劉 歡 李 艷

生長分化因子-15在常見心血管疾病中的研究進(jìn)展*

劉 歡綜述李 艷#審校

生長分化因子-15(GDF-15)是一種壓力損傷性因子，可表達(dá)于心肌細(xì)胞、脂肪細(xì)胞、巨噬細(xì)胞和內(nèi)皮細(xì)胞等。正常生理?xiàng)l件下，GDF-15幾乎不表達(dá)，但在心肌損傷如壓力超負(fù)荷、心力衰竭、缺血再灌注損傷及動脈粥樣硬化等條件下，GDF-15的表達(dá)顯著升高，通過激活Smad2、Smad3及ALK4/5/7等發(fā)揮心血管保護(hù)作用，提示GDF-15可能成為新一代心肌損傷標(biāo)志物。

生長分化因子-15；心肌肥大；冠心?。恍牧λソ?/p>

生長分化因子-15(Growth Differentiation Factor-15，GDF-15)是一種壓力損傷性因子，生理狀態(tài)下幾乎不表達(dá)，在組織損傷和炎癥狀態(tài)下，GDF-15的表達(dá)水平顯著升高，并且與心肌代謝性疾病風(fēng)險相關(guān)，如心肌肥大、心力衰竭、動脈粥樣硬化、肥胖和糖尿病等。許多研究顯示GDF-15在不同組織中發(fā)揮一定的保護(hù)作用；但也有研究發(fā)現(xiàn)，GDF-15缺乏時對機(jī)體抵抗血管損傷和炎癥是有益的。本文就近年來相關(guān)動物及臨床研究對GDF-15在常見心血管疾病中的作用作一綜述。

1 GDF-15的生物學(xué)概述

GDF-15是轉(zhuǎn)化生長因子-β(Transforming Growth Factor-β，TGF-β)超家族成員之一，在合成過程中先形成前體蛋白，蛋白裂解釋放N-端多肽后成為GDF-15的成熟形式，再以25kD的二聚體形式分泌到血清中[1]。GDF-15蛋白前體由308個氨基酸合成，包含29個氨基酸信號肽、167個氨基酸前肽和112個氨基酸成熟域。由于其首次在激活的巨噬細(xì)胞中發(fā)現(xiàn)[1]，且正常情況下在胎盤的表達(dá)水平較高，因此又稱巨噬細(xì)胞抑制因子(Macrophage Inhibitory Cytokine-1，MIC-1)、胎盤轉(zhuǎn)化生長因子-β(Placental Transforming Growth Factor-β，PTGF-β)。健康人中，GDF-15在除胎盤以外的組織中表達(dá)水平極低；病理情況下，如炎癥、腫瘤、心血管疾病時，GDF-15的表達(dá)水平顯著升高。GDF-15的生物學(xué)作用依據(jù)所處環(huán)境而定，在疾病不同階段可能發(fā)揮不同作用[2-5]。如在患有急性心肌梗死的小鼠中，GDF-15可通過直接抑制骨髓細(xì)胞募集來干擾趨化因子信號通路的整合及活化，從而發(fā)揮抗炎作用，阻止心梗后心臟破裂的發(fā)生[5]。但Gabriel A等的研究發(fā)現(xiàn)，GDF-15可通過調(diào)節(jié)血管內(nèi)皮細(xì)胞凋亡和IL-6依賴的炎癥反應(yīng)參與動脈粥樣硬化病變的進(jìn)展，起到一定的促炎作用[3-5]。

2 GDF-15與心血管疾病

研究顯示，在疾病早期，GDF-15表達(dá)水平顯著升高且對相關(guān)心血管事件和死亡的預(yù)測有一定的價值，可預(yù)測急性胸痛、心肌梗死和慢性心絞痛的不良結(jié)局，其水平還與左心室射血分?jǐn)?shù)(Leventricular Ejection Fraction，LVEF)的下降、心肌舒縮功能及運(yùn)動能力的減弱相關(guān)。

2.1 GDF-15與心肌肥大

心肌肥大是指在應(yīng)對生理性刺激和病理性刺激如運(yùn)動、高血壓、缺血性心肌病、瓣膜關(guān)閉不全等，心肌細(xì)胞代償性增多、增大，是臨床心血管疾病中最常見的靶器官損害。流行病學(xué)研究顯示，中國高血壓患者患心肌肥大的概率高達(dá)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風(fēng)險，而這些因素又都與心血管疾病死亡率和發(fā)病率以及全因死亡率相關(guān)[8-9]。盡管左心室肥大的主要病因是高血壓，但也受到其他心血管疾病傳統(tǒng)因素如年齡、性別、生活方式和糖尿病合并癥等的影響。除此之外，一些生長因子和細(xì)胞因子在高血壓患者發(fā)展為心室肥大的病程中也發(fā)揮著重要作用[10]。

