by LCMSE:a virtue of parallel MS acquisition. Mol Cell Proteomics.2006.5(1):144-56.
[30]Zhu W, Smith JW, Huang CM. Mass spectrometry-based label-free quantitative proteomics. J Biomed Biotechnol. 2010.2010:840518.
[31]Voyksner RD, Lee H. Investigating the use of an octupole ion guide for ion storage and high-pass mass filtering to improve the quantitative performance of electrospray ion trap mass spectrometry. Rapid Commun Mass Spectrom. 1999.13(14):1427-37.
[32]Chelius D, Bondarenko PV. Quantitative profiling of proteins in complex mixtures using liquid chromatography and mass spectrometry. J Proteome Res.2002.1(4):317-23.
[33]Bondarenko PV, Chelius D, Shaler TA. Identification and relative quantitation of protein mixtures by enzymatic digestion followed by capillary reversed-phase liquid chromatography-tandem mass spectrometry. Anal Chem.2002. 74(18):4741-9.
[34]Liu H, Sadygov RG,3rd YJR. A model for random sampling and estimation of relative protein abundance in shotgun proteomics. Anal Chem.2004.76(14):4193-201.
[35]Florens L, Carozza MJ, Swanson SK, et al. Analyzing chromatin remodeling complexes using shotgun proteomics and normalized spectral abundance factors. Methods.2006.40(4):303-11.
[36]Zhang B, VerBerkmoes NC, Langston MA, Uberbacher E, Hettich RL, Samatova NF. Detecting differential and correlated protein expression in label-free shotgun proteomics. J Proteome Res.2006.5(11):2909-18.
[37]Ishihama Y, Oda Y, Tabata T, et al. Exponentially modified protein abundance index (emPAI) for estimation of absolute protein amount in proteomics by the number of sequenced peptides per protein. Mol Cell Proteomics.2005. 4(9):1265-72.
[38]Lu P, Vogel C, Wang R, Yao X, Marcotte EM. Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nat Biotechnol.2007.25(1):117-24.
[39]Braisted JC, Kuntumalla S, Vogel C, et al. The APEX Quantitative Proteomics Tool:generating protein quantitation estimates from LC-MS/MS proteomics results. BMC Bioinformatics.2008.9:529.
[40]Mueller LN, Brusniak MY, Mani DR, Aebersold R. An assessment of software solutions for the analysis of mass spectrometry based quantitative proteomics data. J Proteome Res.2008.7(1):51-61.
[41]Rajcevic U, Niclou SP, Jimenez CR. Proteomics strategies for target identification and biomarker discovery in cancer. Front Biosci.2009.14:3292-303.
[42]Lengqvist J, Andrade J, Yang Y, Alvelius G, Lewensohn R, Lehtio J. Robustness and accuracy of high speed LC-MS separations for global peptide quantitation and biomarker discovery. J Chromatogr B Analyt Technol Biomed Life Sci. 2009.877(13):1306-16.
[43]Neubert H, Bonnert TP, Rumpel K, Hunt BT, Henle ES, James IT. Label-free detection of differential protein expression by LC/MALDI mass spectrometry. J Proteome Res.2008.7(6):2270-9.
[44]Xu D, Suenaga N, Edelmann MJ, Fridman R, Muschel RJ, Kessler BM. Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approach. Mol Cell Proteomics.2008.7(11):2215-28.
[45]Shen Z, Li P, Ni RJ, et al. Label-free quantitative proteomics analysis of etiolated maize seedling leaves during greening. Mol Cell Proteomics.2009.8(11):2443-60.
[46]Duan X, Young R, Straubinger RM, et al. A straightforward and highly efficient precipitation/on-pellet digestion procedure coupled with a long gradient nano-LC separation and Orbitrap mass spectrometry for label-free expression profiling of the swine heart mitochondrial proteome. J Proteome Res.2009.8(6):2838-50.
[47]Donoghue PM, Hughes C, Vissers JP, Langridge JI, Dunn MJ. Nonionic detergent phase extraction for the proteomic analysis of heart membrane proteins using label-free LC-MS. Proteomics.2008.8(18):3895-905.
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[23]周文武,林玲,陈军,杨进福,周新民,胡建国.冠脉结扎法制做大鼠心肌缺血模型.中国实验动物学报.2004.12(4)：226·230.
[24]刘开宇,田海,孙露,李大为,贾智博,蒋树林,李仁科.标准化大鼠心肌梗死模型的制作.哈尔滨医科大学学报.2007.41(6)：531-534.
[25]陈红霞,高英茂,邴鲁军.急性大鼠心肌梗死实验模型的制备.中国组织化学与细胞化学杂志.2005.14(1)：70-73.
[26]李玉光,丁洽烽,谭学瑞,陈永松,林吉进.长时间慢性心肌缺血实验动物模型的构建技术.中国临床康复.2005.9(23)：42-43,插图23-1.
[27]孙立军,李敬帮,郭庆林,余厚军,张迎光,孟庆江,王志远,黄志兰,贺洪德.闭胸制备犬慢性心肌缺血和梗塞模型.第四军医大学学报.1997.18(1)：51-53.
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[29]王胜洵,于建波,刘东.猪慢性心肌缺血模型的建立.中国胸心血管外科临床杂志.2004.11(1)：76-77.
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[34]施冰,邓晓丽,吴小兵,高炜.直接心肌内注射血管内皮生长因子基因对慢性缺血心肌侧枝循环生成的影响.中国临床保健杂志.2006.9(1)：56-59.
[35]黄盛东,刘晓红,白辰光,袁扬,龚德军,徐志云.重组腺病毒介导的血管生成素改善缺血性心脏病的实验研究.中华老年心脑血管病杂志.2007.9(3)：192-195.
[36]张端珍,盖鲁粤,董蔚,文应峰,范瑞云.猪缺血心肌侧支血管生成研究.军医进修学院学报.2002.23(3)：217-219.
[37]李可,刘卫金,邹利光,戚跃勇,张启川.闭胸式冠状动脉插管法建立犬急性心肌缺血模型.第三军医大学学报.2007.29(16)：1630-1631.
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[39]宁可永,韩玲,王停.介入法致中国小型猪心肌缺血模型在新药研发中应用的初步探讨.中国新药杂志.2007.16(18)：1467-1468.
[40]李连达,张荣利,冯新庆,宁可永,李贻奎,何君.中国小型猪心导管介入冠状动脉栓塞心肌梗塞模型的建立.中药新药与临床药理.2003.14(3)：143-146.
[41]刘建勋,于震,李欣志.疾病模型动物拟临床研究概念的形成及其应用_自体血栓法制备小型猪心肌缺血模型的研究.中药药理与临床.2007.23(5)：207-209.
[42]刘建勋,于震,李欣志,付建华,尚晓泓,史跃,马彦雷.双参宁心胶囊对心导管介入血栓法制备小型猪心肌缺血模型的影响.中国中西医结合杂志.2006.26(8)：728-731.
