TWEAK与原发性高血压患者心脏重塑的相关性

发布时间：2018-12-14 13:48

【摘要】：研究背景高血压是最常见的心血管系统疾病之一,因其近年来的高发病率和年轻化而日益受到重视。高血压早期心功能的改变以舒张功能减退为主,表现为心肌松弛性下降和僵硬度增加。高血压长期压力负荷增高,心肌细胞和细胞外基质结构和功能进行性改变,引起左心房扩大、左心室肥厚、扩张等心脏重塑表现,并最终导致心律失常、心力衰竭、心脏猝死等不良心血管事件。肿瘤坏死因子样凋亡微弱诱导剂(TWEAK)作为肿瘤坏死因子超家族的成员之一,为一全长249个氨基酸的跨膜同源三聚体,可被氟林蛋白水解为具有多种功能的可溶性细胞因子,目前唯一明确的TWEAK受体是成纤维细胞生长因子诱导早期反应蛋白14(Fn14),TWEAK与Fn14受体结合介导包括增生、迁移、凋亡、分化、血管生成和炎症等生物学过程,并在急性心肌梗死、心力衰竭、高血压病等心血管系统疾病的病理生理过程中起重要调节作用。心脏组织中基质金属蛋白酶(MMPs)活性增高会使心肌细胞外基质的降解加快,而细胞外基质降解之后,其防止心肌细胞被过度拉长的效力消失,随之心肌细胞被拉长、心室壁变薄、左心室扩大,最终导致心脏泵血功能的显著下降。随着对高血压研究的深入以及超声心动图在临床中的应用,高血压引起的早期心脏重塑日益受到重视。本研究通过检测TWEAK、sMMP-1在原发性高血压病患者外周静脉血中的表达水平,超声心动图测量胸骨旁长轴切面左心房直径(LAD)、左心房容积(LAV)、左心房容积指数(LAVI)、二尖瓣血流频谱舒张早期波E峰、二尖瓣血流频谱心房收缩波A峰、E/A和二尖瓣环侧壁运动频谱峰值比值E/E',探讨TWEAK的表达与高血压心脏重塑的关系。目的1.探究肿瘤坏死因子样凋亡微弱诱导剂在原发性高血压患者中的表达及其与原发性高血压患者心脏重塑的关系。方法1.选取原发性高血压5年以上患者88例为高血压组,按照血清TWEAK第50百分位数分为高表达组(n=51)和低表达组(n=37);选取同时期健康体检者20例为对照组。2.采用RT-PCR法检测所有入选者外周静脉血单个核细胞(PBMCs)中TWEAK 和 Fn14 mRNA 表达量。3.ELISA法检测血清中可溶性TWEAK(sTWEAK)、基质金属蛋白酶1(sMMP-1)、超敏C反应蛋白(hs-CRP)、成纤维细胞生长因子诱导早期反应蛋白14(sFn14)表达水平。4.超声心动图测量胸骨旁长轴切面LAD、LAV、LAVI、二尖瓣血流频谱舒张早期波E峰、二尖瓣血流频谱心房收缩波A峰、E/A和二尖瓣环侧壁运动频谱峰值比值E/E'。结果1.高表达组和低表达组TWEAK mRNA表达量均高于对照组(P0.05),且高表达组显著高于低表达组(P0.01)。Fn14 mRNA表达量在各组间无统计学差异。2.低表达组sTWEAK及sMMP-1水平高于对照组(P=0.02;P=0.001),且sTWEAK、sMMP-1在高表达组显著高于低表达组(P=0.006;P0.01)。sFn14水平在各组间无统计学差异。3.高表达组和低表达组LAVI、E/E'均高于对照组(P0.05),且高表达组显著高于低表达组(P0.01)。4.sTWEAK、TWEAK mRNA 与 sMMP-1、LAVI、E/E'及 hs-CRP 分别呈显著正相关性(P0.01)。结论TWEAK在高血压患者中高表达;sMMP-1在高血压患者中高表达;高血压患者心脏重塑与TWEAK高表达有关;TWEAK可能通过诱导sMMP-1表达上调及炎症反应参与心脏重塑的发生发展。
[Abstract]:The study of hypertension is one of the most common cardiovascular system diseases, which has been paid more and more attention due to its high morbidity and young age in recent years. The changes of heart function in the early stage of hypertension were mainly characterized by the decrease of the relaxation function and the increase of the degree of stiffness of the myocardium. The long-term pressure load of high blood pressure, the structure and function of the cardiac muscle cell and the extracellular matrix are gradually changed, resulting in the enlargement of the left atrium, the left ventricular hypertrophy and the expansion of the heart remodeling, and finally leads to the adverse cardiovascular events such as arrhythmia, heart failure, sudden cardiac death, and the like. The tumor necrosis factor-like apoptosis inducing agent (TWEAK), as one of the members of the tumor necrosis factor superfamily, is a cross-membrane homologous trimer with a total length of 249 amino acids, and can be hydrolyzed into a soluble cytokine with a plurality of functions, The only clear TWEAK receptor is the fibroblast growth factor inducing early response protein 14 (Fn14), the binding of TWEAK to the Fn14 receptor mediates the biological processes including proliferation, migration, apoptosis, differentiation, angiogenesis and inflammation, and in the case of acute myocardial infarction, heart failure, It plays an important role in the pathophysiological process of cardiovascular system diseases such as hypertension. The increase of the matrix metalloproteinases (MMPs) in the heart tissue can accelerate the degradation of the extracellular matrix of the cardiac muscle cells, and after the degradation of the extracellular matrix, it prevents the effect of the excessive elongation of