探讨冠状动脉扩张发生的相关机制及生长分化因子-15的内皮保护作用
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摘要
研究背景
冠状动脉扩张(coronary artery ectasia, CAE)是一种非阻塞性冠状动脉疾病,其定义为发生病变后的管腔直径可达临近正常段的1.5倍及以上,临床表现为劳力型心绞痛,甚至发生冠状动脉血栓事件,引发急性冠脉综合征。CAE是一种特殊的冠状动脉异常表现,在心绞痛的严重程度、临床表现、病死率等方面均与冠心病较为相似。临床上,CAE的发生往往合并冠状动脉粥样硬化,所以常被认为是冠状动脉粥样硬化的一种变异性病变。由于在所有冠状动脉造影患者中,其发病率仅占0.3-5.3%,对随机临床试验的实施造成很大困难；另外,由于缺乏对其自然病程的了解,在临床实践中往往低估了CAE的影响,多采用与动脉粥样硬化相同的治疗方法,难以取得良好的治疗效果。
随着冠脉造影技术的普及,越来越多的冠脉扩张患者得到明确诊断,急需正确的临床认识和治疗。明确冠脉扩张与动脉粥样硬化发病机制的异同点,有助于强化医务人员对冠脉扩张的特点的认识及其与动脉粥样硬化的关系的认识,从而针对不同的病症采取针对性治疗措施,以提高治疗效果。
GDF-15是转化生长因子-β(TGF-β)超家族的一员。生理条件下,GDF-15的表达具有组织特异性,在胎盘和前列腺中高表达,而在肝脏、肾脏和心脏中低表达甚至不表达。但是在病理和环境应激条件下,GDF-15的表达量显著上升。Kempf等的研究发现,体外培养的心肌细胞受到缺血或者缺血再灌注的损伤时,心肌细胞中GDF-15的表达显著上调,起到应激保护的作用。Wollert、Kempf和Eggers KM等多项临床实验表明,当心肌细胞受到急性心肌缺血损伤时,大量分泌GDF-15来抵抗心肌受损,而GDF-15的高分泌水平即提示心肌受损程度的升高,同时预示着不良预后。本研究首次研究CAE患者血浆中GDF-15的分泌水平,并首次对GDF-15的内皮保护作用进行体外试验,更有助于探讨CAE的发生机制。
研究目的
1.通过回顾性研究,分析在我院行冠状动脉造影检查并诊断现CAE的患者的临床、冠脉造影结果及其临床意义。
2.通过测定与分析多种细胞分泌因子,包括一氧化氮(nitric oxide, NO)、内皮素-1(endothelin, ET-1)、基质金属蛋白酶-9(matrix metalloproteinase-9, MMP-9)、组织基质金属蛋白酶抑制物-1(Tissue Inhabitor of Metalloproteinase-1, TIMP-1)和生长分化因子-15(Growth differentiation factor-15, GDF-15)等的水平来初步探讨这些因素在冠状动脉损伤如扩张和狭窄的不同病程中参与的不同机制及可能发挥的关键作用。
3.在基因水平上,对ACE Intron 16 I/D, AT1R 1166A/C, MMP-91562C/T及GDF-15-3148C/G五个基因位点进行多态性研究,希望得到CAE和OCAD (Obstructive coronary artery disease)的相关基因,从遗传上探讨两种不同冠脉损伤的差异。
4.通过对体外培养的人脐静脉内皮细胞(Human Umbilical Vein Endothelial Cells, HUVEC)分别加入不同浓度的葡萄糖、胰岛素、HDL、LDL、oxLDL、Angll刺激不同时间,并应用荧光定量逆转录多聚酶链反应(real time RT-PCR)方法探索对GDF-15转录及表达水平的影响,从而在体外研究水平上,探讨GDF-15在内皮细胞受到动脉粥样硬化相关危险因素损伤过程中的可能变化。
5.利用GDF-15体外刺激HUVEC细胞,通过测定内皮细胞的一氧化氮(NO)浓度以及一氧化氮合酶(endothelial nitric oxide synthase, eNOS),内皮素(ET-1),细胞间粘附分子-1(intercellular adhesion molecule, ICAM-1)和血管细胞粘附分子-1(vascular cell adhesion molecule, VCAM-1)的表达水平,进一步研究不同浓度不同时间GDF-15刺激对内皮功能的影响,揭示GDF-15对血管内皮细胞从代偿到损伤过程中的变化规律。
研究方法
1.收集于2005年1月支至2009年12月在我院心内科行冠脉造影检查并诊断为CAE的患者共48例,回顾性研究分析这些CAE患者临床特点和冠脉造影结果,并对其进行电话及门诊随访,记录临床终点事件。’
2.收集CAE患者、冠心病(狭窄阻塞性病变)患者(obstructive coronary artery diseases, OCAD)及正常对照组(Normal coronary artery, NCA)记录其临床资料并收集血浆,采用ELISA方法测定所有研究对象的外周血NO, ET-1, MMP-9, TIMP-1和GDF-15的浓度。根据冠脉损伤的不同特点,将CAE组分为两组：单纯冠脉扩张组(Isolated coronary artery ectasia, ICAE)和冠脉扩张合并狭窄阻塞性病变(coronary with both Ectasia and Stenosis, CAE+Stenosis)组,进一步进行各组间多种细胞分泌因子的浓度差异的比较研究。
3.在基因水平,采用限制性内切酶片段长度多态性,片段长度多态性及直接测序等技术对所有研究对象的基因型ACE Intron 16 I/D、AT1R 1166 A/C、MMP-91562C/T及GDF-15-3148C/G进行多态性分析。
4.采用体外分离培养HUVEC的方法,以HDL、LDL、oxLDL、Angll和信号通路阻断剂SP600125、U0126、SB203580,以及葡萄糖、胰岛素单独或联合刺激,设计不同的刺激浓度梯度和刺激时间,并通过Real-Time PCR检测分析GDF-15转录水平的变化。
5.GDF-15体外刺激HUVEC细胞,按GDF-15作用时间分为2组(36h和72h),每组5个浓度(0、400、600、800、1000、1500pg/mL),利用试剂盒检测内皮细胞上清的一氧化氮浓度,并利用Real-Time PCR分析一氧化氮合酶、内皮素、细胞间粘附分子-1和血管细胞粘附分子-1的表达水平变化。
6.用SPSS13.0软件进行数据统计分析；符合正态分布计量资料以均数±标准差表示,采用独立样本t检验；不符合正态分布的,以中位数(25百分位-75百分位)表示,采用Mann-Whitney U检验；计数资料以频数(百分比)表示,采用Pearson Chi-Square检验；P<0.05 (two-tailed)为差异有统计学意义。
研究结果
1.CAE患者的临床症状及危险因素与因冠心病入院的患者无特殊性。
2.CAE患者以单支病变19例(39.6%)为主,其中单支病变以RCA多见,双支病变以LAD多见。CAE患者以LAD多见(71%)；RCA其次(67%)。CAE患者往往伴随着冠脉动脉粥样硬化损伤,单纯CAE28例(58.3%)；冠脉扩张合并狭窄阻塞性病变20例(41.70%)。
3.CAE组NO水平高于OCAD组,具有统计学差异(p=0.007)。进一步将CAE组分为ICAE组和CAE+Stenosis组进行统计学分析：ICAE组NO水平高于OCAD组,具有统计学差异(P=0.022)；CAE+Stenosis组NO水平高于OCAD组,具有统计学差异(P=0.014)。ET-1在各组之间无统计学差异(P>0.05)。
4.CAE组MMP-9水平高于NCA组和OCAD组,并且具有统计学差异(P=0.004和P=0.025)。进一步将CAE组分为ICAE组和CAE+Stenosis组进行统计学分析：!CAE组MMP-9水平高于NCA组和OCAD组,并且具有统计学差异(P=0.007和P=0.027)：CAE+Stenosis组MMP-9水平高于NCA组,并且具有统计学意义(P=0.042)。NCA组TIMP-1水平显著高于其他各组(P<0.05),但CAE组与OCAD组无显著差异(P>0.05)。