[43]傅向华,刘晓坤,谷新顺,范卫泽,郝国贞,刘君,姜云发,胡少东,蔚永运,张晶,马宁.经导管法冠脉内微球灌注建立小型猪慢性缺血性心力衰竭模型研究.中华医学杂志.2006.86(16)：1129-1132.
[44]朱汉华,李浪,汪熠,陆永光,赵献明,文伟明.大鼠冠状动脉微栓塞模型的建立.中国微循环.2008.12(6)：380-384.
[45]叶明芳,陈良龙,陈丹,洪华山.大鼠冠状动脉微血栓模型.福建医科大学学报.2003.37(1)：58-59.
[46]李欣志,刘建勋,尚晓泓,付建华.重组纳豆激酶对小型猪冠状动脉血栓的溶解作用.中国药学杂志.2006.41(8)：589-592.
[47]章建粱,章同华,秦永文,郑兴,胡建强,陈建国.清醒猫可控制冠状动脉阻塞模型的建立.第二军医大学学报.1997.18(1)：80-81.
[48]王骏,金挺剑,励建安.免可控性心肌缺血模型的建立.中国康复医学杂志.2005.20(5)：327-328,370.
[49]李洵,王树人,沈学宁,黄宁,何晓嫱.猪可控心肌缺血模型.中国病理生理杂志.1994.10(1)：108-111.
[50]王跃民,臧益民,朱妙章.一种新的在体犬冠状动脉定量缺血模型.心脏杂志.2000.12(1)：20-22.
[51]贾广乐,董培智.对肾上腺素性心肌缺血模型大鼠相关指标的探讨.中国实验动物学报.2005.13(2)：106-109.
[52]高海成,孙波,苗春生,高海梅,任立群.大剂量盐酸异丙肾上腺素诱发大鼠心肌缺血性坏死模型的建立.中国生物制品学杂志.2009.22(3)：288-290,296.
[53]汤东,王英,朱永泽.心肌损伤动物模型的建立及应用.解剖与临床.2004.9(2)：126-127.
[54]粱翠宏,田铧.常用缺血模型研究进展.四川解剖学杂志.2006.14(1)：38-40.
[55]赵静,陈镜合,邵敏.开心胶囊对大鼠垂体后叶素心肌缺血模型的影响.广州中医药大学学报.2000.17(1)：69-71.
[56]王洁,吕吉元,张明升,牛拴成,张轩萍,杨彩红.清醒无拘束大鼠心肌缺血模型的制备.山西医科大学学报.2007.38(5)：398-400.
[57]龙子江,王桐生,吕晓英,方义英.心气虚动物模型的研制.中国中医药科技.2003.10(2)：67-68.
[58]严蓓,啊基业,郝海平,王广基,朱萱萱,查伟斌,刘林生,管恩泽,张颖,顾胜华,黄青,郑媛婷.心血瘀阻与气阴两虚证心肌缺血大鼠模型的代谢组学表征与辨识.中国科学C辑：生命科学.2008.38(12)：1143-1151.
[59]邓冰湘,谭大全,张秋雁,王大安,刘新华,张玉生.血府逐瘀汤对大鼠急性心肌缺血心电图及瘀血模型血液流变性的影响.中医研究.2005.18(1)：17-19.
[60]张明雪,曹洪欣.冠心病心阳虚证动物模型的制作.中国中医基础医学杂志.2002.8(4)：311-315.
[61]谢梦洲,李绍芝,朱文锋,黄献平,余皓.心气虚证小鼠心肌NOANFCGRP和超微结构变化的实验研究.中国中医药科技.2001.8(2)：69-70.
[62]吴齐雁,胡小萍,李德新,李贺,贺威琼,江浪进.心气虚证大鼠循环肾素血管紧张素系统激活与血浆纤溶酶原激活物抑制剂活性变化的实验研究.中国中西医结合杂志.2001.21(5)：367-369.
[63]叶耘,陈世宏,尚正录,尚云.大鼠异丙肾上腺素性心肌缺血模型中医证型反证探讨.实用中医药杂志.2005.2 1(5)：259-260.
[64]李欣志,刘建勋,任建勋,于震,李磊,史跃,马彦雷.痰瘀互结证冠心病小型猪模型的建立.中国中西医结 合杂志.2009.29(3)：228-232.
[65]朱丽红,汪克明,王宗殿,毕伟.冠心病痰瘀互结证动物模型复制方法的研究.广州中医药大学学报.2006.23(4)：346-349.
[66]于成瑶,王硕仁,赵明镜,吕希莹.心梗后心衰_心气虚病证大鼠模型梗塞区能量代谢功能基因差异表达谱的特征研究.中国中医基础医学杂志.2005.11(6)：422-424.
[67]王振涛,王硕仁,赵明镜,李敏,王亚红.心梗后左心衰大鼠心气虚证动物模型的研究.中国中医基础医学杂志.2002.8(4)：308-3]0.
[68]王硕仁,王振涛,赵明镜,李敏.心气虚病证动物模型及其评价体系的构建.中国实验动物学报.2002.10(1)：33-38.
[69]郭淑贞,王伟,刘涛,刘蕾,童元元,许文玉,于永新,赵慧辉,李宏.小型猪冠心病心肌缺血血瘀证模型血液流变学及超声评价.中华中医药学刊.2007.25(4)：702-705.
[1]李治国,肖诚,李平.蛋白质组学是中医药现代化研究的重要工具.世界科学技术-中医药现代化.2007.9(3)：81-85.
[2]李世林.蛋白质组研究_分子水平的辨证论治.中国医药导刊.2008.10(9)：1415-1416.
[3]吴红金,马增春,高月,王升启.蛋白质组学技术对冠心病血瘀证相关蛋白的研究.中西医结合心脑血管病杂志.2005.3(3)：189-191.
[4]宋剑南,刘军莲,房祥忠,胡元会,雷燕,牛晓红,吴刚,陈保生,马雅銮,陈冰,金红.高脂血症和动脉粥样硬化不同痰瘀证候患者血浆蛋白质差异表达谱与脏腑功能的关系.中西医结合学报.2008.6(12)：1233-1237.
[5]谭秦湘,吕志平,钟小兰,张晓刚.肝郁证辨证与相关蛋白关系初步研究.辽宁中医杂志.2006.33(2)：157-158.
[6]熊新贵,梁清华,侯俊良,陈疆,刘爱平,鄢东红,关勇军.高血压脑出血肝阳化风证与肝阳上亢证患者血清蛋白质组学研究.实用预防医学.2007.14(6)：1649-1652.
[7]钟广伟,李炜,罗艳红,陈国林,易振佳,陈泽奇,张臣,彭川曼.平肝潜阳药物对高血压病肝阳上亢证患者淋巴细胞蛋白质表达的影响.中南大学学报(医学版).2008.33(11)：1005-1011.
[8]钟广伟,李炜,罗艳红,陈国林,易振佳,胡建军,张莺,尹耀慧,张乐.平肝潜阳药物对偏头痛肝阳上亢证患者的临床疗效及其对血淋巴细胞蛋白质表达的影响.中西医结合学报.2009.7(1)：25-33.
