冠心病血瘀证“瘀毒”病机转变的蛋白质组学研究
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摘要
研究背景：
冠心病(Coronary Heart Disease, CHD)的二级预防是临床防治的重点,在稳定期CHD患者中,有些患者发生了急性心血管事件(Acute Cardiovascular Events, ACEs),有的长期稳定,原因何在?基于此,陈可冀院士带领的973课题组在既往研究的基础上,提出心血管血栓性疾病“瘀毒”病因病机假说,认为血瘀是贯穿于冠心病发展过程的中心环节,也是稳定期患者的基础病理状态。若瘀久化热、酿生毒邪,或从化为毒,可致瘀毒内蕴(潜毒),如迁延日久、失治误治,则正消邪长、气血失衡,一旦外因引动、蕴毒骤发,则蚀肌伤肉,进而毒瘀搏结、痹阻心脉,终致变证丛生,并通过文献研究、实验室研究和稳定期患者前瞻性队列研究,综合分析归纳了CHD稳定期患者“毒”的临床表征和理化指标,制定了CHD稳定期患者“因毒致病”诊断及量化标准,为本研究提供了重要的理论支持。但CHD稳定期“瘀毒”是如何转化的?有何生物学基础?尚有待进一步阐明。
蛋白质组学是研究一个细胞、组织、器官或有机体在一定时间或一定状态下所表达的所有蛋白质,其研究重心是某一层次所有蛋白质及动态变化规律,具有动态性、时间性、空间性、特异性、整体性等特点,与中医“证候”有着惊人的相似。不同证候之间的差异,必然有其相应的物质基础做支撑,证候蛋白质组学研究作为中医证候研究的重要手段,旨在揭示证候发生、发展规律和证候诊断的实质和生物学基础。蛋白质组学从系统整体水平研究生命功能的直接体现者——蛋白质,为诠释复杂的生命活动提供了全新的视角,成为后基因组时代生命科学领域的前沿。它克服了蛋白质表达和基因之间的非线性关系,可以直接研究中医证候的特征与细胞蛋白质整体动态变化之间的内在联系,因而具有高效解码证候生物学基础的潜力,将是揭示证候实质的最有效手段,也为研究CHD稳定期“瘀毒”病机转化的生物学基础提供了技术支撑。
研究目的：
以CHD血瘀证患者发生心血管事件与否为主线,通过不同患者之间、同一患者不同疾病阶段的横向、纵向比较相结合,探索CHD血瘀证发展过程中“瘀毒”病机转变的相关蛋白。
研究方法：
入组冠心病血瘀证(CHD-BSS)、冠心病非血瘀证(CHD-非BSS)、非冠心病血瘀证(非CHD-BSS)、非冠心病非血瘀证(非CHD-非BSS)、急性心肌梗死(AMI)、传统中医毒证6组人群,并对1269例CHD-BSS人群的1年的ACEs进行随访。AMI作为CHD“毒证”组,随访发生ACEs的CHD稳定期患者作为CHD“潜毒”组。采用Matrix Assisted Laser Desorption Ionization/Time-of Flight Mass Spectroscopy (Maldi-Tof-MS)方法对不同人群的差异蛋白进行横向和纵向的比较分析和鉴定,最终确定CHD“瘀毒”病机转化中的关键蛋白。采用ClinProTool2.1软件进行图谱分析和统计学处理,采用BioworksBrowser3.3.1SP1进行SequestTM检索,检索数据库为International Protein Index (IPI human v3.45fasta with71983entries).
