妊娠相关蛋白-A水平及IVS6+95多态性在预测PCI术后再狭窄的价值
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摘要
背景：冠状动脉粥样硬化性心脏病(coronary atherosclerotic heart disease, CAD)是目前临床上多发常见的疾病,同时也是致残率和病死率最高的疾病之一。其发病机理是：体内的炎症反应始终伴随动脉粥样硬化的全过程,并受遗传、环境等因素的影响。在冠脉病变的基础上和炎性因子的刺激下出现易损斑块破裂,引起冠脉血管痉挛、血小板粘附聚集、形成急性血栓致负荷过重,血流急剧减少,导致病变远端的血管非完全性或者完全性闭塞,心肌缺血缺氧,临床上表现为急性冠脉综合症(acute coronary syndrome, ACS)。随着新一代药物洗脱支架(drug eluting stent, DES)的出现,经皮冠脉介入治疗(percutaneous coronary intervention, PCI)的手术指证越来越宽泛,成为CAD患者缓解临床症状、改善生活质量的重要干预手段。尽管PCI术后长期给予双联抗血小板及新型P2Y12受体拮抗剂普拉格雷、替格瑞洛的推广应用,但仍有一部分患者出现术后再狭窄情况并出现相应临床症状,从而影响了手术效果和长期预后。如何在术前准确的预测和评价术后可能会发生再狭窄的患者并给予及时完善的干预措施已成为目前急需解决的问题。
目前临床上准确有效评价术后再狭窄的手段主要是冠脉造影(coronary angiography, CAG)和血管内超声(intravascular ultrasound, IVUS),但这两项检查不仅花费较大而且均属于侵入性检查。而非侵入性检查的炎性生物学标志物可用于CAD的危险分级和实时病情监测,有相当高的临床应用价值。因此寻找一种非侵入性、能够定量定性分析并在临床上普遍推广使用的新血清学炎症标志物十分必要。
妊娠相关蛋白A(pregnancy associated plasma protein A, PAPP-A)就是这样一种生物学指标。它的分子量为800000,是由两个分子量为38000嗜酸性粒细胞主要碱性蛋白前体(pro-form of eosinphi major basic protein, proMBP)和两个分子量为200000—500000的亚基组成。PAPP-A是锌离子依赖性基质金属蛋白酶(matrix metalloproteinase, MMps)家族中的一员,主要与胰岛素样生长因子轴(Insulin-like growth factor axis, IGFAxis)相关并发挥生物学作用。PAPP-A能特异性水解胰岛素样生长因子结合蛋白-4(insulin-like growth factor binding protein-4, IGFBP-4),使其裂解后成为两个小片段,不能再与胰岛素样生长因子(insulin-like growth factor, IGF)结合,引起IGF游离血清学浓度升高。IGF与相应受体结合可促进平滑肌细胞增生迁移、新生内膜形成,导致炎细胞趋化增多和炎症因子释放浸润；引起巨噬细胞、平滑肌细胞吞噬脂质转变为泡沫细胞增多,细胞外基质降解加快,纤维帽状结构变薄,最终导致粥样硬化斑块脆性增加、易破裂。研究发现PAPP-A第14外显子存在基因多态性并与早发CAD易感性有关。Park S等提出PAPP-A基因IVS6+95(C/G)(RS13290387)中也存在单核苷酸多态性(single nucleotide polymorphism, SNP),但目前国内外对其基因多态性研究甚少,作用机理尚不明确。
在机体组织遭受损伤或者处于炎症状态时,正常人体内含量非常少的C-反应蛋白(C reactive protein, CRP)浓度水平迅速升高。CAD本质是一种炎症反应,故CRP可作为CAD患者易损血液的炎性标志物之一。在病理状态下,由肝细胞合成和分泌的hs-CRP大量释放。它能促进低密度脂蛋白(low density lipoprotein, LDL)被氧化,氧化修饰低密度脂蛋白(Oxidized low density lipoprotein, ox-LDL)最终被巨噬细胞摄取,形成最初的病变脂质条纹；同时加速对内膜的损伤,激活并增加内皮细胞粘附分子(endothelial cell adhesion molecule, ECAM)的表达,从而引起内膜增生和PCI术后再狭窄。
尽管体内一些炎性因子的水平被证实与PCI术后再狭窄相关,但PAPP-A及其内含子IVS6+95((C/G))的单核苷酸多态性与术后再狭窄的关系尚不清楚。在本研究中,我们从肘静脉抽取血液标本检测血清可溶性PAPP-A、hs-CRP表达水平及IVS6+95((C/G))的单核苷酸多态性,研究它们与冠脉PCI术后再狭窄的关系。本学位论文的主要研究内容及实验结果如下：
目的：本实验旨在探讨UAP患者PAPP-A的血清水平以及IVS6+95(C/G)基因多态性预测UAP患者PCI术后再狭窄的意义。
方法：选取2011年1月-2012年8月在山东大学附属省立医院心内科病区住院确诊为UAP并行PCI术治疗的患者(TIMI血流达到3级),术后3-9(4.5±2.6)个月进行冠脉造影随访。选取血管腔内径狭窄≥75%者(再狭窄组)86例、无再狭窄组(对照组)152例。所有患者分别于术前、术后24h抽取外周血,应用酶联免疫吸附测定(enzyme-linked immunosorbent assays, ELISA)方法测定血清PAPP-A、hs-CRP水平。采用试剂盒法提取白细胞DNA,应用聚合酶链反应(polymerase chain reaction, PCR)、凝胶电泳成像技术、基因测序方法分析PAPP-A基因IVS6+95(C/G)的多态性,判定其基因型并统计基因型及等位基因的频率。
结果再狭窄组术后较术前血清PAPP-A、hs-CRP水平明显增高(P＜0.001)。对照组术后较术前血清PAPP-A、hs-CRP水平明显降低(P＜0.001)。术后两组间比较,再狭窄组的术后PAPP-A、hs-CRP水平明显高于对照组(P＜0.001)。两组术后PAPP-A、hs-CRP与冠脉内径丢失指数呈正相关(r=0.336,0.488,P＜0.01)。再狭窄组IVS6+95中CC基因频率明显高于未发生组(P＜0.05),而等位基因C频率无明显差异。
结论PCI术后再狭窄组PAPP-A、hs-CRP血清水平明显升高,可作为预测冠脉再狭窄的指标,IVS6+95(C/G)多态性可能与术后再狭窄有关,其中基因型CC是致病的基础。
Background:Coronary atherosclerotic heart disease is one of diseases with the highest morbidity and mortality rates. CAD is a chronic inflammatory reaction involved with genetic and environmental factors. On the basis of the blocked coronary artery and stimulation of inflammatory factors, the rupture of vulnerable plaque, induced vasospasm, platelet adhesion and aggregation and not completely blocked thrombosis are likely to happen, so that blood flow decreases dramatically, leading to myocardial ischemia, hypoxia and clinical manifestations of unstable angina. In recent years, with the emergence of drug-eluting stents, indication of percutaneous coronary intervention becomes broader, and becomes an important means of intervention which can relieve symptoms and improve quality of life. However, there are still about10%of patients facing restenosis after PCI and conventional double antiplatelet therapy, thus affecting the surgical effects and long-term prognosis. How to accurately predict and identify patients with restenosis postoperative and give an effective interventions has become an urgent problem to solve.