[9]戴姣,戴幸平,邢之华,李萃,李家邦,蒋荣鑫.清肝利湿汤干预慢性乙肝肝胆湿热证的蛋白质组学分析.世界华人消化杂志.2009.17(4)：362-367.
[10]谢文光,马晓昌,邵宁生,丁勤学,赵馨,刘农乐,魏钰书,王会信,陈可冀.赤芍治疗热毒血瘀证的血清蛋白质组变化的初步研究.中国中西医结合杂志.2005.25(6)：520-524.
[11]钟小兰,吕志平,钱令嘉,刘晓华,谭秦湘,张晓刚.肝郁证模型大鼠血清蛋白质组的差异表达研究.中华中医药杂志.2006.21(7)：399-401.
[12]钟小兰,吕志平,钱令嘉,刘晓华,谭秦湘,张晓刚.束缚所致肝郁证动物模型肝组织蛋白质组的差异表达研究.中医杂志.2006.47(5)：371-373.
[13]孙鹏,张惠云.经前期综合征_PMS_肝气逆证大鼠下丘脑蛋白差异表达.医学研究杂志.2008.37(9)：39-42.
[14]黄素娟,唐红梅,阳爱云,邓干初,李臻琰,李炜,钟广伟,王素娥,李智,周凌燕.快速埋线对偏头痛肝阳上亢证大鼠下丘脑差异蛋白质表达的影响.中国康复.2007.22(6)：376-378.
[15]战丽彬,刘莉,路小光：宫晓洋.脾阴虚证大鼠海马蛋白质组双向凝胶电泳的研究.中华中医药杂志.2009.24(2)：149-152.
[16]苗兰,刘建勋,任建勋,潘映红.气虚血瘀证模型大鼠血清蛋白质组学初步研究.中国实验方剂学杂志.2009.15(9)：42-46.
[17]刘丽丽,马增春,王宇光,秦红霖,谭洪玲,肖成荣,高月.四物汤对环磷酰胺致血虚证小鼠骨髓蛋白质组的影响.中国中药杂志.2006.31(14)：1172-1175.
[18]马增春,高月,谭洪玲,王升启.四物汤对辐射致血虚证小鼠血清蛋白质表达的影响.中国中药杂志.2003.28(11)：1050-1053.
[19]郭平,马增春,李鹰飞,粱乾德,王继峰,王升启.四物汤对放射线致血虚证小鼠骨髓蛋白质表达的影响.中国中药杂志.2004.29(9)：893-896.
[20]李臻琰,李炜,颜永平,王素娥,钟广伟,周凌燕,李智.天麻钩藤饮对高血压肝阳上亢证大鼠下丘脑差异蛋白质表达的影响.中国临床康复.2006.10(47)：58-61.
[21]周凌燕,陈泽奇,李炜,李智,王素娥,钟广伟,颜永平,傅擎宇.天麻钩藤饮对甲亢肝阳上亢证大鼠下丘脑蛋白质表达的影响.湖南中医药大学学报.2007.27(2)：28-31.
[22]李智,李炜,陈泽奇,颜永平,周凌燕,钟广伟,王素娥,王娟.天麻钩藤饮对偏头痛肝阳上亢证大鼠下丘脑蛋白质的影响.中国临床康复.2006.10(47)：45-48.
[23]周凌燕,陈泽奇,李炜,李智,颜永平.甲状腺功能亢进肝阳上亢证大鼠下丘脑组织蛋白质差异表达的观察.中国中医药信息杂志.2007.14(5)：18-20.
[24]王忆勤,李福凤,王文静,赵立宇,郭丽,王惠芳.慢性胃炎中医湿证血清蛋白组学研究.中西医结合学报.2007.5(5)：514-516.
[25]赵慧辉,郭淑贞,侯娜,王伟.差异凝胶电泳技术寻找冠心病心绞痛血瘀证的相关蛋白.中华中医药杂志.2008.23(12)：1050-1053.
[26]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.化学学报.2009.67(2)：167-173.
[27]赵慧辉,侯娜,王伟.荧光标记法分析心绞痛血瘀证的差异蛋白.光谱学与光谱分析.2009.29(6)：1647-1650.
[28]刘蕾,王伟,宋剑南,郭淑贞,马雅銮,陈冰,许文玉.心肌缺血血瘀证小型猪模型差异蛋白质组学研究.中华中医药杂志.2009.24(6)：716-719.
[29]赵慧辉,侯娜,王伟,黄秀兰.冠心病气虚血瘀证的蛋白质组学特征研究.中国中西医结合杂志.2009.29(6)：489-492.
[1]赵慧辉,王伟.病证结合证候模型研究基本思路.中华中医药杂志.2006.21(12)：762-764
[2]苗阳,赵文静,荆鲁,李立志,史大卓.中西医结合治疗慢性心力衰竭的回顾性分析.中国中西医结合杂志.2008.28(5)：406-409
[3]张鹏,徐伟建.中医证型与冠状动脉病变程度的相关性研究.中西医结合心脑血管病杂志.2007.5(2)：101-103
[4]陈建新,西广成,王伟,赵慧辉,陈静.数据挖掘方法在冠心病临床应用的比较.北京生物医学工程.2008.27(3)：249-252
[5]Wei Wang, Huihui Zhao, Jianxin Chen, Jing Chen, Guangcheng Xi. Bridge the gap between syndrome in Traditional Chinese Medicine and proteome in western medicine by unsupervised pattern discovery algorithm,2008 IEEE International Conference on Networking, Sensing and Control:745-750 (IEEE ICNSC'08)
[1]仇琪,郭淑贞,陈建新,赵慧辉,刘蕾,陈婵,王娟,王伟.基于Shannon熵互信息的冠心病证侯相关理化指标文献研究.中华中医药杂志.2009.24(10)：1284-1287
[2]陈奇.中药药理研究方法,第二版.北京：人民卫生出版社,2006.507-513.
[3]沈自尹.中医虚证辨证参考标准.中国中西医结合杂志.1986.6(10)：598.
[4]闫永红,沈嫱,何怀阳.试述用超声心动图来指导心衰中医辩证分型的探讨.中国临床医药研究杂志.2004.(130)：13909-13910.
[5]方肇勤,潘志强,卢文丽,刘小美,侯俐,廖明娟.大鼠、小鼠常见证侯计量化辨证方法的建立及其评价.中国中医基础医学杂志.2007.13(7)：502-505.
[6]翁维良,黄世敬,洪尚杓.运用“中医舌诊专家系统”对血瘀证舌质的研究.中国中医基础医学杂志.2000.6(10)：58-61.
[7]Bradley Efron, Trevor Hastie, Iain Johnstone. Least angle regression[J].The Annals of Statistics.2004.32(2): 407-451.