正常生理?xiàng)l件下，GDF-15在心臟幾乎不表達(dá)，在出現(xiàn)心血管損傷如壓力過剩、心力衰竭、缺血/再灌注損傷和動脈粥樣硬化等條件下，血清GDF-15水平顯著升高。Hao等[11]的研究結(jié)果顯示，與不伴心室肥大的高血壓患者相比，伴有心室肥大的高血壓患者血清中GDF-15水平顯著升高。再以是否伴有心室肥大作為狀態(tài)變量，GDF-15水平作為檢驗(yàn)變量作ROC曲線分析，結(jié)果顯示，曲線下的面積為0.808，提示GDF-15對診斷高血壓伴心室肥大具有一定的檢驗(yàn)效能。在調(diào)整年齡、性別、體重指數(shù)(BMI)等因素后，多重線性回歸分析顯示，GDF-15水平與左心室質(zhì)量指數(shù)、心室間隔厚度、后壁厚度獨(dú)立相關(guān)[12]。體外研究顯示，接受壓力過載刺激后，與野生型小鼠相比，心臟特異性高表達(dá)GDF-15的轉(zhuǎn)基因小鼠的心室肥大癥狀減弱。相反，GDF-15靶向敲除小鼠更易發(fā)展為心室肥大，說明GDF-15可能通過參與調(diào)控心肌肥大而發(fā)揮一定的心血管保護(hù)作用[13]。另有研究顯示[14]，GDF-15可通過參與調(diào)節(jié)磷脂酰肌醇激酶(Phosphoinositude-3 kinase, PI3K)及細(xì)胞外信號調(diào)節(jié)激酶(Extracellular signal-ragulated kinase, ERK)信號通路及轉(zhuǎn)錄因子R-SMAD1對抗各種凋亡刺激，增強(qiáng)心肌細(xì)胞的肥厚性生長，從而影響心臟重塑。

2.2 GDF-15與冠心病和冠脈綜合征

體內(nèi)研究[5]通過短暫或長期的冠脈結(jié)扎造成的心肌缺血可增加病變區(qū)域GDF15 mRNA及蛋白的表達(dá)水平，且在心肌梗死邊緣區(qū)心肌細(xì)胞處，GDF-15的免疫活性最強(qiáng)，血清GDF-15水平顯著升高，且與炎性因子呈明顯相關(guān)性；而GDF-15-/-的小鼠，出現(xiàn)梗死面積及凋亡程度增加，表明GDF-15可能通過某種抗凋亡機(jī)制而保護(hù)缺血心肌。

與社區(qū)老年人研究相似[15]，在冠脈疾病患者中，GDF-15水平與年齡、糖尿病、吸煙與否、腎功能、血清鈉尿肽及hs-CRP水平獨(dú)立相關(guān)[16-19]。在另一項(xiàng)針對社區(qū)老年人的研究中也得出了相似結(jié)論[20]。血小板抑制及病人療效試驗(yàn)(Platelet Inhibition and Patient Outcomes trial，PLATO)[19]評估了GDF-15對急性冠脈綜合征預(yù)后評估的價值。基于大量的患者和結(jié)果事件，在調(diào)整臨床預(yù)測因素和其它生物標(biāo)志物如心肌肌鈣蛋白I(cardiac troponin I, cTnI)、血氨基末端腦鈉肽(N-terminal pro brain natriuretic peptide，NT- proBNP)、超敏C-反應(yīng)蛋白(high sensitivity C-reactive protein, hs-CRP)和胱抑素C(cystatin C，CYC)[20]的影響后，高水平GDF-15與全因死亡率、心血管疾病死亡率及中風(fēng)風(fēng)險的增加相關(guān)。

2.3 GDF-15與心力衰竭

心力衰竭是所有心血管疾病發(fā)展的終末階段，嚴(yán)重影響著患者的預(yù)后，諸多研究顯示GDF-15水平在心力衰竭患者中顯著升高[21-23]。高水平GDF-15可為慢性心力衰竭患者的NYHA功能分級、左心室射血分?jǐn)?shù)(Left Ventricular Ejection Fraction，LVEF)及NT-proBNP水平提供額外的預(yù)后和預(yù)測信息。除此之外，對于LVEF正常心力衰竭患者的診斷，GDF-15優(yōu)于NT-proBNP[24]；對于病態(tài)肥胖的個體，與NT-pro-BNP相比，GDF-15與舒張功能不全有更好的相關(guān)性[25]。因此，GDF-15與NT-proBNP聯(lián)合檢測可顯著提高心力衰竭患者的診斷價值。Kempf等[22]的研究顯示，GDF-15有望作為評估慢性心力衰竭患者死亡風(fēng)險的新型生物標(biāo)志物并可有效評估患者預(yù)后。該研究顯示，慢性心力衰竭患者GDF-15水平顯著升高，并與全因死亡率呈一定的等級關(guān)系；多重COX回歸分析顯示GDF-15和LVEF是預(yù)測慢性心力衰竭患者死亡的最強(qiáng)因素。血清GDF-15水平與慢性心力衰竭患者年齡、NYHA心功能分級、腎功能損害程度、尿酸水平(可識別慢性心衰病人的代謝異常)[26]及NT-proBNP呈現(xiàn)很好的獨(dú)立相關(guān)關(guān)系，顯示GDF-15與眾多慢性心衰不良預(yù)后的臨床和生化標(biāo)志物均有關(guān)。

3 總結(jié)與展望

綜上所述，GDF-15水平對心血管疾病的診斷和預(yù)后判斷有重要價值，且在不同疾病的不同時期，GDF-15水平可為傳統(tǒng)危險因素和其它血清學(xué)生物標(biāo)志物增加預(yù)測信息，有益于疾病的早期診斷[19,27-29]。因此，需要深入研究GDF-15的上下游通路，為其作為相應(yīng)疾病的治療靶點(diǎn)提供一定依據(jù)。

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本文作者簡介：

劉歡(1990-)，女，滿族，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

國家自然科學(xué)基金(81572069；81501815)

武漢大學(xué)人民醫(yī)院檢驗(yàn)科，武漢 430060#

，E-mail: yanlitf1120@163.com

本文2017-07-16收到，2017-09-10修回