At present, the main accurate and effective means of evaluating restenosis in clinic are coronary angiography (the coronary angiography CAG) and intravascular ultrasound (intravascular ultrasound, IVUS), both of which are not only costly but also invasive. However, non-invasive inflammatory biological markers can be used in risk stratification and disease monitoring of ACS, and have a high clinical value. So to find a new non-invasive and serological inflammatory markers is essential.
Pregnancy associated plasma protein A (PAPP-A) is a biological indicator, located on chromosome9. Its molecular weight is800000, composed of two pro-forms of eosinphi major basic protein proMBP with molecular weight of38000and two subunits with molecular weight of200000to500000. It is a member of the zinc ions dependency matrix metalloproteinases matrix metalloproteinase family, and plays a biological role in the insulin-like growth factor axis. PAPP-A is the insulin-like growth factor binding protein-4-specific proteolytic enzyme, which cannot bind insulin-like growth factor after dissociating into two small fragments, so that the free IGF serological concentration becomes high and can promote the proliferation and migration of smooth muscle cell and neointima formation. Thus the chemotaxis of inflammatory cell increases, cytokines release and foam cells increase, derived from macrophages and smooth muscle cells after phagocytosing lipid, while the extracellular matrix degradation accelerats and the fibrous cap-like structure becomes thin, and ultimately plaques rupture.Study found that14exon of PAPP-A exists gene polymorphism and relates to the susceptibility of premature coronary heart disease. Park S also proposed IVS6+95(C/G) gene of PAPP-A existed single nucleotide polymorphism, however its underlying mechanism is still unclear.
High sensitivity C reactive protein synthesised and secreted by the liver cells can bind to pneumococcal polysaccharide and is considered as a non-specific inflammatory sensitive marker, when the body is in the inflammatory state, quantities of hs-CRP are released, which can promote macrophage to uptake LDL and ox-LDL, accelerate the intimal injury and increase the expression of EC AM. Finally intimal hyperplasia and restenosis happen.
Although in vivo the level of inflammatory cytokines was confirmed to be associated with restenosis after PCI, the relationship betweeen restenosis and PAPP-A and the single nucleotide polymorphisms of its intron IVS6+95((C/G)) is unclear. In this study, we examine the expression levels of PAPP-A, hs-CRP and single nucleotide polymorphism of IVS6+95(C/G) and study the relationship between those markers and restenosis after PCI. The main contents and results of this dissertation are as follows.
Objective:To explore the value of pregnancy associated plasma protein A、high sensitivity C-reactive protein and IVS6+95gene polymorphism in prediction of restenosis after percutaneous coronary intervention.
Methods:The patients with unstable angina pectoris were performed PCI. Those patients were classified as group A (86cases with related coronary artery lumen loss more than75%in diameter3-9months after PCI) and group B (the rest152cases with related coronary lumen loss less than75%). Serum PAPP-A and hs-CRP levels were examined before and24h after coronary angiography. The gene polymorphisms was analyzed by gene sequencing.
Results:Serum PAPP-A and hs-CRP levels were significantly increased In group A and decreased in group B after PCI (P<0.001). The CC gene frequency of PAPP-A gene IVS6+95was significantly higher in group A than in group B(P<0.05). But there were no difference in the frequency of allele C between two groups(P>0.05).
Conclusion:PAPP-A and hs-CRP level increase after PCI have a strong power in prediction of coronary artery restenosis after PCI. The polymorphism of PAPP-A gene IVS6+95(C/G) may be associated with postoperative restenosis and CC genotypes may be the foundation of pathogen.
