血浆HDL中蛋白质组分与冠心病的关系及应用他汀类药后的变化研究
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摘要
一、研究背景
近年来已经对高密度脂蛋白(high density lipoprotein, HDL)蛋白质组分的含量及变化情况进行了研究。结果表明：冠心病(coronary heart disease, CHD)患者的HDL蛋白质组成发生变化,联合应用他汀类药物+烟酸后,CHD患者的HDL蛋白质组成趋向于“正常化”。不过,该领域的研究尚少,结果差异较大,验证性工作不足,有必要开展进一步的研究工作。
本实验室前期应用蛋白质组学技术比较了CHD患者与非CHD患者(对照组)之间的HDL蛋白质组差异,发现与对照组相比,CHD组HDL中的载脂蛋白A-I(apolipoprotein A-Ⅰ, apoA-Ⅰ)水平显著下降,血清淀粉样蛋白A (serum amyloid A protein, SAA)水平显著升高,但是尚缺乏较大样本的验证性研究。目前国内外尚未报道单独应用他汀类药物治疗冠心病患者前后HDL蛋白质组的变化,且研究已显示他汀类药物可与HDL之间存在功能的相互作用,机制并不十分清楚。因此,本研究拟从两方面进行研究：①,验证上述实验室前期获得的结果,探讨HDL中SAA和apoA-Ⅰ蛋白水平的变化及与冠心病的关系;②,采用蛋白质组学技术比较他汀类药物使用前后HDL组分的变化,以探讨CHD患者在服用他汀类药物的调脂治疗过程中HDL蛋白组分是否有变化,这种变化是否与患者的疗效有关。同时也希望从另一角度即HDL组分的变化来探讨他汀类药物的作用机制。
二、研究内容
第一部分冠心病患者血浆HDL中apoA-Ⅰ与SAA组分变化的研究
1.研究目的
比较CHD患者与非CHD患者(对照组)血浆HDL中apoA-Ⅰ与SAA组分差异。
2.研究方法
2.1研究对象：
2.1.1CHD组：至少有一支冠状动脉狭窄大于50%,未服用调脂药；
2.1.2对照组：排除CHD,且年龄、性别与CHD组相匹配；
2.2样品收集与HDL分离：收集空腹血浆,应用溴化钾超高速离心方法分离血浆中的HDL；
2.3ELISA法检测血浆及其HDL中的apoA-Ⅰ和SAA的水平;
2.4统计学分析：pearson相关性分析研究血浆及HDL中apoA-Ⅰ和SAA的相关性；logistic回归分析研究血浆及HDL中这两种蛋白与CHD的关联程度。
3.研究结果
3.1HDL中apoA-Ⅰ和SAA水平变化
3.1.1CHD组(n=67)与对照组(n=67)相比,HDL-apoA-Ⅰ水平降低,差异有统计学意义(7.80±3.32g/mL vs.10.42±5.51g/mL,P=0.001)；校正可能的混杂因素后,其在两组间的显著性差异消失(B=-0.109,P=0.088)。
3.1.2CHD组与对照组相比,log (HDL-SAA)显著升高,差异有统计学意义(1.39±0.58vs.1.15±0.46,P=0.011)；校正可能的混杂因素后,其在两组之间的差异仍有统计学意义(B=1.738,P=0.017),且log(HDL-SAA)每升高个单位,CHD的发生风险升高4.685倍(OR=5.685,95%CI：1.371,23.581)。
3.2血浆中apoA-Ⅰ和SAA水平变化
3.2.1CHD组(n=67)和对照组(n=67)相比,plasma-apoA-Ⅰ的差异无统计学意义(0.7±0.33g/mL vs.0.79±0.28g/mL,P=0.122)。
3.2.2CHD组和对照组相比,log(plasma-SAA)水平升高,差异有统计学意义(1.13±0.54vs.0.88±0.48,P=0.005)；校正可能的混杂因素后,其在两组之间的差异仍有统计学意义(B=1.646,P=0.038),且log(plasma-SAA)每升高1个单位,CHD的发生风险升高4.185倍(OR=5.185,95%CI;1.095,24.544)。
3.3pearson相关性分析：在对照组及CHD组的血浆及HDL中apoA-Ⅰ与SAA的相关系数均无统计学意义。
4.第一部分研究结论
4.1与对照组相比,CHD患者HDL蛋白质组成发生改变：SAA水平明显升高,apoA-Ⅰ有下降趋势。
4.2血浆中apoA-Ⅰ在两组之间无明显差异;CHD组血浆SAA明显升高。提示HDL及血浆中SAA均为CHD的危险因素。
第二部分冠心病患者服用他汀类药物后血浆HDL蛋白质组分变化的研究
