生长分化因子-15在常见心血管疾病中的研究进展*

刘 欢 李 艳

生长分化因子-15在常见心血管疾病中的研究进展*

刘 欢综述李 艳#审校

生长分化因子-15(GDF-15)是一种压力损伤性因子，可表达于心肌细胞、脂肪细胞、巨噬细胞和内皮细胞等。正常生理条件下，GDF-15几乎不表达，但在心肌损伤如压力超负荷、心力衰竭、缺血再灌注损伤及动脉粥样硬化等条件下，GDF-15的表达显著升高，通过激活Smad2、Smad3及ALK4/5/7等发挥心血管保护作用，提示GDF-15可能成为新一代心肌损伤标志物。

生长分化因子-15；心肌肥大；冠心病；心力衰竭

生长分化因子-15(Growth Differentiation Factor-15，GDF-15)是一种压力损伤性因子，生理状态下几乎不表达，在组织损伤和炎症状态下，GDF-15的表达水平显著升高，并且与心肌代谢性疾病风险相关，如心肌肥大、心力衰竭、动脉粥样硬化、肥胖和糖尿病等。许多研究显示GDF-15在不同组织中发挥一定的保护作用；但也有研究发现，GDF-15缺乏时对机体抵抗血管损伤和炎症是有益的。本文就近年来相关动物及临床研究对GDF-15在常见心血管疾病中的作用作一综述。

1 GDF-15的生物学概述

GDF-15是转化生长因子-β(Transforming Growth Factor-β，TGF-β)超家族成员之一，在合成过程中先形成前体蛋白，蛋白裂解释放N-端多肽后成为GDF-15的成熟形式，再以25kD的二聚体形式分泌到血清中[1]。GDF-15蛋白前体由308个氨基酸合成，包含29个氨基酸信号肽、167个氨基酸前肽和112个氨基酸成熟域。由于其首次在激活的巨噬细胞中发现[1]，且正常情况下在胎盘的表达水平较高，因此又称巨噬细胞抑制因子(Macrophage Inhibitory Cytokine-1，MIC-1)、胎盘转化生长因子-β(Placental Transforming Growth Factor-β，PTGF-β)。健康人中，GDF-15在除胎盘以外的组织中表达水平极低；病理情况下，如炎症、肿瘤、心血管疾病时，GDF-15的表达水平显著升高。GDF-15的生物学作用依据所处环境而定，在疾病不同阶段可能发挥不同作用[2-5]。如在患有急性心肌梗死的小鼠中，GDF-15可通过直接抑制骨髓细胞募集来干扰趋化因子信号通路的整合及活化，从而发挥抗炎作用，阻止心梗后心脏破裂的发生[5]。但Gabriel A等的研究发现，GDF-15可通过调节血管内皮细胞凋亡和IL-6依赖的炎症反应参与动脉粥样硬化病变的进展，起到一定的促炎作用[3-5]。

2 GDF-15与心血管疾病

研究显示，在疾病早期，GDF-15表达水平显著升高且对相关心血管事件和死亡的预测有一定的价值，可预测急性胸痛、心肌梗死和慢性心绞痛的不良结局，其水平还与左心室射血分数(Leventricular Ejection Fraction，LVEF)的下降、心肌舒缩功能及运动能力的减弱相关。

2.1 GDF-15与心肌肥大

心肌肥大是指在应对生理性刺激和病理性刺激如运动、高血压、缺血性心肌病、瓣膜关闭不全等，心肌细胞代偿性增多、增大，是临床心血管疾病中最常见的靶器官损害。流行病学研究显示，中国高血压患者患心肌肥大的概率高达25%-35%[6-7]。左心室肥大可增加梗死、冠心病、充血性心力衰竭、心律失常和心源性猝死的风险，而这些因素又都与心血管疾病死亡率和发病率以及全因死亡率相关[8-9]。尽管左心室肥大的主要病因是高血压，但也受到其他心血管疾病传统因素如年龄、性别、生活方式和糖尿病合并症等的影响。除此之外，一些生长因子和细胞因子在高血压患者发展为心室肥大的病程中也发挥着重要作用[10]。

正常生理条件下，GDF-15在心脏几乎不表达，在出现心血管损伤如压力过剩、心力衰竭、缺血/再灌注损伤和动脉粥样硬化等条件下，血清GDF-15水平显著升高。Hao等[11]的研究结果显示，与不伴心室肥大的高血压患者相比，伴有心室肥大的高血压患者血清中GDF-15水平显著升高。再以是否伴有心室肥大作为状态变量，GDF-15水平作为检验变量作ROC曲线分析，结果显示，曲线下的面积为0.808，提示GDF-15对诊断高血压伴心室肥大具有一定的检验效能。在调整年龄、性别、体重指数(BMI)等因素后，多重线性回归分析显示，GDF-15水平与左心室质量指数、心室间隔厚度、后壁厚度独立相关[12]。体外研究显示，接受压力过载刺激后，与野生型小鼠相比，心脏特异性高表达GDF-15的转基因小鼠的心室肥大症状减弱。相反，GDF-15靶向敲除小鼠更易发展为心室肥大，说明GDF-15可能通过参与调控心肌肥大而发挥一定的心血管保护作用[13]。另有研究显示[14]，GDF-15可通过参与调节磷脂酰肌醇激酶(Phosphoinositude-3 kinase, PI3K)及细胞外信号调节激酶(Extracellular signal-ragulated kinase, ERK)信号通路及转录因子R-SMAD1对抗各种凋亡刺激，增强心肌细胞的肥厚性生长，从而影响心脏重塑。