目前临床上准确有效评价术后再狭窄的手段主要是冠脉造影(coronary angiography, CAG)和血管内超声(intravascular ultrasound, IVUS),但这两项检查不仅花费较大而且均属于侵入性检查。而非侵入性检查的炎性生物学标志物可用于CAD的危险分级和实时病情监测,有相当高的临床应用价值。因此寻找一种非侵入性、能够定量定性分析并在临床上普遍推广使用的新血清学炎症标志物十分必要。
妊娠相关蛋白A(pregnancy associated plasma protein A, PAPP-A)就是这样一种生物学指标。它的分子量为800000,是由两个分子量为38000嗜酸性粒细胞主要碱性蛋白前体(pro-form of eosinphi major basic protein, proMBP)和两个分子量为200000—500000的亚基组成。PAPP-A是锌离子依赖性基质金属蛋白酶(matrix metalloproteinase, MMps)家族中的一员,主要与胰岛素样生长因子轴(Insulin-like growth factor axis, IGFAxis)相关并发挥生物学作用。PAPP-A能特异性水解胰岛素样生长因子结合蛋白-4(insulin-like growth factor binding protein-4, IGFBP-4),使其裂解后成为两个小片段,不能再与胰岛素样生长因子(insulin-like growth factor, IGF)结合,引起IGF游离血清学浓度升高。IGF与相应受体结合可促进平滑肌细胞增生迁移、新生内膜形成,导致炎细胞趋化增多和炎症因子释放浸润；引起巨噬细胞、平滑肌细胞吞噬脂质转变为泡沫细胞增多,细胞外基质降解加快,纤维帽状结构变薄,最终导致粥样硬化斑块脆性增加、易破裂。研究发现PAPP-A第14外显子存在基因多态性并与早发CAD易感性有关。Park S等提出PAPP-A基因IVS6+95(C/G)(RS13290387)中也存在单核苷酸多态性(single nucleotide polymorphism, SNP),但目前国内外对其基因多态性研究甚少,作用机理尚不明确。
在机体组织遭受损伤或者处于炎症状态时,正常人体内含量非常少的C-反应蛋白(C reactive protein, CRP)浓度水平迅速升高。CAD本质是一种炎症反应,故CRP可作为CAD患者易损血液的炎性标志物之一。在病理状态下,由肝细胞合成和分泌的hs-CRP大量释放。它能促进低密度脂蛋白(low density lipoprotein, LDL)被氧化,氧化修饰低密度脂蛋白(Oxidized low density lipoprotein, ox-LDL)最终被巨噬细胞摄取,形成最初的病变脂质条纹；同时加速对内膜的损伤,激活并增加内皮细胞粘附分子(endothelial cell adhesion molecule, ECAM)的表达,从而引起内膜增生和PCI术后再狭窄。
尽管体内一些炎性因子的水平被证实与PCI术后再狭窄相关,但PAPP-A及其内含子IVS6+95((C/G))的单核苷酸多态性与术后再狭窄的关系尚不清楚。在本研究中,我们从肘静脉抽取血液标本检测血清可溶性PAPP-A、hs-CRP表达水平及IVS6+95((C/G))的单核苷酸多态性,研究它们与冠脉PCI术后再狭窄的关系。本学位论文的主要研究内容及实验结果如下：
目的：本实验旨在探讨UAP患者PAPP-A的血清水平以及IVS6+95(C/G)基因多态性预测UAP患者PCI术后再狭窄的意义。
方法：选取2011年1月-2012年8月在山东大学附属省立医院心内科病区住院确诊为UAP并行PCI术治疗的患者(TIMI血流达到3级),术后3-9(4.5±2.6)个月进行冠脉造影随访。选取血管腔内径狭窄≥75%者(再狭窄组)86例、无再狭窄组(对照组)152例。所有患者分别于术前、术后24h抽取外周血,应用酶联免疫吸附测定(enzyme-linked immunosorbent assays, ELISA)方法测定血清PAPP-A、hs-CRP水平。采用试剂盒法提取白细胞DNA,应用聚合酶链反应(polymerase chain reaction, PCR)、凝胶电泳成像技术、基因测序方法分析PAPP-A基因IVS6+95(C/G)的多态性,判定其基因型并统计基因型及等位基因的频率。
结果再狭窄组术后较术前血清PAPP-A、hs-CRP水平明显增高(P＜0.001)。对照组术后较术前血清PAPP-A、hs-CRP水平明显降低(P＜0.001)。术后两组间比较,再狭窄组的术后PAPP-A、hs-CRP水平明显高于对照组(P＜0.001)。两组术后PAPP-A、hs-CRP与冠脉内径丢失指数呈正相关(r=0.336,0.488,P＜0.01)。再狭窄组IVS6+95中CC基因频率明显高于未发生组(P＜0.05),而等位基因C频率无明显差异。
结论PCI术后再狭窄组PAPP-A、hs-CRP血清水平明显升高,可作为预测冠脉再狭窄的指标,IVS6+95(C/G)多态性可能与术后再狭窄有关,其中基因型CC是致病的基础。
Background:Coronary atherosclerotic heart disease is one of diseases with the highest morbidity and mortality rates. CAD is a chronic inflammatory reaction involved with genetic and environmental factors. On the basis of the blocked coronary artery and stimulation of inflammatory factors, the rupture of vulnerable plaque, induced vasospasm, platelet adhesion and aggregation and not completely blocked thrombosis are likely to happen, so that blood flow decreases dramatically, leading to myocardial ischemia, hypoxia and clinical manifestations of unstable angina. In recent years, with the emergence of drug-eluting stents, indication of percutaneous coronary intervention becomes broader, and becomes an important means of intervention which can relieve symptoms and improve quality of life. However, there are still about10%of patients facing restenosis after PCI and conventional double antiplatelet therapy, thus affecting the surgical effects and long-term prognosis. How to accurately predict and identify patients with restenosis postoperative and give an effective interventions has become an urgent problem to solve.
At present, the main accurate and effective means of evaluating restenosis in clinic are coronary angiography (the coronary angiography CAG) and intravascular ultrasound (intravascular ultrasound, IVUS), both of which are not only costly but also invasive. However, non-invasive inflammatory biological markers can be used in risk stratification and disease monitoring of ACS, and have a high clinical value. So to find a new non-invasive and serological inflammatory markers is essential.
Pregnancy associated plasma protein A (PAPP-A) is a biological indicator, located on chromosome9. Its molecular weight is800000, composed of two pro-forms of eosinphi major basic protein proMBP with molecular weight of38000and two subunits with molecular weight of200000to500000. It is a member of the zinc ions dependency matrix metalloproteinases matrix metalloproteinase family, and plays a biological role in the insulin-like growth factor axis. PAPP-A is the insulin-like growth factor binding protein-4-specific proteolytic enzyme, which cannot bind insulin-like growth factor after dissociating into two small fragments, so that the free IGF serological concentration becomes high and can promote the proliferation and migration of smooth muscle cell and neointima formation. Thus the chemotaxis of inflammatory cell increases, cytokines release and foam cells increase, derived from macrophages and smooth muscle cells after phagocytosing lipid, while the extracellular matrix degradation accelerats and the fibrous cap-like structure becomes thin, and ultimately plaques rupture.Study found that14exon of PAPP-A exists gene polymorphism and relates to the susceptibility of premature coronary heart disease. Park S also proposed IVS6+95(C/G) gene of PAPP-A existed single nucleotide polymorphism, however its underlying mechanism is still unclear.