(一)冠心病患者服用他汀类药物前后血浆HDL蛋白质组成变化的比较
1.研究目的探索CHD患者服用他汀类药物前后HDL蛋白质的组成及各组分水平的差异。
2.研究方法
2.1研究对象：
2.1.1CHD组(n=9);至少有一支冠状动脉狭窄大于50%,入组时未服用他汀等调脂药,参加随访；
2.1.2对照组(n=10)：排除CHD,且年龄、性别与CHD组相匹配；
2.2样品的收集与分离：收集CHD组服用他汀类药物半年前后(药前组、药后组)及对照组的空腹血浆;溴化钾超高速离心法分离HDL样品；
2.3iTRAQ-LC-MS技术：研究药前组、药后组及对照组之间HDL蛋白质组成及各组分水平的相对定量；
2.4Gene Ontology (GO)功能分析：利用GO功能分析鉴定到的蛋白质分子功能、参与的生物过程及细胞组成分布的特点；
2.5蛋白质聚类分析：三组之间HDL组分差异水平特点。
3.研究结果
3.1在药前组、药后组和对照组的HDL鉴定出196种高置信度的蛋白质组分。
3.2GO分析发现这些蛋白具有多种分子活性,参与多种生物学过程。
3.3聚类分析显示CHD患者服用他汀类药物前与对照组HDL蛋白水平之间的差异大于CHD患者药后与对照组HDL蛋白水平之间的差异。
3.4CHD患者药前药后比较发现14种差异蛋白；在CHD组与对照组之间发现13种差异蛋白；其中serum amyloid A2isoform(SAA2)、complement C5preproprotein和histone H1.0三种蛋白的变化趋势均表现为在CHD组显著升高,服用他汀类药物后其在HDL中的含量显著下降,下降水平接近对照组。
4.研究小结
4.1在CHD药前、药后和对照组的HDL中共鉴定出196种高置信度的蛋白质组分；
4.2GO分析发现这些蛋白具有多种分子活性,参与多种生物学过程；
4.3聚类分析显示CHD患者服用他汀类药物前与对照组HDL蛋白水平之间的差异大于CHD患者药后与对照组HDL蛋白水平之间的差异。
4.4CHD患者药前药后比较发现14种差异蛋白；在CHD组与对照组之间发现13种差异蛋白；其中serum amyloid A2isoform(SAA2)、complement C5preproprotein和histone H1.0三种蛋白的变化趋势均表现为在CHD组显著升高,服用他汀类药物后其在HDL中的含量显著下降,下降水平接近对照组
(二)冠心病患者服用他汀类药物前后血浆HDL中SAA差异水平的变化
1.研究目的
比较CHD患者服用他汀类药物前后HDL中SAA的水平,初步验证iTRAQ-LC-MS中发现的候选差异蛋白SAA2的水平。
2.研究方法
2.1研究对象：
2.1.1CHD组(n=44)；至少有一支冠状动脉狭窄大于50%,入组时未服用他汀等调脂药,参加随访；
2.1.2对照组(n=45)：排除CHD,且年龄、性别与CHD患者相匹配；
2.2样品的收集与分离：收集CHD组服用他汀类药物半年前后(药前组、药后组)及对照组的空腹血浆；溴化钾超高速离心法分离HDL样品；
2.3ELISA法检测：CHD药前组与药后组HDL样品中SAA水平。
3.研究结果
与药前HDL中log(HDLSAA)的水平相比,CHD患者服用他汀类后HDL中的SAA水平明显下降(1.28±0.51vs.1.01±0.51,P=0.014),与iTRAQ结果一致。
4.研究小结
他汀类药物可显著下调HDL中SAA的水平。
(三)服用他汀类药物与未服用他汀类药物的冠心病患者血浆HDL中SAA差异水平的研究
1.研究目的
比较服用他汀类药物半年的CHD患者与未服用他汀类药物的CHD患者血浆HDL中SAA的水平,再次验证iTRAQ-LC-MS中鉴定的候选差异蛋白SAA2水平。
2.研究方法
2.1研究对象：
2.1.1CHD用药组(n=65)：至少有一支冠状动脉狭窄大于50%,入组时已经规律服用他汀类药物半年左右,未合并使用其他调脂药；
2.1.2CHD未用药组(n=67)：至少有一支冠状动脉狭窄大于50%,未服用任何调脂药；
2.2样品收集与HDL分离：收集空腹血浆：超高速离心分离HDL样品；
2.3ELISA法检测：CHD用药组与CHD未用药组HDL样品中SAA水平；
2.4统计学分析：利用协方差分析的方法校正两组之间的基线差异。
3.研究结果
3.1CHD用药组HDL中的log (HDL-SAA)水平与CHD未用药组相比,显著下降(1.34±0.58vs.1.04±0.46, P=0.0002)。