[8]中国中西医结合研究会活血化瘀专业委员会.血瘀证诊断标准.中西医结合杂志.1987.(3)：129
[9]卢良威.略论“心气内虚”及“气虚血癖”的病机.浙江中医学院学报.1978.4(4)：12-14.
[10]王晓才农一兵林谦宋麦芬.138例冠心病患者的证侯分布与组合特点分析.中医杂志.2008.49(1)：62-63,66
[11]李南夷,邓铁涛,文旺秀.心衰证治研究概述.中医信息杂志.1995.(5)：6-10
[1]Shen Z, Li P, Ni RJ, et al. Label-free quantitative proteomics analysis of etiolated maize seedling leaves during greening. Mol Cell Proteomics.2009.8(11):2443-60.
[2]America AH, Cordewener JH, van GMH, et al. Alignment and statistical difference analysis of complex peptide data sets generated by multidimensional LC-MS. Proteomics.2006.6(2):641-53.
[3]Silva JC, Denny R, Dorschel CA, et al. Quantitative proteomic analysis by accurate mass retention time pairs. Anal Chem.2005.77(7):2187-200.
[4]Silva JC, Denny R, Dorschel C, et al. Simultaneous qualitative and quantitative analysis of the Escherichia coli proteome:a sweet tale. Mol Cell Proteomics.2006.5(4):589-607.
[5]Hughes MA, Silva JC, Geromanos SJ, Townsend CA. Quantitative proteomic analysis of drug-induced changes in mycobacteria. J Proteome Res.2006.5(1):54-63.
[6]Roy SM, Becker CH. Quantification of proteins and metabolites by mass spectrometry without isotopic labeling. Methods Mol Biol.2007.359:87-105.
[7]Wang W, Zhou H, Lin H, et al. Quantification of proteins and metabolites by mass spectrometry without isotopic labeling or spiked standards. Anal Chem.2003.75(18):4818-26.
[8]Washburn MP, Wolters D,3rd YJR. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol.2001.19(3):242-7.
[9]Li GZ, Vissers JP, Silva JC, Golick D, Gorenstein MV, Geromanos SJ. Database searching and accounting of multiplexed precursor and product ion spectra from the data independent analysis of simple and complex peptide mixtures. Proteomics.2009.9(6):1696-719.
[10]Silva JC, Denny R, Dorschel CA, et al. Quantitative proteomic analysis by accurate mass retention time pairs. Anal Chem.2005.77(7):2187-200.
[11]Gu J, Wang Y, Li J, Wang J, Jin T. Proteomic analysis of left ventricular tissues following intermittent myocardial ischemia during coronary collateralization in rabbits. Int J Cardiol.2009.131(3):326-35.
[12]Chen CY, Lee BC, Hsu HC, et al. A proteomic study of the effects of ramipril on post-infarction left ventricular remodelling in the rabbit. Eur J Heart Fail.2008.10(8):740-8.
[13]Cieniewski-Bernard C, Mulder P, Henry JP, et al. Proteomic analysis of left ventricular remodeling in an experimental model of heart failure. J Proteome Res.2008.7(11):5004-16.
[14]吴红金,马增春,高月,王升启.蛋白质组学技术对冠心病血瘀证相关蛋白的研究.中西医结合心脑血管病杂志.2005.3(3)：189-191.
[15]赵慧辉,郭淑贞,侯娜,王伟.差异凝胶电泳技术寻找冠心病心绞痛血瘀证的相关蛋白.中华中医药杂志.2008.23(12)：1050-1053.
[16]赵慧辉,侯娜,王伟,黄秀兰.冠心病气虚血瘀证的蛋白质组学特征研究.中国中西医结合杂志.2009.29(6)：489-492.
[17]苗兰,刘建勋,任建勋,潘映红.气虚血瘀证模型大鼠血清蛋白质组学初步研究.中国实验方剂学杂志.2009.15(9)：42-46.
[18]刘蕾,王伟,宋剑南,郭淑贞,马雅銮,陈冰,许文玉.心肌缺血血瘀证小型猪模型差异蛋白质组学研究.中华中医药杂志.2009.24(6)：716-719.
[19]刘涛.气虚血瘀证(心肌缺血)大鼠心肌蛋白质组学的实验研究.北京中医药大学博士论文.2007：87：66.
[20]Sam F, Sawyer DB, Chang DL, et al. Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol Heart Circ Physiol.2000.279(1):H422-8.
[21]Laksanalamai P, Robb FT. Small heat shock proteins from extremophiles:a review. Extremophiles.2004.8(1):1-11.
[2]Neuhoff V, Stamm R, Pardowitz I, Arold N, Ehrhardt W, Taube D. Essential problems in quantification of proteins following colloidal staining with coomassie brilliant blue dyes in polyacrylamide gels, and their solution. Electrophoresis.1990.11(2):101-17.
[3]Lilley KS, Friedman DB. All about DIGE:quantification technology for differential-display 2D-gel proteomics. Expert Rev Proteomics.2004.1(4):401-9.
[4]Martin K, Steinberg TH, Goodman T, et al. Strategies and solid-phase formats for the analysis of protein and peptide phosphorylation employing a novel fluorescent phosphorylation sensor dye. Comb Chem High Throughput Screen. 2003.6(4):331-9.
[5]Steinberg TH, Pretty OTK, Berggren KN, et al. Rapid and simple single nanogram detection of glycoproteins in polyacrylamide gels and on electroblots. Proteomics.2001.1(7):841-55.
[6]于雁灵.比较蛋白质组定量分析及其在疾病研究中的应用.复旦大学博士论文.2004：8-15.
[7]Chen CY, Lee BC, Hsu HC, et al. A proteomic study of the effects of ramipril on post-infarction left ventricular remodelling in the rabbit. Eur J Heart Fail.2008.10(8):740-8.
[8]Cieniewski-Bernard C, Mulder P, Henry JP, et al. Proteomic analysis of left ventricular remodeling in an experimental model of heart failure. J Proteome Res.2008.7(11):5004-16.
[9]Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science.2008.321(5895):1493-5.
[10]Ping P. Getting to the heart of proteomics. N Engl J Med.2009.360(5):532-4.
[11]Gu J, Wang Y, Li J, Wang J, Jin T. Proteomic analysis of left ventricular tissues following intermittent myocardial ischemia during coronary collateralization in rabbits. Int J Cardiol.2009.131(3):326-35.
[12]Julka S, Regnier FE. Recent advancements in differential proteomics based on stable isotope coding. Brief Funct Genomic Proteomic.2005.4(2):158-77.
[13]Kruger M, Moser M, Ussar S, et al. SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function. Cell.2008.134(2):353-64.
[14]Flory MR, Griffin TJ, Martin D, Aebersold R. Advances in quantitative proteomics using stable isotope tags. Trends Biotechnol.2002.20(12 Suppl):S23-9.
[15]Ross PL, Huang YN, Marchese JN, et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics.2004.3(12):1154-69.
[16]Hagglund P, Bunkenborg J, Maeda K, Svensson B. Identification of thioredoxin disulfide targets using a quantitative proteomics approach based on isotope-coded affinity tags. J Proteome Res.2008.7(12):5270-6.