High sensitivity C reactive protein synthesised and secreted by the liver cells can bind to pneumococcal polysaccharide and is considered as a non-specific inflammatory sensitive marker, when the body is in the inflammatory state, quantities of hs-CRP are released, which can promote macrophage to uptake LDL and ox-LDL, accelerate the intimal injury and increase the expression of EC AM. Finally intimal hyperplasia and restenosis happen.
Although in vivo the level of inflammatory cytokines was confirmed to be associated with restenosis after PCI, the relationship betweeen restenosis and PAPP-A and the single nucleotide polymorphisms of its intron IVS6+95((C/G)) is unclear. In this study, we examine the expression levels of PAPP-A, hs-CRP and single nucleotide polymorphism of IVS6+95(C/G) and study the relationship between those markers and restenosis after PCI. The main contents and results of this dissertation are as follows.
Objective:To explore the value of pregnancy associated plasma protein A、high sensitivity C-reactive protein and IVS6+95gene polymorphism in prediction of restenosis after percutaneous coronary intervention.
Methods:The patients with unstable angina pectoris were performed PCI. Those patients were classified as group A (86cases with related coronary artery lumen loss more than75%in diameter3-9months after PCI) and group B (the rest152cases with related coronary lumen loss less than75%). Serum PAPP-A and hs-CRP levels were examined before and24h after coronary angiography. The gene polymorphisms was analyzed by gene sequencing.
Results:Serum PAPP-A and hs-CRP levels were significantly increased In group A and decreased in group B after PCI (P<0.001). The CC gene frequency of PAPP-A gene IVS6+95was significantly higher in group A than in group B(P<0.05). But there were no difference in the frequency of allele C between two groups(P>0.05).
Conclusion:PAPP-A and hs-CRP level increase after PCI have a strong power in prediction of coronary artery restenosis after PCI. The polymorphism of PAPP-A gene IVS6+95(C/G) may be associated with postoperative restenosis and CC genotypes may be the foundation of pathogen.
引文
[1]吴锡桂.我国人群CAD流行现况与趋势[J].中国慢性病预防与控制2003,11(4)：190-191.
[2]Nordlie MA,Wold LE, Kloner RA. Genetic contributors toward increased risk for ischemic heart disease [J].J Mol Cell cardiol,2005,39(4):667-679.
[3]吕树铮.CAD介入治疗器械应用评价[J].生物医学工程与临床,2003,7(4)：241-245.
[4]Pendyala L,Jabara R,Shinke T, et al. Drug-eluting stents:present and future[J].Cardiovasc Hematol Agents Med Chem.2008,6(2):105-115.
[5]徐宝华,赵慧颖.动脉粥样硬化不稳定斑块的研究进展[J].心血管病学进展,2005,26(5)：498-501.
[6]Rifai N,Ridker PM.Proposed cardiovascular risk assessment algorithm using high-sensitivity C-reactive protein and lipid screening[J]. Clin Chem,2001, 47(1):28-30.
[7]Eren E,Yilmaz N,Pence S et al. Diagnostic value of C-reactive protein in patients with angiographically documented coronary heart disease[J].Acta Medica,2002, 45(4):155-160.
[8]Walter DH,Fichtlscherer S,Sellwig M, et al. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation[J]. J Am Coll Cardiol,2001,37(3):839-845.
[9]Altieri DC,Mannucci PM,Capitanio AM.Binding of fibrinogen to human monocytes[J]. J Clin Invest,1986,78(4):968-976.
[10]Straumann E, Bertel O. Acute coronary syndrome and myocardial infarct--new definitions [J].Ther Umsch,2002,59(2):66-67.
[11]Newby,LK. Cardiac marker testing:where should we focus? [J].Am Heart J, 2000,140(3):351-353.
[12]Apple FS,Wu AH,Mair J, et al. Future Biomarkers for detection of ischemia and risk stratification in acute coronary syndrome [J]. Clin Chem,2005, 51(5):810-824.
[13]AlltoniBayes-Genis,CherylA.Conover,RobertS.Schwartz.The Insulin-Like Growth Factor Axis A Review of Atherosclerosis and Restenosis[J]. Circulation Research.2000,86(2):125-130
[14]Bayes-Genis A,Conover CA,Schwartz RS.The insulin-like growth factor axis:A review of atherosclerosis and restenosis [J]. Circ Res,2000,86(2):125-130.
[15]Lin TM, Galbert SP,Kiefer DS, et al. Characterization of four human pregnancy associated plasm a protein[J].Am J Obstet Gyneco,1974,118(2):223-236.
[16]Qin QP, Laitinen P, M ajamaa VolttiK, et al. Release patterns of pregnancy associated plasm a protein-A (PAPP-A)in patients with acute coronary syndromes[J]. Scand Cardiovasc J,2002,36(6):358-361.
[17]Schaefer EJ. Lipoproteins, nutrition, and heart disease[J]. Am J Clin Nutr. 2002,75(2):191-212.
[18]Park S, Youn JC, Shin DJ, et al. Genetic polymorphism in the pregnancy associated plasma protein-A associated with acute myocardial infarction[J]. Coron Artery Dis,2007,18(6):417-422.
[1]He J,Gu D,Wu X, et al. Major causes of death among men and women in China [J].N Engl Med,2005,353(11):1124-1134.
[2]杨洁颖,王飞,于瀛,等.非ST段抬高型急性冠状动脉综合征患者经皮冠状动脉介入术前强化他汀治疗对心血管事件的影响[J].中国医药,2011,6(7)：769-771.
[3]唐毅,李江,罗俊.内皮祖细胞治疗对经皮冠脉支架植入术后再内皮化研究进展[J].医学与哲学,2012,33(451)：35-38.