3.2校正总胆固醇、低密度脂蛋白胆固醇、apoA-Ⅰ、载脂蛋白B、肌酐、血糖及高敏C反应蛋白的水平差异后,log(HDL-SAA)在两组之间的差异仍有统计学意义(P=0.005)。
3.3进一步校正HDL-C的水平,log(HDL-SAA)在两组之间的差异仍有统计学意义(P=0.015)。
4.研究小结
HDL中的SAA水平与CHD患者服用他汀类药物有关。
三、结论
1.CHD患者HDL蛋白质组成发生改变：其中SAA水平明显升高,apoA-Ⅰ有下降趋势。SAA为CHD的危险因素。iTRAQ技术又新发现CHD组与对照组之间有13种差异蛋白(6种在CHD组HDL中上调,7种下调)。
2.CHD患者他汀药治疗后,SAA水平下降至正常水平,且不受其他因素影响。iTRAQ技术又新发现CHD组药后与药前HDL样品中有14种差异蛋白(10种在药后HDL中上调,4种下调)。
3.他汀类调脂药可改变HDL中某些蛋白水平。
4.HDL由多种蛋白质成分组成,可以从HDL蛋白组成研究HDL所具有的生物学功能。
Background
The alteration of proteins existing in high density lipoprotein (HDL) is found to affect its function. It will be helpful to comprehend the relationship between HDL and coronary heart disease (CHD) by studying the protein composition of HDL and to clarify the role of HDL in atherosclerosis further.
Recently, there are several studies exploring the proteins in HDL by proteomics technology, showing that the protein composition in HDL isolated from patients with CHD was different from controls and combined statin and niacin therapy may remodel the HDL proteome. However, the related study was rare and insufficient.
In our laboratory, we have conducted a preliminary study comparing the difference in HDL proteome between patients with CHD and controls and found that a significant decrease in the level of apolipoprotein A-I (apoA-I) and the increase in the level of serum amyloid A protein (SAA), which need to be validated in another independent group with larger sample size. In addition, there is no study exploring the effect of statins per se on HDL proteome at present, and the interaction between statins and HDL has been found in several studies.
Part1:The relationship between apolipoprotein A-I and SAA in high density lipoprotein isolated from patients with coronary heart disease
Object
To compare the difference in the levels of apoA-I and SAA in HDL isolated form patient with CHD and controls and understand the relationship between apoA-I and SAA.