5. CAE组GDF-15水平高于NCA组和OCAD组,并且具有统计学差异(P=0.045和P=0.037)。进一步将CAE组分为ICAE组和CAE+Stenosis组进行统计学分析：CAE+Stenosis组GDF-15水平高于NCA组和OCAD组,并且具有统计学差异(P=0.008和P=0.014)；CAE+Stenosis组GDF-15水平高于ICAE组,但尚未达到统计学差异。
6. ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T及GDF-15-3148C/G在本研究的各组人群之间末达到统计学差异,提示这些位点可能与CAE发生过程无相关性。
7.在本研究中MMP-91562 C/T多态性与血浆中MMP-9表达水平并无显著相关性。
8.在本研究中GDF-15-3148C/G多态性与血浆中GDF-15的表达水平无显著相关性。
9.HUVEC经不同浓度LDL刺激12小时,GDF-15的表达水平变化并不一致,但刺激24时均为使其表达量下调；HUVEC经不同浓度HDL刺激12小时,GDF-15的表达水平变化并不一致,时间延长至24小时上调GDF-15的表达,并且与HDL浓度升高成正比；不同浓度oxLDL刺激12或24小时后,均显著上调GDF-15的表达,并呈时间依赖性,24小时后GDF-15的表达有所下降。
10.高糖刺激12小时和24小时可增加GDF-15的表达；不同浓度胰岛素作用12小时可增加GDF-15的表达,低浓度组随时间延长表达量升高；高糖和不同浓度胰岛素联合作用12及24小时均降低GDF-15的表达,低浓度胰岛素组24小时表达量上升。
11.不同浓度Angll刺激6小时、12小时后均上调HUVEC中GDF-15的表达,呈现明显的浓度依赖性,作用24小时后最低和最高浓度的GDF-15表达量降低。加入SB203580后6小时、12小时和24小时GDF-15表达显著升高。加入SP600125后6小时GDF-15显著升高,12小时后显著降低,24小时后变化不显著。加入U0126后6小时GDF-15表达量升高,但12小时和24小时后GDF-15降低。
12.GDF-15干预HUVEC 36小时,eNOS表达量上调,并且呈浓度依赖性,随着GDF-15浓度升高而升高。GDF-15干预HUVEC72小时,eNOS表达在低浓度400pg/ml时达到峰值,后随浓度升高表达量降低。
13.GDF-15刺激HUVEC36小时和72小时,ET-1的表达量呈下降趋势,并且呈浓度依赖性,与GDF-15的干预浓度呈反比。
14.GDF-15刺激HUVEC36小时,ICAM-1的表达量轻度升高,但是在800pg/ml时显著升高。GDF-15刺激HUVEC72小时,ICAM-1表达量轻度降低,1000pg/ml时显著升高。
15.GDF-15刺激HUVEC36小时,VCAM-1的表达量升高,但是在600pg/ml时显著降低,800pg/ml显著升高。GDF-15刺激HUVEC72小时,VCAM-1表达量轻度降低,1000pg/ml时升高。
16.GDF-15刺激HUVEC36小时和72小时,NO的表达量在400pg/ml时显著下降,随后随浓度身高而升高,1000pg/ml时下降。
结论
1.CAE患者与OCAD患者临床症状相似,以单支病变为主,其中单支病变以RCA为主,CAE患者往往伴随着冠脉动脉粥样硬化损伤。
2.冠脉扩张可能是冠脉为了抵抗动脉粥样硬化而早期启动的机体正常的防御机制。单纯冠脉扩张可能是冠脉粥样硬化损伤前期内皮保护功能亢进阶段。
3.CAE与OCAD在MMP-91562 C/T和GDF-15-3148C/G基因多态性上无统计学差异并且与血浆MMP-9和GDF-15水平无相关性。
4.多种危险因素相关因子和物质均可对HUVEC内GDF-15的转录活性产生一定的影响,结合GDF-15的抗炎症反应、促进肿瘤细胞凋亡、抑制细胞过度增殖的保护作用,说明GDF-15可以由内皮细胞分泌并发挥一定的功能。
5.体外实验证明：在一定浓度范围,GDF-15对内皮细胞有一定的保护作用,增强内皮功能。
创新性
1.冠脉扩张的发病机理并不清晰,以往的研究往往多局限于临床特点的总结,对其与动脉粥样硬化的发病机制的异同点研究甚少,本项目通过冠脉造影结果对冠脉损伤各阶段进行连续性研究,结合血浆中各分泌因子的分泌水平,深入分析冠脉扩张发生的可能机制,并推断CAE可能是动脉粥样硬化前的一种保护机制,为认识CAE提供新的思路。
2.目前,GDF-15是心血管领域关注的热点生物标记物之一。作为公认的心脏的保护因子,科研人员对其机制的研究多集中于心肌细胞和巨噬细胞,而对内皮细胞的作用研究甚少。本研究不但首次研究CAE患者血浆中GDF-15的分泌水平,并且结合患者血清学结果,以GDF-15对内皮细胞的作用机制为切入点进行体外细胞试验研究,具有重要意义。
Background
While coronary artery ectasia (CAE), defined as local or diffuse dilation (exceeding 1.5 times of normal adjacent reference segment), is a non-obstructive coronary artery disease. It can lead to myocardial ischemia, angina pectoris and even myocardial infarction. CAE is a rare coronary artery disease with low incidence, and it is difficult to distinguish CAE from coronary atherosclerosis in terms of severity of angina pectoris and clinical symptoms. CAE usually occurs with concomitant coronary atherosclerosis, and has been suggested to be a variant coronary artery disease. Everyday clinical practice tends to underestimate the impact of coronary ectasia merely due to the yet unknown natural history of this condition, its relative rarity and the subsequent difficulties in conducting randomized trials to compare different forms of treatment. The continuously expanding implementation of coronary angiography in the investigation of cardiovascular disease is likely to acculminate a higher absolute numbers of patients diagnosed with coronary ectasia. In this setting, the need for appropriate clinical recommendations should not be overlooked. However,the pathogenesis of CAE remains poorly understood. CAE has been thought to be related to endothelial dysfunction and inflammation. The relationship between coronary atherosclerosis and CAE is unknown, and their pathology in the development of CHD is unclear. Understanding the mechanisms may be of particular importance on acquiring an insight into the nature of coronary ectasia and its possible relation to the atherosclerotic process, and may also have direct clinical implications in the management and follow-up strategy of this condition.