[4]Bayes-Genis A,Conover C A,Overgaard M T,et al.Pregnancy-associated plasma protein A as a marker of acute coronary syndromes[J].N Engl J Med,2001,345 (14):1022-1029.
[5]Iversen K K,Teisner B,Winkel P, et al. Pregnancy associated plasma protein-A as a marker for myocardial infarction and death in patients with stable coronary artery disease:a prognostic study within the CLARICOR Trial[J]. Atherosclerosis,2011,214(1):203-208.
[6]Naghavi M,Libby P,Falk E, et al.From vulnerable plaque to vulnerable patient:a call for new definitions and risk assessment strategies [J]. Part Ⅱ.Circulation, 2003,108(15):1772-1778.
[7]AlltoniBayes-Genis,CherylA.Conover,RobertS.Schwartz.The insulin- like growth factor axis a review of atherosclerosis and restenosis [J]. Circulation Research.2000,86(2):125-130.
[8]Libby P.Inflammation and atherosclerosis [J] Nature,2002,420 (6917) 868-874.
[9]Nesto R. C-reactive protein,its role in inflammation,Type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones[J].Diabet Med,2004,21(8):810-817.
[10]Verma S,Kuliszewski M A,Li S H, et al. C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function:further evidence of a mechanistic link between C-reactive protein and cardiovascular disease [J]. Circulation,2004,109(17):2058-2067.
[11]姚友杰,杨敏华,许炳灿,等.血清尿酸、胆红素和超敏C反应蛋白与冠状动脉病变程度关系研究[J].中国介入心脏病学杂志,2008,16(6)：323-327.
[12]van Wanrooij E J,van Puijvelde G H,de Vos P, et al. Interruption of the Tnfrsf4/Tnfsf4(OX40/OX40L) pathway attenuates atherogenesis inlow-density lipoprotein receptor-deficient mice[J].Arterioscler Thromb Vasc Biol 2007, 27(1):204-210.
[13]Poon P Y,Szeto C C, Kwan B C, et al. Relationship between CRP polymorphism and cardiovascular events in Chinese peritoneal dialysis patients [J]. Clin J Am Soc Nephrol,2012,7(2):304-309.
[14]Sampietro T,Dal Pino B,Bigazzi F, et al.Increased plasma C-reactive protein in familial hypoalphalipoproteinemia a proinflammatory condition [J]? Circulation,2002,105(1),11-14.
[15]Nobuyoshi M,Kimura T,Nosaka H, et al.Restenosis after successful percutaneous transluminal coronary angioplasty:serial angiographic follow-up of 229 patients [J]. J Am Coll Cardiol,1988,12(3):616-623.
[16]Tomai F,Crea F,Gaspardone A, et al.Unstable angina and elevated c-reactive protein levels predict enhanced vasoreactivity of the lesion[J]. culprit. Circulation,2001,104(13):1471-1476.
[17]Yasojima K,Schwab C,McGeer EG, et al.Generation of C-reactive protein and complement components in atherosclerotic plaques[J].Am J Pathol.2001,158 (3):1039-1051.
[18]Walter DH,Fichtlscherer S,Sellwig M, et al.Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation[J].J Am Coll Cardiol,2001,37(3):839-845.
[19]Boldt H B and Conover C A. Pregnancy-associated plasma protein-A (PAPP-A): a local regulator of IGF bioavailability through cleavage of IGFBPs [J]. Growth Horm IGF Res,2007,17(1):10-18.
[20]Miedema M D, Conover C A, MacDonald H, et al. Pregnancy-associated plasma protein-A elevation in patients with acute coronary syndrome and subsequent atorvastatin therapy [J]. Am J Cardiol,2008,101(1):35-39.
[21]Frosk P, Weiler T, Nylen E, et al. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene[J]. Am J Hum Genet,2002,70(3):663-672.
[22]Henderson C E, Bromek K, Mullin N P, et al. Solution structure and dynamics of the central CCP module pair of a poxvirus complement control protein[J]. J Mol Biol,2001,307(1):323-339.
[1].Boldt H B, Conover CA.Pregnancy-associated plasma protein-A (PAPP-A):a local regulator of IGF bioavailability through cleavage of IGFBPs [J].Growth Horm IGF Res,2007.17(1):p.10-8.
[2].Qin QP, Wittfooth S,Pettersson K.Measurement and clinical significance of circulating PAPP-A in ACS patients [J].Clin Chim Acta,2007.380(1-2):p. 59-67.
[3].Luthgens K,Hoopmann M,Alkier R, et al.[First-trimester screening for trisomies 18 and 13 with the combined use of the risk algorithms for trisomy 21,18 and 13] [J]. Ultraschall Med,2012.33(7):p. E57-61.
[4].Lawrence JB, Oxvig C,Overgaard MT,et al. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A[J]. Proc Natl Acad Sci U S A,1999. 96(6):p.3149-53.
[5].Gyrup C,Oxvig C. Quantitative analysis of insulin-like growth factor-modulated proteolysis of insulin-like growth factor binding protein-4 and -5 by pregnancy-associated plasma protein-A[J]. Biochemistry,2007.46(7):p. 1972-80.
[6].Conover CA,Bale LK,Harrington SC, et al Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells:inhibition by resveratrol[J]. Am J Physiol Cell Physiol, 2006.290(1):p. C183-8.
[7].Conover CA,Harrington SC, Bale LK. Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells[J]. Growth Horm IGF Res,2008.18(3):p.213-20.
[8].Bayes-Genis A,Conover CA,Overgaard MT, et al.Pregnancy-associated plasma protein A as a marker of acute coronary syndromes [J]. N Engl J Med,2001. 345(14):p.1022-9.
[9]. Harrington SC, Simari RD,Conover CA. Genetic deletion of pregnancy-associated plasma protein-A is associated with resistance to atherosclerotic lesion development in apolipoprotein E-deficient mice challenged with a high-fat diet[J]. Circ Res,2007.100(12):p.1696-702.
[10].Iversen KK,Teisner AS,Teisner B, et al. Pregnancy associated plasma protein A, a novel, quick, and sensitive marker in ST-elevation myocardial infarction[J]. Am J Cardiol,2008.101(10):p.1389-94.