Methods
Patients with at least one coronary artery stenosis more that50%and never take statins and other lipids-lowing drugs (CHD group) and a group of age and sex-matched subjects (control group) were enrolled. HDL was isolated by ultracentrifugation. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of apoA-I and SAA in plasma and in HDL. Pearson correlation analysis was used to explore the relationship between apoA-Ⅰ and SAA in HDL. Logistic regression was used to study the association between apoA-Ⅰ and CHD and between SAA and CHD.
Results
1.67patients and67controls were enrolled in this part of study.
2. Compared with controls, the level of apoA-Ⅰ was significantly decreased in HDL isolated from CHD patients (7.80±3.32g/mL vs.10.42±5.51g/mL, P=0.001). However, the difference was disappeared when adjusted by potential confounding factors (B=-0.109, P=0.088). The level of log (HDL-SAA) was significantly higher in CHD patient than the one in control group (1.39±0.58vs.1.15±0.46, P=0.011). The significance was still exist after adjustment for confounding factors (B=1.738, P=0.017). The OR value was5.685, which means that the risk of CHD will increase4.685when the log(HDL-SAA) increase1unit (OR=5.685,95%CI:1.371,23.581).
3. Compared with controls, the level of apoA-Ⅰ in plasma was not different between the two groups (0.7±0.33g/mL vs.0.79±0.28g/mL, P=0.122). The level of log(plasma-SAA) was significantly higher in CHD group than in control group (1.13±0.54vs.0.88±0.48, P=0.005) independently from confounding factors (B=1.646, P=0.038). The OR value for log(plasma-SAA) was5.185(OR=5.185,95%CI:1.095,24.544).
4. The level of apoA-I and SAA did not show any correlation in HDL or in plasma both in the two groups.
Part2:The alteration in HDL proteome by statins among patients with coronary heart disease
Objectives
To study the alteration in HDL proteome by statins among patients with coronary heart disease and the difference of the level of each protein in HDL isolated from CHD patient before and about half year after statins therapy.
Methods
HDL isolated from9patients with CHD before and about half year after statins therapy and10age-sex matched controls was analyzed by isobaric tags for relative and absolute quantitation (iTRAQ)-liquid chromatography-mass spectrometry. GO analysis was performed to understand the function classification and molecular activity of all detected proteins in HDL. Cluster analysis was used to clarify the difference characteristic of all proteins in HDL among the three groups. Treatment-induced decrease in SAA2level of HDL were validated in a second group of44CHD patients and45controls and in a third group of67CHD patients never using statins or other lipid-lowing drugs and65CHD patients who had already taken statins for about half year.
Results
1.196proteins with high confidence coefficient (FDR=0.01and at least two peptides matched) were detected by iTRAQ-LC-MS.
2. The GO analysis indicated that these detected proteins maybe involved in many biological processes, such as lipids-transport, inflammation, innate immune defence, and so on. These proteins also showed multiple activities, for example lipids-binding activity, enzyme inhibitor activity, peptide-chain hydrolysis activity, and so on.
3.14proteins were found different with significance in HDL isolated from CHD patients before statins therapy and after about half year therapy.13proteins were found different between CHD and control. There3proteins, serum amyloid A2isoform(SAA2)、complement C5preproprotein and histone H1.0, showed the same alteration trend in these three groups, which increased in CHD patients when compared with controls, and decreased in CHD patients after statins therapy.
4. The level of SAA was significantly decreased after statins therapy. The level of SAA in HDL among CHD patients was correlated with statins therapy.
Conclusion
1. HDL is composed of many proteins, and these proteins showed multiple activities, for example lipids-binding activity, enzyme inhibitor activity, peptide-chain hydrolysis activity, etc. and may be involved many biological processes, such as lipids-transport, inflammation, innate immune defence, and so on.
2. The HDL proteome is altered in patients with CHD. When compared with control, the level of SAA was significantly increased and there is a decrease trend in the level of apoA-I.13new proteins were found to be different between CHD group and control group in the present study.
3. Level of SAA was significantly decreased after statins therapy.14new proteins altered after statins therapy in the present study, which maybe the new targets of statins.
4. Statins may remodel the HDL proteome.
5. HDL is composed of many proteins, and the alteration of protein composition in HDL may be helpful to study the HDL functions.