GDF-15 is a number of transforming growth factor beta-TGF (beta) super-family. In physiological condition, the expression of GDF-15 is higher in placenta and prostate but lower in liver, kidney and heart. But in stress-induced condition, the expression of GDF-15 increased significantly. The study found that the expression of GDF-15 significantly increased in myocardial cells in vitro when injuryed by ischemia or ischemia-reperfusion. Many clinical trials show that, when the myocardial cells were injuryed by myocardial ischemia, GDF-15 was highly secreted to resistant myocardial lesions. It is important to explore the protective function of GDF-15 in patients of CAE.
Objective
1. By the retrospective study, the clinical significance and coronary angiography images of 48 CAE patients diagnosised as CAE were totally analysed.
2. By measuring a variety of cellular factors, including nitric oxide (NO), endothelin-1 (ET-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and growth differentiation factor-15 (GDF-15), the different mechanisms and the key roles played by these factors were discussed in the process of CAE and stenosic lesions.
3. At the gene level, aiming to get the variation of CAE and OCAD (Obstructive coronary artery disease), we studyed the SNP of ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T and GDF-15-3148C/G.
4. To stimulate the HUVEC with HDL, LDL, oxLDL, Glu, Insulin, Angll and three antagonists of MAPK signal transmission pathway with different concentration and time in vitro. The expressions of GDF-15 in HUVEC were analyzed by real time RT-PCR. Thus to explore the changes of the level of GDF-15 in endothelial cells injured by atherosclerosis risk factors.
5. To explore the roles of GDF-15 played in endothelial cells, we measure the expression of nitric oxide (NO), nitric oxide synthase (eNOS), endothelin (ET-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in HUVEC cells stimulated by GDF-15 at different concentration and time in vitro.
Methods
1. The study group consisted of individuals who had been referred for coronary angiography because of chest pain. Forty-eight patients of CAE admitted to the Cardiology Department of the Peking Union Medical College Hospital were recruited from January 2005 to December 2009 for this study. The clinical characteristics, coronary angiography images and follow-up by telephone and clinic were retrospective analysed.
2. CAE, obstructive coronary artery diseases (OCAD) and the Normal coronary arteries (NCA) were all age-and gender-matched patients who were selected in a consecutive manner from the catheterized patients during the same study period. Age, sex, cigarettes smoking, alcohol drinking, diabetes mellitus (DM), hypertension, hypercholesterolemia, and family history were recorded. The plasma levels of NO, ET-1, MMP-9, TIMP-1 and GDF-15 were determined by ELISA kits. According to the different characteristics of coronary artery injury, the CAE group was divided into two subgroups:isolated coronary artery ectasia (ICAE) and coronary with both Ectasia and Stenosis (CAE+Stenosis). Difference of variety of cellular factors in each group were further anaylsis.
3. In the gene level, using restriction fragment length polymorphism, fragment length polymorphism and direct sequencing techniques, the genotypes of all subjects ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T and GDF-15-3148 C/G polymorphism were analysis.