2.2 GDF-15与冠心病和冠脉综合征

体内研究[5]通过短暂或长期的冠脉结扎造成的心肌缺血可增加病变区域GDF15 mRNA及蛋白的表达水平，且在心肌梗死边缘区心肌细胞处，GDF-15的免疫活性最强，血清GDF-15水平显著升高，且与炎性因子呈明显相关性；而GDF-15-/-的小鼠，出现梗死面积及凋亡程度增加，表明GDF-15可能通过某种抗凋亡机制而保护缺血心肌。

与社区老年人研究相似[15]，在冠脉疾病患者中，GDF-15水平与年龄、糖尿病、吸烟与否、肾功能、血清钠尿肽及hs-CRP水平独立相关[16-19]。在另一项针对社区老年人的研究中也得出了相似结论[20]。血小板抑制及病人疗效试验(Platelet Inhibition and Patient Outcomes trial，PLATO)[19]评估了GDF-15对急性冠脉综合征预后评估的价值。基于大量的患者和结果事件，在调整临床预测因素和其它生物标志物如心肌肌钙蛋白I(cardiac troponin I, cTnI)、血氨基末端脑钠肽(N-terminal pro brain natriuretic peptide，NT- proBNP)、超敏C-反应蛋白(high sensitivity C-reactive protein, hs-CRP)和胱抑素C(cystatin C，CYC)[20]的影响后，高水平GDF-15与全因死亡率、心血管疾病死亡率及中风风险的增加相关。

2.3 GDF-15与心力衰竭

心力衰竭是所有心血管疾病发展的终末阶段，严重影响着患者的预后，诸多研究显示GDF-15水平在心力衰竭患者中显著升高[21-23]。高水平GDF-15可为慢性心力衰竭患者的NYHA功能分级、左心室射血分数(Left Ventricular Ejection Fraction，LVEF)及NT-proBNP水平提供额外的预后和预测信息。除此之外，对于LVEF正常心力衰竭患者的诊断，GDF-15优于NT-proBNP[24]；对于病态肥胖的个体，与NT-pro-BNP相比，GDF-15与舒张功能不全有更好的相关性[25]。因此，GDF-15与NT-proBNP联合检测可显著提高心力衰竭患者的诊断价值。Kempf等[22]的研究显示，GDF-15有望作为评估慢性心力衰竭患者死亡风险的新型生物标志物并可有效评估患者预后。该研究显示，慢性心力衰竭患者GDF-15水平显著升高，并与全因死亡率呈一定的等级关系；多重COX回归分析显示GDF-15和LVEF是预测慢性心力衰竭患者死亡的最强因素。血清GDF-15水平与慢性心力衰竭患者年龄、NYHA心功能分级、肾功能损害程度、尿酸水平(可识别慢性心衰病人的代谢异常)[26]及NT-proBNP呈现很好的独立相关关系，显示GDF-15与众多慢性心衰不良预后的临床和生化标志物均有关。

3 总结与展望

综上所述，GDF-15水平对心血管疾病的诊断和预后判断有重要价值，且在不同疾病的不同时期，GDF-15水平可为传统危险因素和其它血清学生物标志物增加预测信息，有益于疾病的早期诊断[19,27-29]。因此，需要深入研究GDF-15的上下游通路，为其作为相应疾病的治疗靶点提供一定依据。

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本文作者简介：

刘欢(1990-)，女，满族，博士研究生，研究方向：冠心病的防治

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ResearchProgressofGDF-15inCommonCardiovascularDiseases

LIU Huan, LI Yan#

Department of Clinical Laboratory ,Renmin Hospital of Wuhan University ,Wuhan 430060 ,China；#Corresponding author

GDF-15 is a stress-induced factor that can be widely expressed in cardiomyocytes, adipocytes, macrophages and endothelial cells. Under normal physiological conditions, GDF-15 is hardly expressed, but the expression of GDF-15 was significantly increased under the conditions of myocardial overload such as stress overload, heart failure, ischemia-reperfusion injury and atherosclerosis. And GDF-15 plays a cardioprotective role through activating Smad2 , Smad3 and ALK4 / 5/7, which suggesting that GDF-15 may become a new generation of myocardial injury markers.

GDF-15; Cardiac hypertrophy; Coronary heart disease; Heart failure

10.3969/j.issn.1005-1740.2017.04.015

R543.3

A

1005-1740(2017)04-0068-04

国家自然科学基金(81572069；81501815)

武汉大学人民医院检验科，武汉 430060#

，E-mail: yanlitf1120@163.com

本文2017-07-16收到，2017-09-10修回