近年来已经对高密度脂蛋白(high density lipoprotein, HDL)蛋白质组分的含量及变化情况进行了研究。结果表明：冠心病(coronary heart disease, CHD)患者的HDL蛋白质组成发生变化,联合应用他汀类药物+烟酸后,CHD患者的HDL蛋白质组成趋向于“正常化”。不过,该领域的研究尚少,结果差异较大,验证性工作不足,有必要开展进一步的研究工作。
本实验室前期应用蛋白质组学技术比较了CHD患者与非CHD患者(对照组)之间的HDL蛋白质组差异,发现与对照组相比,CHD组HDL中的载脂蛋白A-I(apolipoprotein A-Ⅰ, apoA-Ⅰ)水平显著下降,血清淀粉样蛋白A (serum amyloid A protein, SAA)水平显著升高,但是尚缺乏较大样本的验证性研究。目前国内外尚未报道单独应用他汀类药物治疗冠心病患者前后HDL蛋白质组的变化,且研究已显示他汀类药物可与HDL之间存在功能的相互作用,机制并不十分清楚。因此,本研究拟从两方面进行研究：①,验证上述实验室前期获得的结果,探讨HDL中SAA和apoA-Ⅰ蛋白水平的变化及与冠心病的关系;②,采用蛋白质组学技术比较他汀类药物使用前后HDL组分的变化,以探讨CHD患者在服用他汀类药物的调脂治疗过程中HDL蛋白组分是否有变化,这种变化是否与患者的疗效有关。同时也希望从另一角度即HDL组分的变化来探讨他汀类药物的作用机制。
二、研究内容
第一部分冠心病患者血浆HDL中apoA-Ⅰ与SAA组分变化的研究
1.研究目的
比较CHD患者与非CHD患者(对照组)血浆HDL中apoA-Ⅰ与SAA组分差异。
2.研究方法
2.1研究对象：
2.1.1CHD组：至少有一支冠状动脉狭窄大于50%,未服用调脂药；
2.1.2对照组：排除CHD,且年龄、性别与CHD组相匹配；
2.2样品收集与HDL分离：收集空腹血浆,应用溴化钾超高速离心方法分离血浆中的HDL；
2.3ELISA法检测血浆及其HDL中的apoA-Ⅰ和SAA的水平;
2.4统计学分析：pearson相关性分析研究血浆及HDL中apoA-Ⅰ和SAA的相关性；logistic回归分析研究血浆及HDL中这两种蛋白与CHD的关联程度。
3.研究结果
3.1HDL中apoA-Ⅰ和SAA水平变化
3.1.1CHD组(n=67)与对照组(n=67)相比,HDL-apoA-Ⅰ水平降低,差异有统计学意义(7.80±3.32g/mL vs.10.42±5.51g/mL,P=0.001)；校正可能的混杂因素后,其在两组间的显著性差异消失(B=-0.109,P=0.088)。
3.1.2CHD组与对照组相比,log (HDL-SAA)显著升高,差异有统计学意义(1.39±0.58vs.1.15±0.46,P=0.011)；校正可能的混杂因素后,其在两组之间的差异仍有统计学意义(B=1.738,P=0.017),且log(HDL-SAA)每升高个单位,CHD的发生风险升高4.685倍(OR=5.685,95%CI：1.371,23.581)。
3.2血浆中apoA-Ⅰ和SAA水平变化
3.2.1CHD组(n=67)和对照组(n=67)相比,plasma-apoA-Ⅰ的差异无统计学意义(0.7±0.33g/mL vs.0.79±0.28g/mL,P=0.122)。
3.2.2CHD组和对照组相比,log(plasma-SAA)水平升高,差异有统计学意义(1.13±0.54vs.0.88±0.48,P=0.005)；校正可能的混杂因素后,其在两组之间的差异仍有统计学意义(B=1.646,P=0.038),且log(plasma-SAA)每升高1个单位,CHD的发生风险升高4.185倍(OR=5.185,95%CI;1.095,24.544)。
3.3pearson相关性分析：在对照组及CHD组的血浆及HDL中apoA-Ⅰ与SAA的相关系数均无统计学意义。
4.第一部分研究结论
4.1与对照组相比,CHD患者HDL蛋白质组成发生改变：SAA水平明显升高,apoA-Ⅰ有下降趋势。
4.2血浆中apoA-Ⅰ在两组之间无明显差异;CHD组血浆SAA明显升高。提示HDL及血浆中SAA均为CHD的危险因素。
第二部分冠心病患者服用他汀类药物后血浆HDL蛋白质组分变化的研究
(一)冠心病患者服用他汀类药物前后血浆HDL蛋白质组成变化的比较
1.研究目的探索CHD患者服用他汀类药物前后HDL蛋白质的组成及各组分水平的差异。
2.研究方法
2.1研究对象：
2.1.1CHD组(n=9);至少有一支冠状动脉狭窄大于50%,入组时未服用他汀等调脂药,参加随访；
2.1.2对照组(n=10)：排除CHD,且年龄、性别与CHD组相匹配；
2.2样品的收集与分离：收集CHD组服用他汀类药物半年前后(药前组、药后组)及对照组的空腹血浆;溴化钾超高速离心法分离HDL样品；