4. The HUVEC was stimulated with HDL, LDL, oxLDL, Glu, Insulin, AngⅡand three antagonists of MAPK signal transmission pathway with different concentration and time in vitro. The expressions of GDF-15 in HUVEC were analyzed by real time RT-PCR to detect the level changes.
5. In vitro, HUVEC cells were stimulated by GDF-15 in 2 time groups (36h and 72h) and each of which with five concentrations (0,400,600,800,1000,1500 pg/mL). Endothelial cell nitric oxide concentration in the supernatant was detected by Elisa kit. The expression levels of ET-1, eNOS, ICAM-1 and VCAM-lwere determined bv RT-PCR.
6. All statistical analyses were performed using the SPSS statistics program, version 13.0. Data are presented as means+SD and percentage, as appropriate. We used theχ2 test to analyze category data, the Student's t-test or Mann-Whitney U-test to evaluate differences between 2 groups. The correlation between variables of groups was assessed by the Pearson and Spearman correlation tests for parametric and nonparametric variables. Logistic regression analyses were used to determine whether plasma biomarkers were associated with CAE. All p-values are reported with two-tail test. The alpha-level is 0.05.
Results
1. There were no significant differences in baseline characteristics of risk factors in CAE and OCAD. Clinical symptoms were not effective to distinguish CAE from CAD.
2. Single-vessel lesion were more prevalent in patients with CAE; RCA was the most commonly involved coronary in CAE with single-vessel lesion. In this study, there were 28 cases (58.3%)with isolated coronary artery ectasia and 20 cases (41.7%) with both CAE and stenosis.
3. NO levels in CAE group were significantly higher than OCAD group (P=0.007). In subgroup analysis, NO levels in ICAE and CAE+Stenosis group were significantly higher than OCAD group (P= 0.022, P= 0.014, respectively). There were no statistically differences on ET-1 in each group (P> 0.05).
4. Compared with NCA and OCAD groups, MMP-9 levels in CAE were significantly higher (P= 0.004 and P= 0.025, respectively). For further analysis, ICAE has higher MMP-9 level than OCAD (P=0.027), and the MMP-9 in CAE+Stenosis group were higher than ICAE. TIMP-1 levels in NCA Group were significantly higher than other groups (P<0.05), but there were no significantly difference between the CAE and OCAD group.
5. Compared with NCA and OCAD groups, GDF-15 levels in CAE were significantly higher (P= 0.045 and P= 0.037, respectively). Subgroup analysis showed that ICAE had higher GDF-15 level than OCAD (P=0.027), and the GDF-15 in CAE+Stenosis group were higher than ICAE.
6. There were no significantly differences of ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T and GDF-15-3148C/G polymorphism among these groups. It is suggested that these genotypes has no correlation with the CAE process.
7. In this study, there were no relationship between MMP-91562 C/T polymorphism and plasma levels of MMP-9.
8. In this study, there were no relationship between GDF-15-3148C/G polymorphism and plasma levels of GDF-15.
9. HUVEC stimulated by different concentrations of LDL for 12 hours, GDF-15 expression levels are not the same, but GDF-15 expression levels at 24 hours were decreased; HUVEC stimulated by different concentrations of HDL for 24 hours, GDF-15 expression levels were upregulated; after stimulation of different concentrations of oxLDL 12 or 24 hours, the expression of GDF-15 were significantly upregulated.
10. High glucose can increase the expression of GDF-15; different concentrations of insulin for 12 hours increased the expression of GDF-15, low-concentration group increased expression with longer time; high glucose with different concentrations of insulin combined for 12 and 24 hours can decreased the expression of GDF-15.
11. After stimulated by different concentrations of AngⅡc for 6 hours or 12 hours, the expression of GDF-15 was upregulated in a obviously concentration dependent meaner. GDF-15 expression was significantly increased with SB203580 after added for 6 hours,12 hours and 24 hours. The expression of GDF-15 was significantly increased after SP600125 was added for 6 hours but decreased significantly after 12 hours. GDF-15 expression increased after U0126 was added for 6 hours, but decreased after 12 hours and 24 hours'stimulation.
12. GDF-15 could increase the expression of eNOS in HUVEC in a concentration dependent manner, but higher concentration with longer time stimulation of GDF-15 caused a decrease of eNOS.
13. With stimulation of GDF-15 for 36 hours and 72 hours, the HUVEC expression of ET-1 decreased.
14. GDF-15 could decrease the expression of ICAM-1 in HUVEC in a certain concentration.
15. GDF-15 could decrease the expression of VCAM-1 in HUVEC in a certain concentration.
16. With stimulation of GDF-15 for 36 hours and 72 hours, the secretion of NO in HUVEC increased in certain concentration.
Conclusions
1. The clinical symptoms of CAE and OCAD patients were similar. Single-vessel lesion were most commonly seen in CAE. RCA was the most commonly involved coronary artery. The ectasic arteries of CAE patients were often coexcisting with coronary atherosclerosis.
2. A cardiovascular protective mechanism may compensate the existing cardiovascular risk factors in coronary ectasia and such mechanism was significantly diminished in coronary artery atherosclerosis. Coronary ectasia may present as an early stage of coronary atherosclerosis. Biomarkers might be useful in predicting different stages of coronary atherosclerosis.
3. MMP-91562 C/T and GDF-15-3148C/G polymorphisms were not statistically different between CAE and OCAD. And they were not associated with plasma MMP-9 and GDF-15 levels.
4. A variety of risk factors could impact the expression of GDF-15 in HUVEC. Since GDF-15 has some benefial effect, such as reducing inflammation, promoting tumor cell apoptosis, inhibiting cell proliferation. The results indicated that GDF-15 may-play a certain protective role in endothelial cells.
5. Experiments in vitro suggested:with a certain concentration range, GDF-15 plays certain protective role in endothelial cells and could enhance endothelial function.