the cardiac muscle cells, and then the cardiac muscle cells are elongated, the ventricular wall is thin, the left ventricle is expanded, resulting in a significant decrease in the blood function of the heart pump. With the in-depth of the study of hypertension and the application of echocardiography in the clinical, the early heart remodeling caused by hypertension is becoming more and more important. The expression of TWEAK and sMMP-1 in peripheral venous blood of patients with essential hypertension was measured by echocardiography. The left atrial diameter (LAD), left atrial volume (LAV), left atrial volume index (LAVI), and early wave E of mitral flow were measured by echocardiography. Peak ratio E/ E of the peak of atrial contraction wave A, E/ A and the side wall of the mitral annulus in the mitral flow To study the relationship between the expression of TWEAK and the remodeling of hypertensive heart. Purpose 1. To investigate the expression of tumor necrosis factor-like apoptosis-inducing agent in essential hypertension and its relationship with heart remodeling in patients with essential hypertension. 88 patients with essential hypertension were selected as hypertension group, and the 50th percentile of serum TWEAK was divided into high expression group (n = 51) and low expression group (n = 37), and 20 cases of healthy physical examination in the same period were selected as control group. The expression of TWEAK and Fn14 mRNA in peripheral venous blood mononuclear cells (PBMCs) was detected by RT-PCR. The soluble TWEAK (sTWEAK), matrix metalloproteinase-1 (sMMP-1), hypersensitive C-reactive protein (hs-CRP) and fibroblast growth factor were detected by ELISA. Echocardiography was used to measure the peak value ratio E/ E 'of the longitudinal axis of the sternal long axis, the LAD, the LAV, the LAVI, the mitral flow, the early wave E, the mitral flow, the atrial contraction wave A, the E/ A and the side wall motion of the mitral annulus.. Results 1. The expression of TWEAK mRNA in the high-and low-expression groups was higher than that in the control group (P0.05), and the high-expression group was significantly higher than that of the low-expression group (P0.01). The expression of Fn14 mRNA was not statistically different among the groups. The levels of sTWEAK and sMMP-1 in the low expression group were higher than that in the control group (P = 0.02; P = 0.001), and sTWEAK and sMMP-1 were significantly higher in the high expression group than in the lower expression group (P = 0. 006; P 0.01). sFn14 levels were not statistically different between groups. high expression group and low expression group LAVI, E/ E The expression of TWEAK, TWEAK and sMMP-1, LAVI, E/ E' was higher than that in the control group (P0.05). There was a significant positive correlation between hs-CRP and hs-CRP (P0.01). Conclusion TWEAK is highly expressed in patients with high blood pressure; sMMP-1 is highly expressed in patients with high blood pressure; cardiac remodeling in patients with hypertension is related to high expression of TWEAK; TWEAK may be involved in the development of cardiac remodeling by inducing an up-regulation and inflammatory response of sMMP-1.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R544.11

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