2.3iTRAQ-LC-MS技术：研究药前组、药后组及对照组之间HDL蛋白质组成及各组分水平的相对定量；
2.4Gene Ontology (GO)功能分析：利用GO功能分析鉴定到的蛋白质分子功能、参与的生物过程及细胞组成分布的特点；
2.5蛋白质聚类分析：三组之间HDL组分差异水平特点。
3.研究结果
3.1在药前组、药后组和对照组的HDL鉴定出196种高置信度的蛋白质组分。
3.2GO分析发现这些蛋白具有多种分子活性,参与多种生物学过程。
3.3聚类分析显示CHD患者服用他汀类药物前与对照组HDL蛋白水平之间的差异大于CHD患者药后与对照组HDL蛋白水平之间的差异。
3.4CHD患者药前药后比较发现14种差异蛋白；在CHD组与对照组之间发现13种差异蛋白；其中serum amyloid A2isoform(SAA2)、complement C5preproprotein和histone H1.0三种蛋白的变化趋势均表现为在CHD组显著升高,服用他汀类药物后其在HDL中的含量显著下降,下降水平接近对照组。
4.研究小结
4.1在CHD药前、药后和对照组的HDL中共鉴定出196种高置信度的蛋白质组分；
4.2GO分析发现这些蛋白具有多种分子活性,参与多种生物学过程；
4.3聚类分析显示CHD患者服用他汀类药物前与对照组HDL蛋白水平之间的差异大于CHD患者药后与对照组HDL蛋白水平之间的差异。
4.4CHD患者药前药后比较发现14种差异蛋白；在CHD组与对照组之间发现13种差异蛋白；其中serum amyloid A2isoform(SAA2)、complement C5preproprotein和histone H1.0三种蛋白的变化趋势均表现为在CHD组显著升高,服用他汀类药物后其在HDL中的含量显著下降,下降水平接近对照组
(二)冠心病患者服用他汀类药物前后血浆HDL中SAA差异水平的变化
1.研究目的
比较CHD患者服用他汀类药物前后HDL中SAA的水平,初步验证iTRAQ-LC-MS中发现的候选差异蛋白SAA2的水平。
2.研究方法
2.1研究对象：
2.1.1CHD组(n=44)；至少有一支冠状动脉狭窄大于50%,入组时未服用他汀等调脂药,参加随访；
2.1.2对照组(n=45)：排除CHD,且年龄、性别与CHD患者相匹配；
2.2样品的收集与分离：收集CHD组服用他汀类药物半年前后(药前组、药后组)及对照组的空腹血浆；溴化钾超高速离心法分离HDL样品；
2.3ELISA法检测：CHD药前组与药后组HDL样品中SAA水平。
3.研究结果
与药前HDL中log(HDLSAA)的水平相比,CHD患者服用他汀类后HDL中的SAA水平明显下降(1.28±0.51vs.1.01±0.51,P=0.014),与iTRAQ结果一致。
4.研究小结
他汀类药物可显著下调HDL中SAA的水平。
(三)服用他汀类药物与未服用他汀类药物的冠心病患者血浆HDL中SAA差异水平的研究
1.研究目的
比较服用他汀类药物半年的CHD患者与未服用他汀类药物的CHD患者血浆HDL中SAA的水平,再次验证iTRAQ-LC-MS中鉴定的候选差异蛋白SAA2水平。
2.研究方法
2.1研究对象：
2.1.1CHD用药组(n=65)：至少有一支冠状动脉狭窄大于50%,入组时已经规律服用他汀类药物半年左右,未合并使用其他调脂药；
2.1.2CHD未用药组(n=67)：至少有一支冠状动脉狭窄大于50%,未服用任何调脂药；
2.2样品收集与HDL分离：收集空腹血浆：超高速离心分离HDL样品；
2.3ELISA法检测：CHD用药组与CHD未用药组HDL样品中SAA水平；
2.4统计学分析：利用协方差分析的方法校正两组之间的基线差异。
3.研究结果
3.1CHD用药组HDL中的log (HDL-SAA)水平与CHD未用药组相比,显著下降(1.34±0.58vs.1.04±0.46, P=0.0002)。
3.2校正总胆固醇、低密度脂蛋白胆固醇、apoA-Ⅰ、载脂蛋白B、肌酐、血糖及高敏C反应蛋白的水平差异后,log(HDL-SAA)在两组之间的差异仍有统计学意义(P=0.005)。
3.3进一步校正HDL-C的水平,log(HDL-SAA)在两组之间的差异仍有统计学意义(P=0.015)。
4.研究小结
HDL中的SAA水平与CHD患者服用他汀类药物有关。
三、结论
1.CHD患者HDL蛋白质组成发生改变：其中SAA水平明显升高,apoA-Ⅰ有下降趋势。SAA为CHD的危险因素。iTRAQ技术又新发现CHD组与对照组之间有13种差异蛋白(6种在CHD组HDL中上调,7种下调)。
2.CHD患者他汀药治疗后,SAA水平下降至正常水平,且不受其他因素影响。iTRAQ技术又新发现CHD组药后与药前HDL样品中有14种差异蛋白(10种在药后HDL中上调,4种下调)。
3.他汀类调脂药可改变HDL中某些蛋白水平。