冠状动脉扩张(coronary artery ectasia, CAE)是一种非阻塞性冠状动脉疾病,其定义为发生病变后的管腔直径可达临近正常段的1.5倍及以上,临床表现为劳力型心绞痛,甚至发生冠状动脉血栓事件,引发急性冠脉综合征。CAE是一种特殊的冠状动脉异常表现,在心绞痛的严重程度、临床表现、病死率等方面均与冠心病较为相似。临床上,CAE的发生往往合并冠状动脉粥样硬化,所以常被认为是冠状动脉粥样硬化的一种变异性病变。由于在所有冠状动脉造影患者中,其发病率仅占0.3-5.3%,对随机临床试验的实施造成很大困难；另外,由于缺乏对其自然病程的了解,在临床实践中往往低估了CAE的影响,多采用与动脉粥样硬化相同的治疗方法,难以取得良好的治疗效果。
随着冠脉造影技术的普及,越来越多的冠脉扩张患者得到明确诊断,急需正确的临床认识和治疗。明确冠脉扩张与动脉粥样硬化发病机制的异同点,有助于强化医务人员对冠脉扩张的特点的认识及其与动脉粥样硬化的关系的认识,从而针对不同的病症采取针对性治疗措施,以提高治疗效果。
GDF-15是转化生长因子-β(TGF-β)超家族的一员。生理条件下,GDF-15的表达具有组织特异性,在胎盘和前列腺中高表达,而在肝脏、肾脏和心脏中低表达甚至不表达。但是在病理和环境应激条件下,GDF-15的表达量显著上升。Kempf等的研究发现,体外培养的心肌细胞受到缺血或者缺血再灌注的损伤时,心肌细胞中GDF-15的表达显著上调,起到应激保护的作用。Wollert、Kempf和Eggers KM等多项临床实验表明,当心肌细胞受到急性心肌缺血损伤时,大量分泌GDF-15来抵抗心肌受损,而GDF-15的高分泌水平即提示心肌受损程度的升高,同时预示着不良预后。本研究首次研究CAE患者血浆中GDF-15的分泌水平,并首次对GDF-15的内皮保护作用进行体外试验,更有助于探讨CAE的发生机制。
研究目的
1.通过回顾性研究,分析在我院行冠状动脉造影检查并诊断现CAE的患者的临床、冠脉造影结果及其临床意义。
2.通过测定与分析多种细胞分泌因子,包括一氧化氮(nitric oxide, NO)、内皮素-1(endothelin, ET-1)、基质金属蛋白酶-9(matrix metalloproteinase-9, MMP-9)、组织基质金属蛋白酶抑制物-1(Tissue Inhabitor of Metalloproteinase-1, TIMP-1)和生长分化因子-15(Growth differentiation factor-15, GDF-15)等的水平来初步探讨这些因素在冠状动脉损伤如扩张和狭窄的不同病程中参与的不同机制及可能发挥的关键作用。
3.在基因水平上,对ACE Intron 16 I/D, AT1R 1166A/C, MMP-91562C/T及GDF-15-3148C/G五个基因位点进行多态性研究,希望得到CAE和OCAD (Obstructive coronary artery disease)的相关基因,从遗传上探讨两种不同冠脉损伤的差异。
4.通过对体外培养的人脐静脉内皮细胞(Human Umbilical Vein Endothelial Cells, HUVEC)分别加入不同浓度的葡萄糖、胰岛素、HDL、LDL、oxLDL、Angll刺激不同时间,并应用荧光定量逆转录多聚酶链反应(real time RT-PCR)方法探索对GDF-15转录及表达水平的影响,从而在体外研究水平上,探讨GDF-15在内皮细胞受到动脉粥样硬化相关危险因素损伤过程中的可能变化。
5.利用GDF-15体外刺激HUVEC细胞,通过测定内皮细胞的一氧化氮(NO)浓度以及一氧化氮合酶(endothelial nitric oxide synthase, eNOS),内皮素(ET-1),细胞间粘附分子-1(intercellular adhesion molecule, ICAM-1)和血管细胞粘附分子-1(vascular cell adhesion molecule, VCAM-1)的表达水平,进一步研究不同浓度不同时间GDF-15刺激对内皮功能的影响,揭示GDF-15对血管内皮细胞从代偿到损伤过程中的变化规律。
研究方法
1.收集于2005年1月支至2009年12月在我院心内科行冠脉造影检查并诊断为CAE的患者共48例,回顾性研究分析这些CAE患者临床特点和冠脉造影结果,并对其进行电话及门诊随访,记录临床终点事件。’
2.收集CAE患者、冠心病(狭窄阻塞性病变)患者(obstructive coronary artery diseases, OCAD)及正常对照组(Normal coronary artery, NCA)记录其临床资料并收集血浆,采用ELISA方法测定所有研究对象的外周血NO, ET-1, MMP-9, TIMP-1和GDF-15的浓度。根据冠脉损伤的不同特点,将CAE组分为两组：单纯冠脉扩张组(Isolated coronary artery ectasia, ICAE)和冠脉扩张合并狭窄阻塞性病变(coronary with both Ectasia and Stenosis, CAE+Stenosis)组,进一步进行各组间多种细胞分泌因子的浓度差异的比较研究。
3.在基因水平,采用限制性内切酶片段长度多态性,片段长度多态性及直接测序等技术对所有研究对象的基因型ACE Intron 16 I/D、AT1R 1166 A/C、MMP-91562C/T及GDF-15-3148C/G进行多态性分析。
4.采用体外分离培养HUVEC的方法,以HDL、LDL、oxLDL、Angll和信号通路阻断剂SP600125、U0126、SB203580,以及葡萄糖、胰岛素单独或联合刺激,设计不同的刺激浓度梯度和刺激时间,并通过Real-Time PCR检测分析GDF-15转录水平的变化。
5.GDF-15体外刺激HUVEC细胞,按GDF-15作用时间分为2组(36h和72h),每组5个浓度(0、400、600、800、1000、1500pg/mL),利用试剂盒检测内皮细胞上清的一氧化氮浓度,并利用Real-Time PCR分析一氧化氮合酶、内皮素、细胞间粘附分子-1和血管细胞粘附分子-1的表达水平变化。
6.用SPSS13.0软件进行数据统计分析；符合正态分布计量资料以均数±标准差表示,采用独立样本t检验；不符合正态分布的,以中位数(25百分位-75百分位)表示,采用Mann-Whitney U检验；计数资料以频数(百分比)表示,采用Pearson Chi-Square检验；P<0.05 (two-tailed)为差异有统计学意义。
研究结果
1.CAE患者的临床症状及危险因素与因冠心病入院的患者无特殊性。
2.CAE患者以单支病变19例(39.6%)为主,其中单支病变以RCA多见,双支病变以LAD多见。CAE患者以LAD多见(71%)；RCA其次(67%)。CAE患者往往伴随着冠脉动脉粥样硬化损伤,单纯CAE28例(58.3%)；冠脉扩张合并狭窄阻塞性病变20例(41.70%)。
3.CAE组NO水平高于OCAD组,具有统计学差异(p=0.007)。进一步将CAE组分为ICAE组和CAE+Stenosis组进行统计学分析：ICAE组NO水平高于OCAD组,具有统计学差异(P=0.022)；CAE+Stenosis组NO水平高于OCAD组,具有统计学差异(P=0.014)。ET-1在各组之间无统计学差异(P>0.05)。
4.CAE组MMP-9水平高于NCA组和OCAD组,并且具有统计学差异(P=0.004和P=0.025)。进一步将CAE组分为ICAE组和CAE+Stenosis组进行统计学分析：!CAE组MMP-9水平高于NCA组和OCAD组,并且具有统计学差异(P=0.007和P=0.027)：CAE+Stenosis组MMP-9水平高于NCA组,并且具有统计学意义(P=0.042)。NCA组TIMP-1水平显著高于其他各组(P<0.05),但CAE组与OCAD组无显著差异(P>0.05)。
5. CAE组GDF-15水平高于NCA组和OCAD组,并且具有统计学差异(P=0.045和P=0.037)。进一步将CAE组分为ICAE组和CAE+Stenosis组进行统计学分析：CAE+Stenosis组GDF-15水平高于NCA组和OCAD组,并且具有统计学差异(P=0.008和P=0.014)；CAE+Stenosis组GDF-15水平高于ICAE组,但尚未达到统计学差异。
6. ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T及GDF-15-3148C/G在本研究的各组人群之间末达到统计学差异,提示这些位点可能与CAE发生过程无相关性。
7.在本研究中MMP-91562 C/T多态性与血浆中MMP-9表达水平并无显著相关性。
8.在本研究中GDF-15-3148C/G多态性与血浆中GDF-15的表达水平无显著相关性。
9.HUVEC经不同浓度LDL刺激12小时,GDF-15的表达水平变化并不一致,但刺激24时均为使其表达量下调；HUVEC经不同浓度HDL刺激12小时,GDF-15的表达水平变化并不一致,时间延长至24小时上调GDF-15的表达,并且与HDL浓度升高成正比；不同浓度oxLDL刺激12或24小时后,均显著上调GDF-15的表达,并呈时间依赖性,24小时后GDF-15的表达有所下降。
10.高糖刺激12小时和24小时可增加GDF-15的表达；不同浓度胰岛素作用12小时可增加GDF-15的表达,低浓度组随时间延长表达量升高；高糖和不同浓度胰岛素联合作用12及24小时均降低GDF-15的表达,低浓度胰岛素组24小时表达量上升。
11.不同浓度Angll刺激6小时、12小时后均上调HUVEC中GDF-15的表达,呈现明显的浓度依赖性,作用24小时后最低和最高浓度的GDF-15表达量降低。加入SB203580后6小时、12小时和24小时GDF-15表达显著升高。加入SP600125后6小时GDF-15显著升高,12小时后显著降低,24小时后变化不显著。加入U0126后6小时GDF-15表达量升高,但12小时和24小时后GDF-15降低。
12.GDF-15干预HUVEC 36小时,eNOS表达量上调,并且呈浓度依赖性,随着GDF-15浓度升高而升高。GDF-15干预HUVEC72小时,eNOS表达在低浓度400pg/ml时达到峰值,后随浓度升高表达量降低。
13.GDF-15刺激HUVEC36小时和72小时,ET-1的表达量呈下降趋势,并且呈浓度依赖性,与GDF-15的干预浓度呈反比。
14.GDF-15刺激HUVEC36小时,ICAM-1的表达量轻度升高,但是在800pg/ml时显著升高。GDF-15刺激HUVEC72小时,ICAM-1表达量轻度降低,1000pg/ml时显著升高。
15.GDF-15刺激HUVEC36小时,VCAM-1的表达量升高,但是在600pg/ml时显著降低,800pg/ml显著升高。GDF-15刺激HUVEC72小时,VCAM-1表达量轻度降低,1000pg/ml时升高。
16.GDF-15刺激HUVEC36小时和72小时,NO的表达量在400pg/ml时显著下降,随后随浓度身高而升高,1000pg/ml时下降。
结论
1.CAE患者与OCAD患者临床症状相似,以单支病变为主,其中单支病变以RCA为主,CAE患者往往伴随着冠脉动脉粥样硬化损伤。
2.冠脉扩张可能是冠脉为了抵抗动脉粥样硬化而早期启动的机体正常的防御机制。单纯冠脉扩张可能是冠脉粥样硬化损伤前期内皮保护功能亢进阶段。
3.CAE与OCAD在MMP-91562 C/T和GDF-15-3148C/G基因多态性上无统计学差异并且与血浆MMP-9和GDF-15水平无相关性。
4.多种危险因素相关因子和物质均可对HUVEC内GDF-15的转录活性产生一定的影响,结合GDF-15的抗炎症反应、促进肿瘤细胞凋亡、抑制细胞过度增殖的保护作用,说明GDF-15可以由内皮细胞分泌并发挥一定的功能。
5.体外实验证明：在一定浓度范围,GDF-15对内皮细胞有一定的保护作用,增强内皮功能。
创新性
1.冠脉扩张的发病机理并不清晰,以往的研究往往多局限于临床特点的总结,对其与动脉粥样硬化的发病机制的异同点研究甚少,本项目通过冠脉造影结果对冠脉损伤各阶段进行连续性研究,结合血浆中各分泌因子的分泌水平,深入分析冠脉扩张发生的可能机制,并推断CAE可能是动脉粥样硬化前的一种保护机制,为认识CAE提供新的思路。
2.目前,GDF-15是心血管领域关注的热点生物标记物之一。作为公认的心脏的保护因子,科研人员对其机制的研究多集中于心肌细胞和巨噬细胞,而对内皮细胞的作用研究甚少。本研究不但首次研究CAE患者血浆中GDF-15的分泌水平,并且结合患者血清学结果,以GDF-15对内皮细胞的作用机制为切入点进行体外细胞试验研究,具有重要意义。
Background
While coronary artery ectasia (CAE), defined as local or diffuse dilation (exceeding 1.5 times of normal adjacent reference segment), is a non-obstructive coronary artery disease. It can lead to myocardial ischemia, angina pectoris and even myocardial infarction. CAE is a rare coronary artery disease with low incidence, and it is difficult to distinguish CAE from coronary atherosclerosis in terms of severity of angina pectoris and clinical symptoms. CAE usually occurs with concomitant coronary atherosclerosis, and has been suggested to be a variant coronary artery disease. Everyday clinical practice tends to underestimate the impact of coronary ectasia merely due to the yet unknown natural history of this condition, its relative rarity and the subsequent difficulties in conducting randomized trials to compare different forms of treatment. The continuously expanding implementation of coronary angiography in the investigation of cardiovascular disease is likely to acculminate a higher absolute numbers of patients diagnosed with coronary ectasia. In this setting, the need for appropriate clinical recommendations should not be overlooked. However,the pathogenesis of CAE remains poorly understood. CAE has been thought to be related to endothelial dysfunction and inflammation. The relationship between coronary atherosclerosis and CAE is unknown, and their pathology in the development of CHD is unclear. Understanding the mechanisms may be of particular importance on acquiring an insight into the nature of coronary ectasia and its possible relation to the atherosclerotic process, and may also have direct clinical implications in the management and follow-up strategy of this condition.