[11].Gururajan P, Gurumurthy P, Nayar P, et al.Pregnancy associated plasma protein-A (PAPP-A) as an early marker for the diagnosis of acute coronary syndrome[J]. Indian Heart J,2012.64(2):p.141-5.
[12].Iversen KK,Teisne AS, Teisner B, et al. Pregnancy associated plasma protein A, a potential marker for vulnerable plaque in patients with non-ST-segment elevation acute coronary syndrome[J]. Clin Biochem,2009.42(9):p.828-34.
[13].Lund J,Wittfooth S, Qin QP, et al. Free vs total pregnancy-associated plasma protein A (PAPP-A) as a predictor of 1-year outcome in patients presenting with non-ST-elevation acute coronary syndrome[J]. Clin Chem,2010.56(7):p. 1158-65.
[14].Li Y, Zhou C, Zhou X,et al. PAPP-A in cardiac and non-cardiac conditions[J]. Clin Chim Acta,2013.417:p.67-72.
[15].Consuegra-Sanchez L, Fredericks S, Kaski JC. Pregnancy-associated plasma protein-A (PAPP-A) and cardiovascular risk[J]. Atherosclerosis,2009.203(2):p. 346-52.
[16].Aso Y, Okumura K, Wakabayashi S, et al. Elevated pregnancy-associated plasma protein-a in sera from type 2 diabetic patients with hypercholesterolemia: associations with carotid atherosclerosis and toe-brachial index[J]. J Clin Endocrinol Metab,2004.89(11):p.5713-7.
[17].Sangiorgi G, Mauriello A, Bonanno E, et al. Pregnancy-associated plasma protein-a is markedly expressed by monocyte-macrophage cells in vulnerable and ruptured carotid atherosclerotic plaques:a link between inflammation and cerebrovascular events[J]. J Am Coll Cardiol,2006.47(11):p.2201-11.
[18].Heider P, Pfaffle N, Pelisek J,et al. Is serum pregnancy-associated plasma protein A really a potential marker of atherosclerotic carotid plaque stability[J]? Eur J Vasc Endovasc Surg,2010.39(6):p.668-75.
[19].Pellitero S, Reverter JL, Pizarro E, et al.Pregnancy-associated plasma protein-a levels are related to glycemic control but not to lipid profile or hemostatic parameters in type 2 diabetes[J]. Diabetes Care,2007.30(12):p.3083-5.
[20].Pellitero S, Reverter JL, Granada ML, et al. Association of the IGF 1/pregnancy-associated plasma protein-A system and adipocytokine levels with the presence and the morphology of carotid plaques in type 2 diabetes mellitus patients with stable glycaemic control[J]. Eur J Endocrinol,2009. 160(6):p.925-32.
[21].Miedema MD, Conover CA, MacDonald H, et al. Pregnancy-associated plasma protein-A elevation in patients with acute coronary syndrome and subsequent atorvastatin therapy[J]. Am J Cardiol,2008.101(1):p.35-9.
[22].Conover CA, Bale LK. Loss of pregnancy-associated plasma protein A extends lifespan in mice[J]. Aging Cell,2007.6(5):p.727-9.
[23].Kalli KR, Chen BK, Bale LK, et al. Pregnancy-associated plasma protein-A (PAPP-A) expression and insulin-like growth factor binding protein-4 protease activity in normal and malignant ovarian surface epithelial cells[J]. Int J Cancer, 2004.110(5):p.633-40.
[24].Ryan AJ, Napoletano S, Fitzpatrick PA, et al. Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer[J]. Br J Cancer,2009.101(2):p.278-86.
[25].Coskun A, Duran S, Apaydin S, et al. Pregnancy-associated plasma protein-A: evaluation of a new biomarker in renal transplant patients[J]. Transplant Proc, 2007.39(10):p.3072-6.
[26].Sancho A, Pastor MC, Bayes B, et al. Posttransplant inflammation associated with onset of chronic kidney disease[J]. Transplant Proc,2010.42(8):p.2896-8.
[27].Lauzurica R, Pastor C, Bayes B, et al. Pretransplant pregnancy-associated plasma protein-a as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events [J]. Transplantation,2005.80(10):p.1441-6.
[2]Nordlie MA,Wold LE, Kloner RA. Genetic contributors toward increased risk for ischemic heart disease [J].J Mol Cell cardiol,2005,39(4):667-679.
[3]吕树铮.CAD介入治疗器械应用评价[J].生物医学工程与临床,2003,7(4)：241-245.
[4]Pendyala L,Jabara R,Shinke T, et al. Drug-eluting stents:present and future[J].Cardiovasc Hematol Agents Med Chem.2008,6(2):105-115.
[5]徐宝华,赵慧颖.动脉粥样硬化不稳定斑块的研究进展[J].心血管病学进展,2005,26(5)：498-501.
[6]Rifai N,Ridker PM.Proposed cardiovascular risk assessment algorithm using high-sensitivity C-reactive protein and lipid screening[J]. Clin Chem,2001, 47(1):28-30.
[7]Eren E,Yilmaz N,Pence S et al. Diagnostic value of C-reactive protein in patients with angiographically documented coronary heart disease[J].Acta Medica,2002, 45(4):155-160.
[8]Walter DH,Fichtlscherer S,Sellwig M, et al. Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation[J]. J Am Coll Cardiol,2001,37(3):839-845.
[9]Altieri DC,Mannucci PM,Capitanio AM.Binding of fibrinogen to human monocytes[J]. J Clin Invest,1986,78(4):968-976.
[10]Straumann E, Bertel O. Acute coronary syndrome and myocardial infarct--new definitions [J].Ther Umsch,2002,59(2):66-67.
[11]Newby,LK. Cardiac marker testing:where should we focus? [J].Am Heart J, 2000,140(3):351-353.
[12]Apple FS,Wu AH,Mair J, et al. Future Biomarkers for detection of ischemia and risk stratification in acute coronary syndrome [J]. Clin Chem,2005, 51(5):810-824.