4.HDL由多种蛋白质成分组成,可以从HDL蛋白组成研究HDL所具有的生物学功能。
Background
The alteration of proteins existing in high density lipoprotein (HDL) is found to affect its function. It will be helpful to comprehend the relationship between HDL and coronary heart disease (CHD) by studying the protein composition of HDL and to clarify the role of HDL in atherosclerosis further.
Recently, there are several studies exploring the proteins in HDL by proteomics technology, showing that the protein composition in HDL isolated from patients with CHD was different from controls and combined statin and niacin therapy may remodel the HDL proteome. However, the related study was rare and insufficient.
In our laboratory, we have conducted a preliminary study comparing the difference in HDL proteome between patients with CHD and controls and found that a significant decrease in the level of apolipoprotein A-I (apoA-I) and the increase in the level of serum amyloid A protein (SAA), which need to be validated in another independent group with larger sample size. In addition, there is no study exploring the effect of statins per se on HDL proteome at present, and the interaction between statins and HDL has been found in several studies.
Part1:The relationship between apolipoprotein A-I and SAA in high density lipoprotein isolated from patients with coronary heart disease
Object
To compare the difference in the levels of apoA-I and SAA in HDL isolated form patient with CHD and controls and understand the relationship between apoA-I and SAA.
Methods
Patients with at least one coronary artery stenosis more that50%and never take statins and other lipids-lowing drugs (CHD group) and a group of age and sex-matched subjects (control group) were enrolled. HDL was isolated by ultracentrifugation. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of apoA-I and SAA in plasma and in HDL. Pearson correlation analysis was used to explore the relationship between apoA-Ⅰ and SAA in HDL. Logistic regression was used to study the association between apoA-Ⅰ and CHD and between SAA and CHD.