GDF-15 is a number of transforming growth factor beta-TGF (beta) super-family. In physiological condition, the expression of GDF-15 is higher in placenta and prostate but lower in liver, kidney and heart. But in stress-induced condition, the expression of GDF-15 increased significantly. The study found that the expression of GDF-15 significantly increased in myocardial cells in vitro when injuryed by ischemia or ischemia-reperfusion. Many clinical trials show that, when the myocardial cells were injuryed by myocardial ischemia, GDF-15 was highly secreted to resistant myocardial lesions. It is important to explore the protective function of GDF-15 in patients of CAE.
Objective
1. By the retrospective study, the clinical significance and coronary angiography images of 48 CAE patients diagnosised as CAE were totally analysed.
2. By measuring a variety of cellular factors, including nitric oxide (NO), endothelin-1 (ET-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and growth differentiation factor-15 (GDF-15), the different mechanisms and the key roles played by these factors were discussed in the process of CAE and stenosic lesions.
3. At the gene level, aiming to get the variation of CAE and OCAD (Obstructive coronary artery disease), we studyed the SNP of ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T and GDF-15-3148C/G.
4. To stimulate the HUVEC with HDL, LDL, oxLDL, Glu, Insulin, Angll and three antagonists of MAPK signal transmission pathway with different concentration and time in vitro. The expressions of GDF-15 in HUVEC were analyzed by real time RT-PCR. Thus to explore the changes of the level of GDF-15 in endothelial cells injured by atherosclerosis risk factors.
5. To explore the roles of GDF-15 played in endothelial cells, we measure the expression of nitric oxide (NO), nitric oxide synthase (eNOS), endothelin (ET-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in HUVEC cells stimulated by GDF-15 at different concentration and time in vitro.
Methods
1. The study group consisted of individuals who had been referred for coronary angiography because of chest pain. Forty-eight patients of CAE admitted to the Cardiology Department of the Peking Union Medical College Hospital were recruited from January 2005 to December 2009 for this study. The clinical characteristics, coronary angiography images and follow-up by telephone and clinic were retrospective analysed.
2. CAE, obstructive coronary artery diseases (OCAD) and the Normal coronary arteries (NCA) were all age-and gender-matched patients who were selected in a consecutive manner from the catheterized patients during the same study period. Age, sex, cigarettes smoking, alcohol drinking, diabetes mellitus (DM), hypertension, hypercholesterolemia, and family history were recorded. The plasma levels of NO, ET-1, MMP-9, TIMP-1 and GDF-15 were determined by ELISA kits. According to the different characteristics of coronary artery injury, the CAE group was divided into two subgroups:isolated coronary artery ectasia (ICAE) and coronary with both Ectasia and Stenosis (CAE+Stenosis). Difference of variety of cellular factors in each group were further anaylsis.
3. In the gene level, using restriction fragment length polymorphism, fragment length polymorphism and direct sequencing techniques, the genotypes of all subjects ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T and GDF-15-3148 C/G polymorphism were analysis.