[13]AlltoniBayes-Genis,CherylA.Conover,RobertS.Schwartz.The Insulin-Like Growth Factor Axis A Review of Atherosclerosis and Restenosis[J]. Circulation Research.2000,86(2):125-130
[14]Bayes-Genis A,Conover CA,Schwartz RS.The insulin-like growth factor axis:A review of atherosclerosis and restenosis [J]. Circ Res,2000,86(2):125-130.
[15]Lin TM, Galbert SP,Kiefer DS, et al. Characterization of four human pregnancy associated plasm a protein[J].Am J Obstet Gyneco,1974,118(2):223-236.
[16]Qin QP, Laitinen P, M ajamaa VolttiK, et al. Release patterns of pregnancy associated plasm a protein-A (PAPP-A)in patients with acute coronary syndromes[J]. Scand Cardiovasc J,2002,36(6):358-361.
[17]Schaefer EJ. Lipoproteins, nutrition, and heart disease[J]. Am J Clin Nutr. 2002,75(2):191-212.
[18]Park S, Youn JC, Shin DJ, et al. Genetic polymorphism in the pregnancy associated plasma protein-A associated with acute myocardial infarction[J]. Coron Artery Dis,2007,18(6):417-422.
[1]He J,Gu D,Wu X, et al. Major causes of death among men and women in China [J].N Engl Med,2005,353(11):1124-1134.
[2]杨洁颖,王飞,于瀛,等.非ST段抬高型急性冠状动脉综合征患者经皮冠状动脉介入术前强化他汀治疗对心血管事件的影响[J].中国医药,2011,6(7)：769-771.
[3]唐毅,李江,罗俊.内皮祖细胞治疗对经皮冠脉支架植入术后再内皮化研究进展[J].医学与哲学,2012,33(451)：35-38.
[4]Bayes-Genis A,Conover C A,Overgaard M T,et al.Pregnancy-associated plasma protein A as a marker of acute coronary syndromes[J].N Engl J Med,2001,345 (14):1022-1029.
[5]Iversen K K,Teisner B,Winkel P, et al. Pregnancy associated plasma protein-A as a marker for myocardial infarction and death in patients with stable coronary artery disease:a prognostic study within the CLARICOR Trial[J]. Atherosclerosis,2011,214(1):203-208.
[6]Naghavi M,Libby P,Falk E, et al.From vulnerable plaque to vulnerable patient:a call for new definitions and risk assessment strategies [J]. Part Ⅱ.Circulation, 2003,108(15):1772-1778.
[7]AlltoniBayes-Genis,CherylA.Conover,RobertS.Schwartz.The insulin- like growth factor axis a review of atherosclerosis and restenosis [J]. Circulation Research.2000,86(2):125-130.
[8]Libby P.Inflammation and atherosclerosis [J] Nature,2002,420 (6917) 868-874.
[9]Nesto R. C-reactive protein,its role in inflammation,Type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones[J].Diabet Med,2004,21(8):810-817.
[10]Verma S,Kuliszewski M A,Li S H, et al. C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function:further evidence of a mechanistic link between C-reactive protein and cardiovascular disease [J]. Circulation,2004,109(17):2058-2067.
[11]姚友杰,杨敏华,许炳灿,等.血清尿酸、胆红素和超敏C反应蛋白与冠状动脉病变程度关系研究[J].中国介入心脏病学杂志,2008,16(6)：323-327.
[12]van Wanrooij E J,van Puijvelde G H,de Vos P, et al. Interruption of the Tnfrsf4/Tnfsf4(OX40/OX40L) pathway attenuates atherogenesis inlow-density lipoprotein receptor-deficient mice[J].Arterioscler Thromb Vasc Biol 2007, 27(1):204-210.
[13]Poon P Y,Szeto C C, Kwan B C, et al. Relationship between CRP polymorphism and cardiovascular events in Chinese peritoneal dialysis patients [J]. Clin J Am Soc Nephrol,2012,7(2):304-309.
[14]Sampietro T,Dal Pino B,Bigazzi F, et al.Increased plasma C-reactive protein in familial hypoalphalipoproteinemia a proinflammatory condition [J]? Circulation,2002,105(1),11-14.
[15]Nobuyoshi M,Kimura T,Nosaka H, et al.Restenosis after successful percutaneous transluminal coronary angioplasty:serial angiographic follow-up of 229 patients [J]. J Am Coll Cardiol,1988,12(3):616-623.
[16]Tomai F,Crea F,Gaspardone A, et al.Unstable angina and elevated c-reactive protein levels predict enhanced vasoreactivity of the lesion[J]. culprit. Circulation,2001,104(13):1471-1476.
[17]Yasojima K,Schwab C,McGeer EG, et al.Generation of C-reactive protein and complement components in atherosclerotic plaques[J].Am J Pathol.2001,158 (3):1039-1051.
[18]Walter DH,Fichtlscherer S,Sellwig M, et al.Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation[J].J Am Coll Cardiol,2001,37(3):839-845.
[19]Boldt H B and Conover C A. Pregnancy-associated plasma protein-A (PAPP-A): a local regulator of IGF bioavailability through cleavage of IGFBPs [J]. Growth Horm IGF Res,2007,17(1):10-18.
[20]Miedema M D, Conover C A, MacDonald H, et al. Pregnancy-associated plasma protein-A elevation in patients with acute coronary syndrome and subsequent atorvastatin therapy [J]. Am J Cardiol,2008,101(1):35-39.
[21]Frosk P, Weiler T, Nylen E, et al. Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene[J]. Am J Hum Genet,2002,70(3):663-672.
[22]Henderson C E, Bromek K, Mullin N P, et al. Solution structure and dynamics of the central CCP module pair of a poxvirus complement control protein[J]. J Mol Biol,2001,307(1):323-339.
[1].Boldt H B, Conover CA.Pregnancy-associated plasma protein-A (PAPP-A):a local regulator of IGF bioavailability through cleavage of IGFBPs [J].Growth Horm IGF Res,2007.17(1):p.10-8.