Results
1.67patients and67controls were enrolled in this part of study.
2. Compared with controls, the level of apoA-Ⅰ was significantly decreased in HDL isolated from CHD patients (7.80±3.32g/mL vs.10.42±5.51g/mL, P=0.001). However, the difference was disappeared when adjusted by potential confounding factors (B=-0.109, P=0.088). The level of log (HDL-SAA) was significantly higher in CHD patient than the one in control group (1.39±0.58vs.1.15±0.46, P=0.011). The significance was still exist after adjustment for confounding factors (B=1.738, P=0.017). The OR value was5.685, which means that the risk of CHD will increase4.685when the log(HDL-SAA) increase1unit (OR=5.685,95%CI:1.371,23.581).
3. Compared with controls, the level of apoA-Ⅰ in plasma was not different between the two groups (0.7±0.33g/mL vs.0.79±0.28g/mL, P=0.122). The level of log(plasma-SAA) was significantly higher in CHD group than in control group (1.13±0.54vs.0.88±0.48, P=0.005) independently from confounding factors (B=1.646, P=0.038). The OR value for log(plasma-SAA) was5.185(OR=5.185,95%CI:1.095,24.544).
4. The level of apoA-I and SAA did not show any correlation in HDL or in plasma both in the two groups.
Part2:The alteration in HDL proteome by statins among patients with coronary heart disease
Objectives
To study the alteration in HDL proteome by statins among patients with coronary heart disease and the difference of the level of each protein in HDL isolated from CHD patient before and about half year after statins therapy.
Methods
HDL isolated from9patients with CHD before and about half year after statins therapy and10age-sex matched controls was analyzed by isobaric tags for relative and absolute quantitation (iTRAQ)-liquid chromatography-mass spectrometry. GO analysis was performed to understand the function classification and molecular activity of all detected proteins in HDL. Cluster analysis was used to clarify the difference characteristic of all proteins in HDL among the three groups. Treatment-induced decrease in SAA2level of HDL were validated in a second group of44CHD patients and45controls and in a third group of67CHD patients never using statins or other lipid-lowing drugs and65CHD patients who had already taken statins for about half year.
Results
1.196proteins with high confidence coefficient (FDR=0.01and at least two peptides matched) were detected by iTRAQ-LC-MS.
2. The GO analysis indicated that these detected proteins maybe involved in many biological processes, such as lipids-transport, inflammation, innate immune defence, and so on. These proteins also showed multiple activities, for example lipids-binding activity, enzyme inhibitor activity, peptide-chain hydrolysis activity, and so on.
3.14proteins were found different with significance in HDL isolated from CHD patients before statins therapy and after about half year therapy.13proteins were found different between CHD and control. There3proteins, serum amyloid A2isoform(SAA2)、complement C5preproprotein and histone H1.0, showed the same alteration trend in these three groups, which increased in CHD patients when compared with controls, and decreased in CHD patients after statins therapy.
4. The level of SAA was significantly decreased after statins therapy. The level of SAA in HDL among CHD patients was correlated with statins therapy.
Conclusion
1. HDL is composed of many proteins, and these proteins showed multiple activities, for example lipids-binding activity, enzyme inhibitor activity, peptide-chain hydrolysis activity, etc. and may be involved many biological processes, such as lipids-transport, inflammation, innate immune defence, and so on.
2. The HDL proteome is altered in patients with CHD. When compared with control, the level of SAA was significantly increased and there is a decrease trend in the level of apoA-I.13new proteins were found to be different between CHD group and control group in the present study.
3. Level of SAA was significantly decreased after statins therapy.14new proteins altered after statins therapy in the present study, which maybe the new targets of statins.
4. Statins may remodel the HDL proteome.
5. HDL is composed of many proteins, and the alteration of protein composition in HDL may be helpful to study the HDL functions.
引文
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