4. The HUVEC was stimulated with HDL, LDL, oxLDL, Glu, Insulin, AngⅡand three antagonists of MAPK signal transmission pathway with different concentration and time in vitro. The expressions of GDF-15 in HUVEC were analyzed by real time RT-PCR to detect the level changes.
5. In vitro, HUVEC cells were stimulated by GDF-15 in 2 time groups (36h and 72h) and each of which with five concentrations (0,400,600,800,1000,1500 pg/mL). Endothelial cell nitric oxide concentration in the supernatant was detected by Elisa kit. The expression levels of ET-1, eNOS, ICAM-1 and VCAM-lwere determined bv RT-PCR.
6. All statistical analyses were performed using the SPSS statistics program, version 13.0. Data are presented as means+SD and percentage, as appropriate. We used theχ2 test to analyze category data, the Student's t-test or Mann-Whitney U-test to evaluate differences between 2 groups. The correlation between variables of groups was assessed by the Pearson and Spearman correlation tests for parametric and nonparametric variables. Logistic regression analyses were used to determine whether plasma biomarkers were associated with CAE. All p-values are reported with two-tail test. The alpha-level is 0.05.
Results
1. There were no significant differences in baseline characteristics of risk factors in CAE and OCAD. Clinical symptoms were not effective to distinguish CAE from CAD.
2. Single-vessel lesion were more prevalent in patients with CAE; RCA was the most commonly involved coronary in CAE with single-vessel lesion. In this study, there were 28 cases (58.3%)with isolated coronary artery ectasia and 20 cases (41.7%) with both CAE and stenosis.
3. NO levels in CAE group were significantly higher than OCAD group (P=0.007). In subgroup analysis, NO levels in ICAE and CAE+Stenosis group were significantly higher than OCAD group (P= 0.022, P= 0.014, respectively). There were no statistically differences on ET-1 in each group (P> 0.05).
4. Compared with NCA and OCAD groups, MMP-9 levels in CAE were significantly higher (P= 0.004 and P= 0.025, respectively). For further analysis, ICAE has higher MMP-9 level than OCAD (P=0.027), and the MMP-9 in CAE+Stenosis group were higher than ICAE. TIMP-1 levels in NCA Group were significantly higher than other groups (P<0.05), but there were no significantly difference between the CAE and OCAD group.
5. Compared with NCA and OCAD groups, GDF-15 levels in CAE were significantly higher (P= 0.045 and P= 0.037, respectively). Subgroup analysis showed that ICAE had higher GDF-15 level than OCAD (P=0.027), and the GDF-15 in CAE+Stenosis group were higher than ICAE.
6. There were no significantly differences of ACE Intron 16 I/D, AT1R 1166 A/C, MMP-91562 C/T and GDF-15-3148C/G polymorphism among these groups. It is suggested that these genotypes has no correlation with the CAE process.
7. In this study, there were no relationship between MMP-91562 C/T polymorphism and plasma levels of MMP-9.
8. In this study, there were no relationship between GDF-15-3148C/G polymorphism and plasma levels of GDF-15.
9. HUVEC stimulated by different concentrations of LDL for 12 hours, GDF-15 expression levels are not the same, but GDF-15 expression levels at 24 hours were decreased; HUVEC stimulated by different concentrations of HDL for 24 hours, GDF-15 expression levels were upregulated; after stimulation of different concentrations of oxLDL 12 or 24 hours, the expression of GDF-15 were significantly upregulated.
10. High glucose can increase the expression of GDF-15; different concentrations of insulin for 12 hours increased the expression of GDF-15, low-concentration group increased expression with longer time; high glucose with different concentrations of insulin combined for 12 and 24 hours can decreased the expression of GDF-15.
11. After stimulated by different concentrations of AngⅡc for 6 hours or 12 hours, the expression of GDF-15 was upregulated in a obviously concentration dependent meaner. GDF-15 expression was significantly increased with SB203580 after added for 6 hours,12 hours and 24 hours. The expression of GDF-15 was significantly increased after SP600125 was added for 6 hours but decreased significantly after 12 hours. GDF-15 expression increased after U0126 was added for 6 hours, but decreased after 12 hours and 24 hours'stimulation.
12. GDF-15 could increase the expression of eNOS in HUVEC in a concentration dependent manner, but higher concentration with longer time stimulation of GDF-15 caused a decrease of eNOS.
13. With stimulation of GDF-15 for 36 hours and 72 hours, the HUVEC expression of ET-1 decreased.
14. GDF-15 could decrease the expression of ICAM-1 in HUVEC in a certain concentration.
15. GDF-15 could decrease the expression of VCAM-1 in HUVEC in a certain concentration.
16. With stimulation of GDF-15 for 36 hours and 72 hours, the secretion of NO in HUVEC increased in certain concentration.
Conclusions
1. The clinical symptoms of CAE and OCAD patients were similar. Single-vessel lesion were most commonly seen in CAE. RCA was the most commonly involved coronary artery. The ectasic arteries of CAE patients were often coexcisting with coronary atherosclerosis.
2. A cardiovascular protective mechanism may compensate the existing cardiovascular risk factors in coronary ectasia and such mechanism was significantly diminished in coronary artery atherosclerosis. Coronary ectasia may present as an early stage of coronary atherosclerosis. Biomarkers might be useful in predicting different stages of coronary atherosclerosis.
3. MMP-91562 C/T and GDF-15-3148C/G polymorphisms were not statistically different between CAE and OCAD. And they were not associated with plasma MMP-9 and GDF-15 levels.
4. A variety of risk factors could impact the expression of GDF-15 in HUVEC. Since GDF-15 has some benefial effect, such as reducing inflammation, promoting tumor cell apoptosis, inhibiting cell proliferation. The results indicated that GDF-15 may-play a certain protective role in endothelial cells.
5. Experiments in vitro suggested:with a certain concentration range, GDF-15 plays certain protective role in endothelial cells and could enhance endothelial function.
引文
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