研究结果：
(1)共分析出与CHD相关的16个多肽,其中在CHD组表达明显升高的有2个,降低的有14个。
(2)本研究中与BBS相关的多肽未达到统计学差异。与"CHD-BBS"相关的多肽有76个,表达明显增高的有28个,表达明显降低的有48个。
(3)通过比较CHD-BSS、CHD-非BSS、非CHD-BSS、非CHD-非BSS、AMI组的差异蛋白,最终确定与CHD“瘀一毒”转化相关的多肽有6个,分子量分别是：1945.31Da、1981.25Da、1071.55Da、4644.76Da、6631.28Da、9527.44Da,与CHD“非瘀一毒”转化相关的多肽(在"CHD-BSS"中没有该多肽链的表达,但随访心血管事件过程中该多肽链表达有变化,称之为“非瘀一毒”转化相关蛋白)有3个分子量分别是：3883.4Da、6432.56Da、4230.19Da。上述两组多肽中,质谱鉴定成功的有5个,其中随着CHD“毒”证的增加("FB-FA-D")表达逐渐升高的包括同种型高分子量激肽原1的前体(Isoform HMW of Kininogen-1precursor, KNG1)、过氧化物还原酶-1(Peroxiredoxin-1, PRDX1),表达逐渐降低的有纤维蛋白原α链的前体1(Isoform1of Fibrinogen alpha chain precursor, FGA),在"FB-FA-D"中逐渐降低但在"Ffa-FF"中有短暂升高者包括载脂蛋白C-I前体(APOC1Apolipoprotein C-I precursor, APOC1)和血浆丝氨酸蛋白酶抑制剂前体(Plasma serine protease inhibitor precursor, SERPINA5)(FB:CHD-BSS中随访没有发生事件的患者；FA:CHD-BSS中随访发生事件的患者；D：急性心肌梗死患者；FF：随访发生事件患者复查且血样保存完整的患者；Ffa：复查组患者入组时点的血样)。利用KNG1和PRDX1两个蛋白进行建模,对FA、FB两组别进行分类,得到的FA组的识别率为90.2%,预测率为89.6%。
(4)CHD“瘀毒”证与传统毒证组相比较,共有4个多肽链表达明显不同,其中在CHD“瘀毒”组表达较高的多肽分子量为2022.61Da、1062.13Da,在传统毒证组表达较高的为2863.13Da和3540.44Da。对组间差异最大的多肽2022.61Da进行了鉴定,为补体C3的类似物,相对于传统毒证,该蛋白在CHD“瘀毒”组患者中表达较高。
研究结论：
初步筛选到了CHD稳定期“瘀毒”病机转变相关蛋白：KNGI和PRDX1,提示其生物学基础可能与凝血纤溶系统、缓激肽作用和氧化应激反应有关。FGA、APOC1和SERPINA5还需要进一步深入研究；并利用KNG1、PRDX1构建了基于“瘀毒致变”理论早期识别CHD稳定期高危患者的模型,有待进一步验证。
Background:
The secondary prevention is very important in patients with Stable Angina (SA), with the same treatment, some SA patients develop acute cardiovascular events (ACEs), while others do not in a very long period, why? Based on this question, National973Project leaded by Chen Keji academician presented a hypothesis of "blood-stasis→toxin" etiology and pathogenesis in cardiovascular thrombotic diseases, they considered blood stasis syndrome (BSS) was the basic syndrome in the development of CHD. Toxin was generally formed and accumulated by long-time BSS that brewed heat, or transformed from other pathologic factors. If lasting for a long time, delayed treatment or mistreatment, the accumulated toxin could be suddenly triggered by external causes and injured the tissue. The conglutination of toxin and blood-stasis further obstructed the heart vessel and leaded to ACEs. Therefore,"blood-stasis&toxin causing catastrophe" is the main etiology and key pathogenesis in SA patients who develop ACEs. Chen Keji academician and his fellow researchers further concluded the clinical manifestations of "toxin syndrome" in patient with SA by lots of literature studies and a prospective cohort study, they also made up a diagnostic and quantitative standard for the patients with SA complicated by "potential toxin syndrome". It is the basic or primary theory for us to study further. However, how to transform between BSS and "toxin syndrome"? And what is the biological substance in this process? All these questions need to study further.