[2].Qin QP, Wittfooth S,Pettersson K.Measurement and clinical significance of circulating PAPP-A in ACS patients [J].Clin Chim Acta,2007.380(1-2):p. 59-67.
[3].Luthgens K,Hoopmann M,Alkier R, et al.[First-trimester screening for trisomies 18 and 13 with the combined use of the risk algorithms for trisomy 21,18 and 13] [J]. Ultraschall Med,2012.33(7):p. E57-61.
[4].Lawrence JB, Oxvig C,Overgaard MT,et al. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A[J]. Proc Natl Acad Sci U S A,1999. 96(6):p.3149-53.
[5].Gyrup C,Oxvig C. Quantitative analysis of insulin-like growth factor-modulated proteolysis of insulin-like growth factor binding protein-4 and -5 by pregnancy-associated plasma protein-A[J]. Biochemistry,2007.46(7):p. 1972-80.
[6].Conover CA,Bale LK,Harrington SC, et al Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells:inhibition by resveratrol[J]. Am J Physiol Cell Physiol, 2006.290(1):p. C183-8.
[7].Conover CA,Harrington SC, Bale LK. Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells[J]. Growth Horm IGF Res,2008.18(3):p.213-20.
[8].Bayes-Genis A,Conover CA,Overgaard MT, et al.Pregnancy-associated plasma protein A as a marker of acute coronary syndromes [J]. N Engl J Med,2001. 345(14):p.1022-9.
[9]. Harrington SC, Simari RD,Conover CA. Genetic deletion of pregnancy-associated plasma protein-A is associated with resistance to atherosclerotic lesion development in apolipoprotein E-deficient mice challenged with a high-fat diet[J]. Circ Res,2007.100(12):p.1696-702.
[10].Iversen KK,Teisner AS,Teisner B, et al. Pregnancy associated plasma protein A, a novel, quick, and sensitive marker in ST-elevation myocardial infarction[J]. Am J Cardiol,2008.101(10):p.1389-94.
[11].Gururajan P, Gurumurthy P, Nayar P, et al.Pregnancy associated plasma protein-A (PAPP-A) as an early marker for the diagnosis of acute coronary syndrome[J]. Indian Heart J,2012.64(2):p.141-5.
[12].Iversen KK,Teisne AS, Teisner B, et al. Pregnancy associated plasma protein A, a potential marker for vulnerable plaque in patients with non-ST-segment elevation acute coronary syndrome[J]. Clin Biochem,2009.42(9):p.828-34.
[13].Lund J,Wittfooth S, Qin QP, et al. Free vs total pregnancy-associated plasma protein A (PAPP-A) as a predictor of 1-year outcome in patients presenting with non-ST-elevation acute coronary syndrome[J]. Clin Chem,2010.56(7):p. 1158-65.
[14].Li Y, Zhou C, Zhou X,et al. PAPP-A in cardiac and non-cardiac conditions[J]. Clin Chim Acta,2013.417:p.67-72.
[15].Consuegra-Sanchez L, Fredericks S, Kaski JC. Pregnancy-associated plasma protein-A (PAPP-A) and cardiovascular risk[J]. Atherosclerosis,2009.203(2):p. 346-52.
[16].Aso Y, Okumura K, Wakabayashi S, et al. Elevated pregnancy-associated plasma protein-a in sera from type 2 diabetic patients with hypercholesterolemia: associations with carotid atherosclerosis and toe-brachial index[J]. J Clin Endocrinol Metab,2004.89(11):p.5713-7.
[17].Sangiorgi G, Mauriello A, Bonanno E, et al. Pregnancy-associated plasma protein-a is markedly expressed by monocyte-macrophage cells in vulnerable and ruptured carotid atherosclerotic plaques:a link between inflammation and cerebrovascular events[J]. J Am Coll Cardiol,2006.47(11):p.2201-11.
[18].Heider P, Pfaffle N, Pelisek J,et al. Is serum pregnancy-associated plasma protein A really a potential marker of atherosclerotic carotid plaque stability[J]? Eur J Vasc Endovasc Surg,2010.39(6):p.668-75.
[19].Pellitero S, Reverter JL, Pizarro E, et al.Pregnancy-associated plasma protein-a levels are related to glycemic control but not to lipid profile or hemostatic parameters in type 2 diabetes[J]. Diabetes Care,2007.30(12):p.3083-5.
[20].Pellitero S, Reverter JL, Granada ML, et al. Association of the IGF 1/pregnancy-associated plasma protein-A system and adipocytokine levels with the presence and the morphology of carotid plaques in type 2 diabetes mellitus patients with stable glycaemic control[J]. Eur J Endocrinol,2009. 160(6):p.925-32.
[21].Miedema MD, Conover CA, MacDonald H, et al. Pregnancy-associated plasma protein-A elevation in patients with acute coronary syndrome and subsequent atorvastatin therapy[J]. Am J Cardiol,2008.101(1):p.35-9.
[22].Conover CA, Bale LK. Loss of pregnancy-associated plasma protein A extends lifespan in mice[J]. Aging Cell,2007.6(5):p.727-9.
[23].Kalli KR, Chen BK, Bale LK, et al. Pregnancy-associated plasma protein-A (PAPP-A) expression and insulin-like growth factor binding protein-4 protease activity in normal and malignant ovarian surface epithelial cells[J]. Int J Cancer, 2004.110(5):p.633-40.
[24].Ryan AJ, Napoletano S, Fitzpatrick PA, et al. Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer[J]. Br J Cancer,2009.101(2):p.278-86.
[25].Coskun A, Duran S, Apaydin S, et al. Pregnancy-associated plasma protein-A: evaluation of a new biomarker in renal transplant patients[J]. Transplant Proc, 2007.39(10):p.3072-6.
[26].Sancho A, Pastor MC, Bayes B, et al. Posttransplant inflammation associated with onset of chronic kidney disease[J]. Transplant Proc,2010.42(8):p.2896-8.
[27].Lauzurica R, Pastor C, Bayes B, et al. Pretransplant pregnancy-associated plasma protein-a as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events [J]. Transplantation,2005.80(10):p.1441-6.