[17]Fu C, Hu J, Liu T, Ago T, Sadoshima J, Li H. Quantitative analysis of redox-sensitive proteome with DIGE and ICAT. J Proteome Res.2008.7(9):3789-802.
[18]Zhou H, Ranish JA, Watts JD, Aebersold R. Quantitative proteome analysis by solid-phase isotope tagging and mass spectrometry. Nat Biotechnol.2002.20(5):512-5.
[19]Hansen KC, Schmitt-Ulms G, Chalkley RJ, Hirsch J, Baldwin MA, Burlingame AL. Mass spectrometric analysis of protein mixtures at low levels using cleavable 13C-isotope-coded affinity tag and multidimensional chromatography. Mol Cell Proteomics.2003.2(5):299-314.
[20]Hagglund P, Bunkenborg J, Maeda K, Svensson B. Identification of thioredoxin disulfide targets using a quantitative proteomics approach based on isotope-coded affinity tags. J Proteome Res.2008.7(12):5270-6.
[21]Zhang Y, Wolf-Yadlin A, Ross PL, et al. Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules. Mol Cell Proteomics.2005.4(9): 1240-50.
[22]Hornshoj H, Bendixen E, Conley LN, et al. Transcriptomic and proteomic profiling of two porcine tissues using high-throughput technologies. BMC Genomics.2009.10:30.
[23]Wu WW, Wang G, Baek SJ, Shen RF. Comparative study of three proteomic quantitative methods, DIGE, cICAT, and iTRAQ, using 2D gel-or LC-MALDI TOF/TOF. J Proteome Res.2006.5(3):651-8.
[24]Fu C, Wu C, Liu T, et al. Elucidation of thioredoxin target protein networks in mouse. Mol Cell Proteomics.2009. 8(7):1674-87.
[25]Boja ES, Phillips D, French SA, Harris RA, Balaban RS. Quantitative mitochondrial phosphoproteomics using iTRAQ on an LTQ-Orbitrap with high energy collision dissociation. J Proteome Res.2009.8(10):4665-75.
[26]Wolters DA, Washburn MP,3rd YJR. An automated multidimensional protein identification technology for shotgun proteomics. Anal Chem.2001.73(23):5683-90.
[27]Kislinger T, Gramolini AO, MacLennan DH, Emili A. Multidimensional protein identification technology (MudPIT): technical overview of a profiling method optimized for the comprehensive proteomic investigation of normal and diseased heart tissue. J Am Soc Mass Spectrom.2005.16(8):1207-20.
[28]Bousette N, Kislinger T, Fong V, et al. Large scale characterization and analysis of the murine cardiac proteome. J Proteome Res.2009.8:1887-1901.
[29]Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ. Absolute quantification of proteins by LCMSE:a virtue of parallel MS acquisition. Mol Cell Proteomics.2006.5(1):144-56.
[30]Zhu W, Smith JW, Huang CM. Mass spectrometry-based label-free quantitative proteomics. J Biomed Biotechnol. 2010.2010:840518.
[31]Voyksner RD, Lee H. Investigating the use of an octupole ion guide for ion storage and high-pass mass filtering to improve the quantitative performance of electrospray ion trap mass spectrometry. Rapid Commun Mass Spectrom. 1999.13(14):1427-37.
[32]Chelius D, Bondarenko PV. Quantitative profiling of proteins in complex mixtures using liquid chromatography and mass spectrometry. J Proteome Res.2002.1(4):317-23.
[33]Bondarenko PV, Chelius D, Shaler TA. Identification and relative quantitation of protein mixtures by enzymatic digestion followed by capillary reversed-phase liquid chromatography-tandem mass spectrometry. Anal Chem.2002. 74(18):4741-9.
[34]Liu H, Sadygov RG,3rd YJR. A model for random sampling and estimation of relative protein abundance in shotgun proteomics. Anal Chem.2004.76(14):4193-201.
[35]Florens L, Carozza MJ, Swanson SK, et al. Analyzing chromatin remodeling complexes using shotgun proteomics and normalized spectral abundance factors. Methods.2006.40(4):303-11.
[36]Zhang B, VerBerkmoes NC, Langston MA, Uberbacher E, Hettich RL, Samatova NF. Detecting differential and correlated protein expression in label-free shotgun proteomics. J Proteome Res.2006.5(11):2909-18.
[37]Ishihama Y, Oda Y, Tabata T, et al. Exponentially modified protein abundance index (emPAI) for estimation of absolute protein amount in proteomics by the number of sequenced peptides per protein. Mol Cell Proteomics.2005. 4(9):1265-72.
[38]Lu P, Vogel C, Wang R, Yao X, Marcotte EM. Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nat Biotechnol.2007.25(1):117-24.
[39]Braisted JC, Kuntumalla S, Vogel C, et al. The APEX Quantitative Proteomics Tool:generating protein quantitation estimates from LC-MS/MS proteomics results. BMC Bioinformatics.2008.9:529.
[40]Mueller LN, Brusniak MY, Mani DR, Aebersold R. An assessment of software solutions for the analysis of mass spectrometry based quantitative proteomics data. J Proteome Res.2008.7(1):51-61.
[41]Rajcevic U, Niclou SP, Jimenez CR. Proteomics strategies for target identification and biomarker discovery in cancer. Front Biosci.2009.14:3292-303.
[42]Lengqvist J, Andrade J, Yang Y, Alvelius G, Lewensohn R, Lehtio J. Robustness and accuracy of high speed LC-MS separations for global peptide quantitation and biomarker discovery. J Chromatogr B Analyt Technol Biomed Life Sci. 2009.877(13):1306-16.
[43]Neubert H, Bonnert TP, Rumpel K, Hunt BT, Henle ES, James IT. Label-free detection of differential protein expression by LC/MALDI mass spectrometry. J Proteome Res.2008.7(6):2270-9.
[44]Xu D, Suenaga N, Edelmann MJ, Fridman R, Muschel RJ, Kessler BM. Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approach. Mol Cell Proteomics.2008.7(11):2215-28.
[45]Shen Z, Li P, Ni RJ, et al. Label-free quantitative proteomics analysis of etiolated maize seedling leaves during greening. Mol Cell Proteomics.2009.8(11):2443-60.
[46]Duan X, Young R, Straubinger RM, et al. A straightforward and highly efficient precipitation/on-pellet digestion procedure coupled with a long gradient nano-LC separation and Orbitrap mass spectrometry for label-free expression profiling of the swine heart mitochondrial proteome. J Proteome Res.2009.8(6):2838-50.
[47]Donoghue PM, Hughes C, Vissers JP, Langridge JI, Dunn MJ. Nonionic detergent phase extraction for the proteomic analysis of heart membrane proteins using label-free LC-MS. Proteomics.2008.8(18):3895-905.
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[23]周文武,林玲,陈军,杨进福,周新民,胡建国.冠脉结扎法制做大鼠心肌缺血模型.中国实验动物学报.2004.12(4)：226·230.