The proteome is a subject studying all the proteins in a cell, a kind of tissue or an organism in specific conditions or at specific times, it aims to all proteins and all the changes of these proteins. The proteome is similar to syndromes of Traditional Chinese Medicine (TCM) for its dynamics, timeliness, spatiality, specificity, integrality and et al. Different syndromes certainly have different biological substance, therefore, syndrome proteomics has been an important method to study TCM syndromes because it can reveal the biological substance of syndromes and their changes. The proteome is a subject studying proteins which can reflect biological function immediately, it has given us a new approach for explaining physical activities and has been a life science frontier in the time of post genome. The proteome has conquered the non-linear relationship between protein and gene, and could interpret the internal relationship between TCM syndromes and the biological substance, so far, the proteome has been one of the most effective approaches for revealing biological essence of syndromes.
Objectives:
To find the relative proteins of "Blood-stasis→toxin syndrome" pathogenesis transformation in the progress of CHD-BSS by comparing different diseases or syndromes in a cross sectional study and a cohort study, the ACEs should be considered in this study.
Methods:
We included patients in6different groups including CHD-BSS, CHD-nonBSS, nonCHD-BSS, nonCHD-nonBSS, AMI and traditional toxic syndrome, a1-year follow-up was performed in1269CHD-BSS patients for ACEs. Patients in AMI were defined as "toxin syndrome" group, and SA patients who appeared ACEs in1year follow-up were defined as "potential toxin syndrome" group. Matrix Assisted Laser Desorption Ionization/Time-of Flight Mass Spectroscopy (Maldi-Tof-MS) technology was used to analyze and identify the differential proteins through horizontal and longitudinal contrast in these groups, and the key proteins for CHD " blood-stasis→toxin" were identified finally. Using ClinProTool2.1software to analysis the polypeptide mass spectrum, using BioworksBrowser3.3.1SP1to Sequest search, the database for researching is International Protein Index (IPI human v3.45fasta with71983entries).
Resul ts:
(1)16peptides were found for "CHD",2of16peptides showed higher expression and14peptides showed lower expression.
(2) No peptide showed significant difference for "BSS"(P>0.05).76peptides was found for "CHD-BSS"(P≤0.05),28of76peptides showed higher expression and48peptides showed lower expression.
(3)6peptides were found for "blood-stasis→toxin" transformation, the mass including1945.31Da,1981.25Da,1071.55Da,4644.76Da,6631.28Da and9527.44Da.3peptides were considered as "non blood-stasis→toxin", the mass including3883.4Da,6432.56Da and4230.19Da.5of9proteins were ident if ied. The express ion of Isoform HMW of Kininogen-1precursor (KNG1) and Peroxiredoxin-1(PRDX1) showed increased gradually in "FB-FA-D"; the expression of Isoform1of Fibrinogen alpha chain precursor(FGA) showed decreased gradually in "FB-FA-D"; the expression of Apol ipoprotein Cl (APO C1) and Serine protease inhibitor (SERPINA5) showed decreased gradually in "FB-FA-D" but showed increased temporarily in "Ffa-FF"(FA: Patients developed ACEs in1-year follow-up; FB: Patients did not developed ACEs in follow-up; D: Patients in AMI; FF: Blood sample in reexamination for patients in FA and their blood samples were storaged very well; Ffa: Blood sample in enrollment for patients in FF). KNG1and PRDX1were used for modeling using SNN to distinguish FA and FB, discrimination power for FA was90.2%, predictive values for FA was89.6%.
(4)4peptides were found for distinguishing CHD "blood-stasis&toxin" and traditional "toxin syndrome", peptides in higher expression in CHD "blood-stasis&toxin" were2022.61Da and1062.13Da, peptides in higher expression in traditional "toxin syndrome" were2863.13Da and3540.44Da. LOC653879(Similar to Complement C3) was identified, it showed high expression in CHD "blood-stasis&toxin"
Conclus ions:
KNG1and PRDX1were identified as biomarker for "blood-stasisz→toxin" pathogenesis transformation, which might be related to the blood coagulation, fibrinolysis, effect of bradykinin and oxidative stress; FGA, AP0C1and SERPINA5A were also identified as biomarker for "blood-stas is→toxin" pathogenesis transformation but need to study further; Model made up by KNG1and PRDX1for distinguishing "high-risk" patients in SA was established but need to check in the further.
