血清可溶性Sema4D蛋白、MMP14水平与老年慢性心衰心室重构的关系

发布时间：2018-09-12 13:43

【摘要】：背景与目的心力衰竭(heart failure,HF)是全球心血管疾病死亡的主要原因,也是人类社会的一个主要健康问题[1]。与晚期恶性肿瘤相比,心衰的发病率、住院率和死亡率更高[2],尤其是以老年患者多见[3],心衰患者院外的平均预期生存时间大约是5.5年[4],对于年龄≥65岁的慢性心衰患者,一年的死亡率大约是25%-40%[5-11],两年的死亡率是22%-52.9%[12,13]。因此,慢性心衰是一个全球性的卫生保健服务难题。慢性心力衰竭(chronic heart failure,CHF)是各种不同病因引起心脏疾病进展的最终阶段,随着人们对慢性心力衰竭的深入研究,已经发现心室重构(ventricular remodeling,VR)是心衰进展的重要病理生理基础。研究发现,免疫信号素4D(Semaphorin4D,Sema4D)为I型跨膜糖蛋白分子,主要表达于T细胞、B细胞、血小板、内皮细胞、心肌细胞等,在各种炎症因子刺激下,细胞表面Sema4D活化为可溶性Sema4D(sSema4D),与其受体plexin-B1结合,通过细胞表面Met结构的酪氨酸激酶使下游的相关信号分子发生磷酸化,参与新生血管产生、组织胶原纤维化形成、血栓形成、动脉粥样硬化性疾病等。基质金属蛋白酶14(Matrix metalloproteinases-14),即膜型基质金属蛋白酶1(membrane-type 1 matrix metalloproteinases,MMT1-MMP),是基质金属蛋白酶类的亚家族成员,以活性酶形式表达于细胞膜表面,可降解细胞外基质中的Ⅰ、Ⅲ型胶原纤维和纤维连接蛋白,参与心肌纤维化的发生和心力衰竭的进展。有研究显示Sema4D可在膜型基质金属蛋白酶1(MT1-MMP)的作用下成为可溶性Sema4D(sSema4D),发挥相应的生物学功能[16],目前对于二者关系的研究尚少见。有研究发现,在心衰患者中s Sema4D和MMP14的水平是升高的,但二者是否与老年慢性心衰心室重构有关尚未见报道。本研究通过测定老年慢性心力衰竭患者血清sSema4D、MMP14水平变化和观察超声心动图的相关指标,探讨sSema4D、MMP14与老年慢性心力衰竭心室重构的相关性,为慢性心力衰竭提供新的治疗靶点。方法选取2014年08月至2015年12月在郑州大学第一附属医院老年心血管科住院的慢性心衰患者116例,包括扩张型心肌病(dilated cardiomyopathy,DCM)32例、冠心病(coronary heart disease,CHD)49例、房颤(atrial fibrillation,AF)35例。按照纽约心功能分级法(NYHA分级)分为心功能II级组(n=28)、心功能III级组(n=58)、心功能IV级组(n=30)。另选取郑大一附院门诊保健科健康体检者35例作为正常对照组。酶联免疫吸附法检测血清sSema4D、MMP14、B型利钠肽原(proBNP)、超敏C反应蛋白(hs-CRP)水平;彩色多普勒超声心动仪检测左心房内径(LAD)、右心室内径(RVD)、左心室射血分数(LVEF)、左心室舒张末期内径(LVDd)、左心室短轴缩短率(LVFS)。采用SPSS21.0软件进行统计学分析,计量资料以x±S表示,两组间比较采用t检验。单因素方差分析进行多组间的比较,Bonferroni法用于组间两两比较,简单线性相关分析采用Pearson法。多因素相关性采用多元(重)回归分析。以P0.05为检验标准,差异有统计学意义。结果1.慢性心衰组心功能II级、III级、IV级患者血清sSema4D、MMP14、proBNP水平均较正常对照组升高(F为175.496、325.862、77.403,P0.001),且不同心功能分级组间两两比较,差异有统计学意义(P0.05)。2.慢性心衰治疗前血清sSema4D、MMP14、proBNP水平较正常对照组升高(t分别是15.65、28.95、34.54,P0.001),且治疗前三者水平均高于治疗后(t分别是7.95、26.64、22.28,P0.001),差异有统计学意义。3.慢性心衰组左心室舒张末期内径、左房直径、右室直径较正常对照组增大(t分别为22.43、18.83、3.34,P0.01),左心室射血分数、左室短轴缩短率较正常对照组下降(t分别为-38.23、-29.40,P0.001),差异均有统计学意义。4.DCM、CHD、AF三组间血清sSema4D、MMP14、pro-BNP水平比较差异无统计学意义(F分别为0.243、0.247、0.284,P0.05)。5.多因素回归分析显示血浆sSema4D、MMP14、hsCRP对左室舒张末期内径的影响有统计学意义(P0.05),但是pro-BNP的影响没有统计学意义(P0.05)。且血清sSema4D对左室舒张末期内径扩大的贡献最大(β=0.268,P=0.019),MMP14次之(β=0.234,P=0.037)6.相关分析结果显示sSema4D与MMP14的表达水平呈正相关(r=0.462,P0.05),与左心室舒张末期内径、pro-BNP呈正相关(r分别为0.643、0.464,P0.001),与左室射血分数呈负相关(r=-0.554,P0.001);MMP14与左心室舒张末期内径、pro-BNP呈正相关(r分别为0.541、0.365,P0.001),与左室射血分数呈负相关(r=-0.462,P0.001)。结论1.老年慢性心力衰竭患者血清sSema4D、MMP14水平升高。2.老年慢性心力衰竭患者血清s Sema4D蛋白与MMP14蛋白水平、左心室舒张末期内径呈正相关。3.血清sSema4D可能与慢性心衰心室重构有关。4.血清sSema4D、MMP14是老年慢性心衰进展的一个危险因素;或可成为治疗慢性心力衰竭的一个新靶点。
[Abstract]:BACKGROUND AND OBJECTIVE Heart failure (HF) is a major cause of death from cardiovascular diseases worldwide and a major health problem in human society. About 5.5 years [4], the one-year mortality rate is about 25% - 40% [5-11], and the two-year mortality rate is 22% - 52.9% [12,13]. In the final stage, with the in-depth study of chronic heart failure, ventricular remodeling (VR) has been found to be an important pathophysiological basis for the progress of heart failure. Cells, etc., stimulated by various inflammatory factors, Sema4D on the cell surface is activated as soluble Sema4D (sSema4D), which binds to its receptor plexin-B1, phosphorylates downstream signal molecules through the Met-structured tyrosine kinase on the cell surface, participates in angiogenesis, collagen fibrosis, thrombosis, and atherosclerotic diseases. Matrix metalloproteinases-14, or membrane-type 1 matrix metalloproteinases (MMT1-MMP), are subfamily members of matrix metalloproteinases. They are expressed on the surface of cell membrane in the form of active enzymes and can degrade collagen type I and type III fibers and fibronection in extracellular matrix. Receptor proteins are involved in the development of myocardial fibrosis