[24]刘开宇,田海,孙露,李大为,贾智博,蒋树林,李仁科.标准化大鼠心肌梗死模型的制作.哈尔滨医科大学学报.2007.41(6)：531-534.
[25]陈红霞,高英茂,邴鲁军.急性大鼠心肌梗死实验模型的制备.中国组织化学与细胞化学杂志.2005.14(1)：70-73.
[26]李玉光,丁洽烽,谭学瑞,陈永松,林吉进.长时间慢性心肌缺血实验动物模型的构建技术.中国临床康复.2005.9(23)：42-43,插图23-1.
[27]孙立军,李敬帮,郭庆林,余厚军,张迎光,孟庆江,王志远,黄志兰,贺洪德.闭胸制备犬慢性心肌缺血和梗塞模型.第四军医大学学报.1997.18(1)：51-53.
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[30]李元涛,王芳,刘菊英,王祟全.猪慢性心肌缺血模型的制作.郧阳医学院学报.2002.21(6)：368-369.
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[34]施冰,邓晓丽,吴小兵,高炜.直接心肌内注射血管内皮生长因子基因对慢性缺血心肌侧枝循环生成的影响.中国临床保健杂志.2006.9(1)：56-59.
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[36]张端珍,盖鲁粤,董蔚,文应峰,范瑞云.猪缺血心肌侧支血管生成研究.军医进修学院学报.2002.23(3)：217-219.
[37]李可,刘卫金,邹利光,戚跃勇,张启川.闭胸式冠状动脉插管法建立犬急性心肌缺血模型.第三军医大学学报.2007.29(16)：1630-1631.
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[39]宁可永,韩玲,王停.介入法致中国小型猪心肌缺血模型在新药研发中应用的初步探讨.中国新药杂志.2007.16(18)：1467-1468.
[40]李连达,张荣利,冯新庆,宁可永,李贻奎,何君.中国小型猪心导管介入冠状动脉栓塞心肌梗塞模型的建立.中药新药与临床药理.2003.14(3)：143-146.
[41]刘建勋,于震,李欣志.疾病模型动物拟临床研究概念的形成及其应用_自体血栓法制备小型猪心肌缺血模型的研究.中药药理与临床.2007.23(5)：207-209.
[42]刘建勋,于震,李欣志,付建华,尚晓泓,史跃,马彦雷.双参宁心胶囊对心导管介入血栓法制备小型猪心肌缺血模型的影响.中国中西医结合杂志.2006.26(8)：728-731.
[43]傅向华,刘晓坤,谷新顺,范卫泽,郝国贞,刘君,姜云发,胡少东,蔚永运,张晶,马宁.经导管法冠脉内微球灌注建立小型猪慢性缺血性心力衰竭模型研究.中华医学杂志.2006.86(16)：1129-1132.
[44]朱汉华,李浪,汪熠,陆永光,赵献明,文伟明.大鼠冠状动脉微栓塞模型的建立.中国微循环.2008.12(6)：380-384.
[45]叶明芳,陈良龙,陈丹,洪华山.大鼠冠状动脉微血栓模型.福建医科大学学报.2003.37(1)：58-59.
[46]李欣志,刘建勋,尚晓泓,付建华.重组纳豆激酶对小型猪冠状动脉血栓的溶解作用.中国药学杂志.2006.41(8)：589-592.
[47]章建粱,章同华,秦永文,郑兴,胡建强,陈建国.清醒猫可控制冠状动脉阻塞模型的建立.第二军医大学学报.1997.18(1)：80-81.
[48]王骏,金挺剑,励建安.免可控性心肌缺血模型的建立.中国康复医学杂志.2005.20(5)：327-328,370.
[49]李洵,王树人,沈学宁,黄宁,何晓嫱.猪可控心肌缺血模型.中国病理生理杂志.1994.10(1)：108-111.
[50]王跃民,臧益民,朱妙章.一种新的在体犬冠状动脉定量缺血模型.心脏杂志.2000.12(1)：20-22.
[51]贾广乐,董培智.对肾上腺素性心肌缺血模型大鼠相关指标的探讨.中国实验动物学报.2005.13(2)：106-109.
[52]高海成,孙波,苗春生,高海梅,任立群.大剂量盐酸异丙肾上腺素诱发大鼠心肌缺血性坏死模型的建立.中国生物制品学杂志.2009.22(3)：288-290,296.
[53]汤东,王英,朱永泽.心肌损伤动物模型的建立及应用.解剖与临床.2004.9(2)：126-127.
[54]粱翠宏,田铧.常用缺血模型研究进展.四川解剖学杂志.2006.14(1)：38-40.
[55]赵静,陈镜合,邵敏.开心胶囊对大鼠垂体后叶素心肌缺血模型的影响.广州中医药大学学报.2000.17(1)：69-71.
[56]王洁,吕吉元,张明升,牛拴成,张轩萍,杨彩红.清醒无拘束大鼠心肌缺血模型的制备.山西医科大学学报.2007.38(5)：398-400.
[57]龙子江,王桐生,吕晓英,方义英.心气虚动物模型的研制.中国中医药科技.2003.10(2)：67-68.
[58]严蓓,啊基业,郝海平,王广基,朱萱萱,查伟斌,刘林生,管恩泽,张颖,顾胜华,黄青,郑媛婷.心血瘀阻与气阴两虚证心肌缺血大鼠模型的代谢组学表征与辨识.中国科学C辑：生命科学.2008.38(12)：1143-1151.
[59]邓冰湘,谭大全,张秋雁,王大安,刘新华,张玉生.血府逐瘀汤对大鼠急性心肌缺血心电图及瘀血模型血液流变性的影响.中医研究.2005.18(1)：17-19.
[60]张明雪,曹洪欣.冠心病心阳虚证动物模型的制作.中国中医基础医学杂志.2002.8(4)：311-315.
[61]谢梦洲,李绍芝,朱文锋,黄献平,余皓.心气虚证小鼠心肌NOANFCGRP和超微结构变化的实验研究.中国中医药科技.2001.8(2)：69-70.
[62]吴齐雁,胡小萍,李德新,李贺,贺威琼,江浪进.心气虚证大鼠循环肾素血管紧张素系统激活与血浆纤溶酶原激活物抑制剂活性变化的实验研究.中国中西医结合杂志.2001.21(5)：367-369.
[63]叶耘,陈世宏,尚正录,尚云.大鼠异丙肾上腺素性心肌缺血模型中医证型反证探讨.实用中医药杂志.2005.2 1(5)：259-260.
[64]李欣志,刘建勋,任建勋,于震,李磊,史跃,马彦雷.痰瘀互结证冠心病小型猪模型的建立.中国中西医结 合杂志.2009.29(3)：228-232.
[65]朱丽红,汪克明,王宗殿,毕伟.冠心病痰瘀互结证动物模型复制方法的研究.广州中医药大学学报.2006.23(4)：346-349.