冠心病(Coronary Heart Disease, CHD)的二级预防是临床防治的重点,在稳定期CHD患者中,有些患者发生了急性心血管事件(Acute Cardiovascular Events, ACEs),有的长期稳定,原因何在?基于此,陈可冀院士带领的973课题组在既往研究的基础上,提出心血管血栓性疾病“瘀毒”病因病机假说,认为血瘀是贯穿于冠心病发展过程的中心环节,也是稳定期患者的基础病理状态。若瘀久化热、酿生毒邪,或从化为毒,可致瘀毒内蕴(潜毒),如迁延日久、失治误治,则正消邪长、气血失衡,一旦外因引动、蕴毒骤发,则蚀肌伤肉,进而毒瘀搏结、痹阻心脉,终致变证丛生,并通过文献研究、实验室研究和稳定期患者前瞻性队列研究,综合分析归纳了CHD稳定期患者“毒”的临床表征和理化指标,制定了CHD稳定期患者“因毒致病”诊断及量化标准,为本研究提供了重要的理论支持。但CHD稳定期“瘀毒”是如何转化的?有何生物学基础?尚有待进一步阐明。
蛋白质组学是研究一个细胞、组织、器官或有机体在一定时间或一定状态下所表达的所有蛋白质,其研究重心是某一层次所有蛋白质及动态变化规律,具有动态性、时间性、空间性、特异性、整体性等特点,与中医“证候”有着惊人的相似。不同证候之间的差异,必然有其相应的物质基础做支撑,证候蛋白质组学研究作为中医证候研究的重要手段,旨在揭示证候发生、发展规律和证候诊断的实质和生物学基础。蛋白质组学从系统整体水平研究生命功能的直接体现者——蛋白质,为诠释复杂的生命活动提供了全新的视角,成为后基因组时代生命科学领域的前沿。它克服了蛋白质表达和基因之间的非线性关系,可以直接研究中医证候的特征与细胞蛋白质整体动态变化之间的内在联系,因而具有高效解码证候生物学基础的潜力,将是揭示证候实质的最有效手段,也为研究CHD稳定期“瘀毒”病机转化的生物学基础提供了技术支撑。
研究目的：
以CHD血瘀证患者发生心血管事件与否为主线,通过不同患者之间、同一患者不同疾病阶段的横向、纵向比较相结合,探索CHD血瘀证发展过程中“瘀毒”病机转变的相关蛋白。
研究方法：
入组冠心病血瘀证(CHD-BSS)、冠心病非血瘀证(CHD-非BSS)、非冠心病血瘀证(非CHD-BSS)、非冠心病非血瘀证(非CHD-非BSS)、急性心肌梗死(AMI)、传统中医毒证6组人群,并对1269例CHD-BSS人群的1年的ACEs进行随访。AMI作为CHD“毒证”组,随访发生ACEs的CHD稳定期患者作为CHD“潜毒”组。采用Matrix Assisted Laser Desorption Ionization/Time-of Flight Mass Spectroscopy (Maldi-Tof-MS)方法对不同人群的差异蛋白进行横向和纵向的比较分析和鉴定,最终确定CHD“瘀毒”病机转化中的关键蛋白。采用ClinProTool2.1软件进行图谱分析和统计学处理,采用BioworksBrowser3.3.1SP1进行SequestTM检索,检索数据库为International Protein Index (IPI human v3.45fasta with71983entries).