and heart failure. Studies have shown that Sema4D can be soluble under the action of matrix metalloproteinase 1 (MT1-MMP) and play a corresponding biological role [16]. At present, the relationship between them is rare. The relationship between sSema4D, MMP14 and ventricular remodeling in elderly patients with chronic heart failure has not been reported. Methods 116 patients with chronic heart failure, including 32 patients with dilated cardiomyopathy (DCM), 49 patients with coronary heart disease (CHD) and 35 patients with atrial fibrillation (AF), were enrolled in the Department of Geriatric Cardiology, First Affiliated Hospital of Zhengzhou University from August 2014 to December 2015. According to the New York Heart Function Grading (NYHA), the patients were divided into three groups: Heart Function Grade II (n = 28), Heart Function Grade III (n = 58) and Heart Function Grade IV (n = 30). Thirty-five healthy subjects were selected as normal control group. Serum sSema4D, MMP14, proBNP, hs-CRP were detected by ELISA. Level; Left atrial diameter (LAD), right ventricular diameter (RVD), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd) and left ventricular short-axis shortening rate (LVFS) were measured by color Doppler echocardiography. SPSS21.0 software was used for statistical analysis. The measurement data were expressed as X 65 Bonferroni method was used to compare between groups. Pearson method was used to analyze the simple linear correlation. Multivariate (heavy) regression analysis was used to analyze the multivariate correlation. The levels of serum sSema4D, MMP14 and proBNP were higher in the control group than in the control group before treatment (t was 15.65, 28.95, 34.54, P 0.001), and the levels of sSema4D, MMP14 and proBNP before treatment were higher than those after treatment (t was 7.95, respectively). Left ventricular end-diastolic diameter, left atrial diameter and right ventricular diameter in chronic heart failure group were larger than those in normal control group (t 22.43, 18.83, 3.34, P 0.01, respectively). Left ventricular ejection fraction and left ventricular short axis shortening rate were lower than those in normal control group (t - 38.23, - 29.40, P 0.001, respectively). There was no significant difference in serum sSema4D, MMP14, pro-BNP levels among the three groups (F 0.243, 0.247, 0.284, P 0.05). 5. Multivariate regression analysis showed that plasma sSema4D, MMP14, and hsCRP had statistically significant effects on left ventricular end-diastolic diameter (P 0.05), but the effect of pro-BNP had no statistical significance (P 0.05). Serum sSema4D had the greatest contribution to the enlargement of left ventricular end-diastolic diameter (beta = 0.268, P = 0.019), followed by MMP14 (beta = 0.234, P = 0.037) 6. Correlation analysis showed that sSema4D was positively correlated with the expression of MMP14 (r = 0.462, P 0.05), positively correlated with left ventricular end-diastolic diameter, pro-BNP (r = 0.643, 0.464, P 0.001), and negatively correlated with left ventricular ejection fraction. MMP14 was positively correlated with left ventricular end-diastolic diameter (r = 0.541, 0.365, P 0.001), and negatively correlated with left ventricular ejection fraction (r = - 0.462, P 0.001). Conclusion 1. Serum levels of sSema4D and MMP14 were elevated in elderly patients with chronic heart failure. Serum sSema4D may be associated with ventricular remodeling in chronic heart failure. 4. Serum sSema4D and MMP14 may be a risk factor for the progression of chronic heart failure in the elderly, or may be a new target for chronic heart failure.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R541.6

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