[66]于成瑶,王硕仁,赵明镜,吕希莹.心梗后心衰_心气虚病证大鼠模型梗塞区能量代谢功能基因差异表达谱的特征研究.中国中医基础医学杂志.2005.11(6)：422-424.
[67]王振涛,王硕仁,赵明镜,李敏,王亚红.心梗后左心衰大鼠心气虚证动物模型的研究.中国中医基础医学杂志.2002.8(4)：308-3]0.
[68]王硕仁,王振涛,赵明镜,李敏.心气虚病证动物模型及其评价体系的构建.中国实验动物学报.2002.10(1)：33-38.
[69]郭淑贞,王伟,刘涛,刘蕾,童元元,许文玉,于永新,赵慧辉,李宏.小型猪冠心病心肌缺血血瘀证模型血液流变学及超声评价.中华中医药学刊.2007.25(4)：702-705.
[1]李治国,肖诚,李平.蛋白质组学是中医药现代化研究的重要工具.世界科学技术-中医药现代化.2007.9(3)：81-85.
[2]李世林.蛋白质组研究_分子水平的辨证论治.中国医药导刊.2008.10(9)：1415-1416.
[3]吴红金,马增春,高月,王升启.蛋白质组学技术对冠心病血瘀证相关蛋白的研究.中西医结合心脑血管病杂志.2005.3(3)：189-191.
[4]宋剑南,刘军莲,房祥忠,胡元会,雷燕,牛晓红,吴刚,陈保生,马雅銮,陈冰,金红.高脂血症和动脉粥样硬化不同痰瘀证候患者血浆蛋白质差异表达谱与脏腑功能的关系.中西医结合学报.2008.6(12)：1233-1237.
[5]谭秦湘,吕志平,钟小兰,张晓刚.肝郁证辨证与相关蛋白关系初步研究.辽宁中医杂志.2006.33(2)：157-158.
[6]熊新贵,梁清华,侯俊良,陈疆,刘爱平,鄢东红,关勇军.高血压脑出血肝阳化风证与肝阳上亢证患者血清蛋白质组学研究.实用预防医学.2007.14(6)：1649-1652.
[7]钟广伟,李炜,罗艳红,陈国林,易振佳,陈泽奇,张臣,彭川曼.平肝潜阳药物对高血压病肝阳上亢证患者淋巴细胞蛋白质表达的影响.中南大学学报(医学版).2008.33(11)：1005-1011.
[8]钟广伟,李炜,罗艳红,陈国林,易振佳,胡建军,张莺,尹耀慧,张乐.平肝潜阳药物对偏头痛肝阳上亢证患者的临床疗效及其对血淋巴细胞蛋白质表达的影响.中西医结合学报.2009.7(1)：25-33.
[9]戴姣,戴幸平,邢之华,李萃,李家邦,蒋荣鑫.清肝利湿汤干预慢性乙肝肝胆湿热证的蛋白质组学分析.世界华人消化杂志.2009.17(4)：362-367.
[10]谢文光,马晓昌,邵宁生,丁勤学,赵馨,刘农乐,魏钰书,王会信,陈可冀.赤芍治疗热毒血瘀证的血清蛋白质组变化的初步研究.中国中西医结合杂志.2005.25(6)：520-524.
[11]钟小兰,吕志平,钱令嘉,刘晓华,谭秦湘,张晓刚.肝郁证模型大鼠血清蛋白质组的差异表达研究.中华中医药杂志.2006.21(7)：399-401.
[12]钟小兰,吕志平,钱令嘉,刘晓华,谭秦湘,张晓刚.束缚所致肝郁证动物模型肝组织蛋白质组的差异表达研究.中医杂志.2006.47(5)：371-373.
[13]孙鹏,张惠云.经前期综合征_PMS_肝气逆证大鼠下丘脑蛋白差异表达.医学研究杂志.2008.37(9)：39-42.
[14]黄素娟,唐红梅,阳爱云,邓干初,李臻琰,李炜,钟广伟,王素娥,李智,周凌燕.快速埋线对偏头痛肝阳上亢证大鼠下丘脑差异蛋白质表达的影响.中国康复.2007.22(6)：376-378.
[15]战丽彬,刘莉,路小光：宫晓洋.脾阴虚证大鼠海马蛋白质组双向凝胶电泳的研究.中华中医药杂志.2009.24(2)：149-152.
[16]苗兰,刘建勋,任建勋,潘映红.气虚血瘀证模型大鼠血清蛋白质组学初步研究.中国实验方剂学杂志.2009.15(9)：42-46.
[17]刘丽丽,马增春,王宇光,秦红霖,谭洪玲,肖成荣,高月.四物汤对环磷酰胺致血虚证小鼠骨髓蛋白质组的影响.中国中药杂志.2006.31(14)：1172-1175.
[18]马增春,高月,谭洪玲,王升启.四物汤对辐射致血虚证小鼠血清蛋白质表达的影响.中国中药杂志.2003.28(11)：1050-1053.
[19]郭平,马增春,李鹰飞,粱乾德,王继峰,王升启.四物汤对放射线致血虚证小鼠骨髓蛋白质表达的影响.中国中药杂志.2004.29(9)：893-896.
[20]李臻琰,李炜,颜永平,王素娥,钟广伟,周凌燕,李智.天麻钩藤饮对高血压肝阳上亢证大鼠下丘脑差异蛋白质表达的影响.中国临床康复.2006.10(47)：58-61.
[21]周凌燕,陈泽奇,李炜,李智,王素娥,钟广伟,颜永平,傅擎宇.天麻钩藤饮对甲亢肝阳上亢证大鼠下丘脑蛋白质表达的影响.湖南中医药大学学报.2007.27(2)：28-31.
[22]李智,李炜,陈泽奇,颜永平,周凌燕,钟广伟,王素娥,王娟.天麻钩藤饮对偏头痛肝阳上亢证大鼠下丘脑蛋白质的影响.中国临床康复.2006.10(47)：45-48.
[23]周凌燕,陈泽奇,李炜,李智,颜永平.甲状腺功能亢进肝阳上亢证大鼠下丘脑组织蛋白质差异表达的观察.中国中医药信息杂志.2007.14(5)：18-20.
[24]王忆勤,李福凤,王文静,赵立宇,郭丽,王惠芳.慢性胃炎中医湿证血清蛋白组学研究.中西医结合学报.2007.5(5)：514-516.
[25]赵慧辉,郭淑贞,侯娜,王伟.差异凝胶电泳技术寻找冠心病心绞痛血瘀证的相关蛋白.中华中医药杂志.2008.23(12)：1050-1053.
[26]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.化学学报.2009.67(2)：167-173.
[27]赵慧辉,侯娜,王伟.荧光标记法分析心绞痛血瘀证的差异蛋白.光谱学与光谱分析.2009.29(6)：1647-1650.
[28]刘蕾,王伟,宋剑南,郭淑贞,马雅銮,陈冰,许文玉.心肌缺血血瘀证小型猪模型差异蛋白质组学研究.中华中医药杂志.2009.24(6)：716-719.