研究结果：
(1)共分析出与CHD相关的16个多肽,其中在CHD组表达明显升高的有2个,降低的有14个。
(2)本研究中与BBS相关的多肽未达到统计学差异。与"CHD-BBS"相关的多肽有76个,表达明显增高的有28个,表达明显降低的有48个。
(3)通过比较CHD-BSS、CHD-非BSS、非CHD-BSS、非CHD-非BSS、AMI组的差异蛋白,最终确定与CHD“瘀一毒”转化相关的多肽有6个,分子量分别是：1945.31Da、1981.25Da、1071.55Da、4644.76Da、6631.28Da、9527.44Da,与CHD“非瘀一毒”转化相关的多肽(在"CHD-BSS"中没有该多肽链的表达,但随访心血管事件过程中该多肽链表达有变化,称之为“非瘀一毒”转化相关蛋白)有3个分子量分别是：3883.4Da、6432.56Da、4230.19Da。上述两组多肽中,质谱鉴定成功的有5个,其中随着CHD“毒”证的增加("FB-FA-D")表达逐渐升高的包括同种型高分子量激肽原1的前体(Isoform HMW of Kininogen-1precursor, KNG1)、过氧化物还原酶-1(Peroxiredoxin-1, PRDX1),表达逐渐降低的有纤维蛋白原α链的前体1(Isoform1of Fibrinogen alpha chain precursor, FGA),在"FB-FA-D"中逐渐降低但在"Ffa-FF"中有短暂升高者包括载脂蛋白C-I前体(APOC1Apolipoprotein C-I precursor, APOC1)和血浆丝氨酸蛋白酶抑制剂前体(Plasma serine protease inhibitor precursor, SERPINA5)(FB:CHD-BSS中随访没有发生事件的患者；FA:CHD-BSS中随访发生事件的患者；D：急性心肌梗死患者；FF：随访发生事件患者复查且血样保存完整的患者；Ffa：复查组患者入组时点的血样)。利用KNG1和PRDX1两个蛋白进行建模,对FA、FB两组别进行分类,得到的FA组的识别率为90.2%,预测率为89.6%。
(4)CHD“瘀毒”证与传统毒证组相比较,共有4个多肽链表达明显不同,其中在CHD“瘀毒”组表达较高的多肽分子量为2022.61Da、1062.13Da,在传统毒证组表达较高的为2863.13Da和3540.44Da。对组间差异最大的多肽2022.61Da进行了鉴定,为补体C3的类似物,相对于传统毒证,该蛋白在CHD“瘀毒”组患者中表达较高。
研究结论：
初步筛选到了CHD稳定期“瘀毒”病机转变相关蛋白：KNGI和PRDX1,提示其生物学基础可能与凝血纤溶系统、缓激肽作用和氧化应激反应有关。FGA、APOC1和SERPINA5还需要进一步深入研究；并利用KNG1、PRDX1构建了基于“瘀毒致变”理论早期识别CHD稳定期高危患者的模型,有待进一步验证。
Background:
The secondary prevention is very important in patients with Stable Angina (SA), with the same treatment, some SA patients develop acute cardiovascular events (ACEs), while others do not in a very long period, why? Based on this question, National973Project leaded by Chen Keji academician presented a hypothesis of "blood-stasis→toxin" etiology and pathogenesis in cardiovascular thrombotic diseases, they considered blood stasis syndrome (BSS) was the basic syndrome in the development of CHD. Toxin was generally formed and accumulated by long-time BSS that brewed heat, or transformed from other pathologic factors. If lasting for a long time, delayed treatment or mistreatment, the accumulated toxin could be suddenly triggered by external causes and injured the tissue. The conglutination of toxin and blood-stasis further obstructed the heart vessel and leaded to ACEs. Therefore,"blood-stasis&toxin causing catastrophe" is the main etiology and key pathogenesis in SA patients who develop ACEs. Chen Keji academician and his fellow researchers further concluded the clinical manifestations of "toxin syndrome" in patient with SA by lots of literature studies and a prospective cohort study, they also made up a diagnostic and quantitative standard for the patients with SA complicated by "potential toxin syndrome". It is the basic or primary theory for us to study further. However, how to transform between BSS and "toxin syndrome"? And what is the biological substance in this process? All these questions need to study further.