[29]赵慧辉,侯娜,王伟,黄秀兰.冠心病气虚血瘀证的蛋白质组学特征研究.中国中西医结合杂志.2009.29(6)：489-492.
[1]赵慧辉,王伟.病证结合证候模型研究基本思路.中华中医药杂志.2006.21(12)：762-764
[2]苗阳,赵文静,荆鲁,李立志,史大卓.中西医结合治疗慢性心力衰竭的回顾性分析.中国中西医结合杂志.2008.28(5)：406-409
[3]张鹏,徐伟建.中医证型与冠状动脉病变程度的相关性研究.中西医结合心脑血管病杂志.2007.5(2)：101-103
[4]陈建新,西广成,王伟,赵慧辉,陈静.数据挖掘方法在冠心病临床应用的比较.北京生物医学工程.2008.27(3)：249-252
[5]Wei Wang, Huihui Zhao, Jianxin Chen, Jing Chen, Guangcheng Xi. Bridge the gap between syndrome in Traditional Chinese Medicine and proteome in western medicine by unsupervised pattern discovery algorithm,2008 IEEE International Conference on Networking, Sensing and Control:745-750 (IEEE ICNSC'08)
[1]仇琪,郭淑贞,陈建新,赵慧辉,刘蕾,陈婵,王娟,王伟.基于Shannon熵互信息的冠心病证侯相关理化指标文献研究.中华中医药杂志.2009.24(10)：1284-1287
[2]陈奇.中药药理研究方法,第二版.北京：人民卫生出版社,2006.507-513.
[3]沈自尹.中医虚证辨证参考标准.中国中西医结合杂志.1986.6(10)：598.
[4]闫永红,沈嫱,何怀阳.试述用超声心动图来指导心衰中医辩证分型的探讨.中国临床医药研究杂志.2004.(130)：13909-13910.
[5]方肇勤,潘志强,卢文丽,刘小美,侯俐,廖明娟.大鼠、小鼠常见证侯计量化辨证方法的建立及其评价.中国中医基础医学杂志.2007.13(7)：502-505.
[6]翁维良,黄世敬,洪尚杓.运用“中医舌诊专家系统”对血瘀证舌质的研究.中国中医基础医学杂志.2000.6(10)：58-61.
[7]Bradley Efron, Trevor Hastie, Iain Johnstone. Least angle regression[J].The Annals of Statistics.2004.32(2): 407-451.
[8]中国中西医结合研究会活血化瘀专业委员会.血瘀证诊断标准.中西医结合杂志.1987.(3)：129
[9]卢良威.略论“心气内虚”及“气虚血癖”的病机.浙江中医学院学报.1978.4(4)：12-14.
[10]王晓才农一兵林谦宋麦芬.138例冠心病患者的证侯分布与组合特点分析.中医杂志.2008.49(1)：62-63,66
[11]李南夷,邓铁涛,文旺秀.心衰证治研究概述.中医信息杂志.1995.(5)：6-10
[1]Shen Z, Li P, Ni RJ, et al. Label-free quantitative proteomics analysis of etiolated maize seedling leaves during greening. Mol Cell Proteomics.2009.8(11):2443-60.
[2]America AH, Cordewener JH, van GMH, et al. Alignment and statistical difference analysis of complex peptide data sets generated by multidimensional LC-MS. Proteomics.2006.6(2):641-53.
[3]Silva JC, Denny R, Dorschel CA, et al. Quantitative proteomic analysis by accurate mass retention time pairs. Anal Chem.2005.77(7):2187-200.
[4]Silva JC, Denny R, Dorschel C, et al. Simultaneous qualitative and quantitative analysis of the Escherichia coli proteome:a sweet tale. Mol Cell Proteomics.2006.5(4):589-607.
[5]Hughes MA, Silva JC, Geromanos SJ, Townsend CA. Quantitative proteomic analysis of drug-induced changes in mycobacteria. J Proteome Res.2006.5(1):54-63.
[6]Roy SM, Becker CH. Quantification of proteins and metabolites by mass spectrometry without isotopic labeling. Methods Mol Biol.2007.359:87-105.
[7]Wang W, Zhou H, Lin H, et al. Quantification of proteins and metabolites by mass spectrometry without isotopic labeling or spiked standards. Anal Chem.2003.75(18):4818-26.
[8]Washburn MP, Wolters D,3rd YJR. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol.2001.19(3):242-7.
[9]Li GZ, Vissers JP, Silva JC, Golick D, Gorenstein MV, Geromanos SJ. Database searching and accounting of multiplexed precursor and product ion spectra from the data independent analysis of simple and complex peptide mixtures. Proteomics.2009.9(6):1696-719.
[10]Silva JC, Denny R, Dorschel CA, et al. Quantitative proteomic analysis by accurate mass retention time pairs. Anal Chem.2005.77(7):2187-200.
[11]Gu J, Wang Y, Li J, Wang J, Jin T. Proteomic analysis of left ventricular tissues following intermittent myocardial ischemia during coronary collateralization in rabbits. Int J Cardiol.2009.131(3):326-35.
[12]Chen CY, Lee BC, Hsu HC, et al. A proteomic study of the effects of ramipril on post-infarction left ventricular remodelling in the rabbit. Eur J Heart Fail.2008.10(8):740-8.
[13]Cieniewski-Bernard C, Mulder P, Henry JP, et al. Proteomic analysis of left ventricular remodeling in an experimental model of heart failure. J Proteome Res.2008.7(11):5004-16.
[14]吴红金,马增春,高月,王升启.蛋白质组学技术对冠心病血瘀证相关蛋白的研究.中西医结合心脑血管病杂志.2005.3(3)：189-191.
[15]赵慧辉,郭淑贞,侯娜,王伟.差异凝胶电泳技术寻找冠心病心绞痛血瘀证的相关蛋白.中华中医药杂志.2008.23(12)：1050-1053.
[16]赵慧辉,侯娜,王伟,黄秀兰.冠心病气虚血瘀证的蛋白质组学特征研究.中国中西医结合杂志.2009.29(6)：489-492.
[17]苗兰,刘建勋,任建勋,潘映红.气虚血瘀证模型大鼠血清蛋白质组学初步研究.中国实验方剂学杂志.2009.15(9)：42-46.
[18]刘蕾,王伟,宋剑南,郭淑贞,马雅銮,陈冰,许文玉.心肌缺血血瘀证小型猪模型差异蛋白质组学研究.中华中医药杂志.2009.24(6)：716-719.
[19]刘涛.气虚血瘀证(心肌缺血)大鼠心肌蛋白质组学的实验研究.北京中医药大学博士论文.2007：87：66.
[20]Sam F, Sawyer DB, Chang DL, et al. Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol Heart Circ Physiol.2000.279(1):H422-8.
[21]Laksanalamai P, Robb FT. Small heat shock proteins from extremophiles:a review. Extremophiles.2004.8(1):1-11.