The proteome is a subject studying all the proteins in a cell, a kind of tissue or an organism in specific conditions or at specific times, it aims to all proteins and all the changes of these proteins. The proteome is similar to syndromes of Traditional Chinese Medicine (TCM) for its dynamics, timeliness, spatiality, specificity, integrality and et al. Different syndromes certainly have different biological substance, therefore, syndrome proteomics has been an important method to study TCM syndromes because it can reveal the biological substance of syndromes and their changes. The proteome is a subject studying proteins which can reflect biological function immediately, it has given us a new approach for explaining physical activities and has been a life science frontier in the time of post genome. The proteome has conquered the non-linear relationship between protein and gene, and could interpret the internal relationship between TCM syndromes and the biological substance, so far, the proteome has been one of the most effective approaches for revealing biological essence of syndromes.
Objectives:
To find the relative proteins of "Blood-stasis→toxin syndrome" pathogenesis transformation in the progress of CHD-BSS by comparing different diseases or syndromes in a cross sectional study and a cohort study, the ACEs should be considered in this study.
Methods:
We included patients in6different groups including CHD-BSS, CHD-nonBSS, nonCHD-BSS, nonCHD-nonBSS, AMI and traditional toxic syndrome, a1-year follow-up was performed in1269CHD-BSS patients for ACEs. Patients in AMI were defined as "toxin syndrome" group, and SA patients who appeared ACEs in1year follow-up were defined as "potential toxin syndrome" group. Matrix Assisted Laser Desorption Ionization/Time-of Flight Mass Spectroscopy (Maldi-Tof-MS) technology was used to analyze and identify the differential proteins through horizontal and longitudinal contrast in these groups, and the key proteins for CHD " blood-stasis→toxin" were identified finally. Using ClinProTool2.1software to analysis the polypeptide mass spectrum, using BioworksBrowser3.3.1SP1to Sequest search, the database for researching is International Protein Index (IPI human v3.45fasta with71983entries).
Resul ts:
(1)16peptides were found for "CHD",2of16peptides showed higher expression and14peptides showed lower expression.
(2) No peptide showed significant difference for "BSS"(P>0.05).76peptides was found for "CHD-BSS"(P≤0.05),28of76peptides showed higher expression and48peptides showed lower expression.
(3)6peptides were found for "blood-stasis→toxin" transformation, the mass including1945.31Da,1981.25Da,1071.55Da,4644.76Da,6631.28Da and9527.44Da.3peptides were considered as "non blood-stasis→toxin", the mass including3883.4Da,6432.56Da and4230.19Da.5of9proteins were ident if ied. The express ion of Isoform HMW of Kininogen-1precursor (KNG1) and Peroxiredoxin-1(PRDX1) showed increased gradually in "FB-FA-D"; the expression of Isoform1of Fibrinogen alpha chain precursor(FGA) showed decreased gradually in "FB-FA-D"; the expression of Apol ipoprotein Cl (APO C1) and Serine protease inhibitor (SERPINA5) showed decreased gradually in "FB-FA-D" but showed increased temporarily in "Ffa-FF"(FA: Patients developed ACEs in1-year follow-up; FB: Patients did not developed ACEs in follow-up; D: Patients in AMI; FF: Blood sample in reexamination for patients in FA and their blood samples were storaged very well; Ffa: Blood sample in enrollment for patients in FF). KNG1and PRDX1were used for modeling using SNN to distinguish FA and FB, discrimination power for FA was90.2%, predictive values for FA was89.6%.
(4)4peptides were found for distinguishing CHD "blood-stasis&toxin" and traditional "toxin syndrome", peptides in higher expression in CHD "blood-stasis&toxin" were2022.61Da and1062.13Da, peptides in higher expression in traditional "toxin syndrome" were2863.13Da and3540.44Da. LOC653879(Similar to Complement C3) was identified, it showed high expression in CHD "blood-stasis&toxin"
Conclus ions:
KNG1and PRDX1were identified as biomarker for "blood-stasisz→toxin" pathogenesis transformation, which might be related to the blood coagulation, fibrinolysis, effect of bradykinin and oxidative stress; FGA, AP0C1and SERPINA5A were also identified as biomarker for "blood-stas is→toxin" pathogenesis transformation but need to study further; Model made up by KNG1and PRDX1for distinguishing "high-risk" patients in SA was established but need to check in the further.
引文
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