载脂蛋白A-I模拟肽的研究进展

刘湘，欧志君，李艳，区景松,5Δ

(1.中山大学附属第一医院 心脏外科，广东 广州 510080；2.中山大学中山医学院卫生部辅助循环重点实验室，广东 广州 510275；3.中山大学附属第一医院高血压血管病科，广东 广州 510080；4.中山大学附属第一医院血管疾病诊治国家地方联合工程实验室，广东 广州 510080；5.广东省脑功能与脑疾病重点实验室，广东 广州 510080)

载脂蛋白A-I模拟肽的研究进展

刘湘1,2,4，欧志君3,4，李艳1,2,4，区景松1,2,4,5Δ

(1.中山大学附属第一医院 心脏外科，广东 广州 510080；2.中山大学中山医学院卫生部辅助循环重点实验室，广东 广州 510275；3.中山大学附属第一医院高血压血管病科，广东 广州 510080；4.中山大学附属第一医院血管疾病诊治国家地方联合工程实验室，广东 广州 510080；5.广东省脑功能与脑疾病重点实验室，广东 广州 510080)

高密度脂蛋白胆固醇(high density lipoprotein cholesterol，HDL-C)由于其心血管保护作用而受到广泛的关注。研究发现，正常HDL在机体内起着逆转运胆固醇、抗炎、抗氧化和促进血管新生等保护心血管的功能。作为HDL含量最高的蛋白质，载脂蛋白A-I(apolipoptrotein A-I，apoA-I)在HDL的各种功能活动中起关键作用。根据apoA-I的两亲性α-螺旋结构特点，设计了一系列旨在模拟apoA-I功能的模拟肽。ApoA-I模拟肽的功能和代谢取决于它的氨基酸组成和序列，并被证实在心血管疾病、感染、炎症和氧化损伤、代谢综合征和肿瘤等疾病状态下发挥保护作用。部分临床试验肯定了apoA-I模拟肽的效益，但由于其高昂的成本而限制了它的实际应用。

载脂蛋白A-I；心血管疾病；炎症；代谢综合征

流行病学调查发现，血浆高密度脂蛋白胆固醇(high density lipoprotein cholesterol，HDL-C)的水平与心血管的患病率呈负相关[1]。正常HDL在正常机体内不仅起着逆转运胆固醇的作用，同时还具有抗炎、抗氧化、激活内皮一氧化氮合酶(endothelial nitric oxide synthase，eNOS)和促进血管新生等功能[2-5]。然而，也有研究显示HDL-C水平正常的人同样会患冠心病，HDL-C水平明显高于正常人但同时有清道夫受体B1(scavenger receptor class B type I，SR-B1)受体变异的人患冠心病的风险明显增加[6]。HDL-C的水平与冠心病患者死亡风险呈J型相关，即高HDL-C和低HDL-C水平均增加患者死亡率[7]。本课题组最新的研究结果也证实HDL-C水平高的鼻咽癌患者预后差，长期生存率低[8]。而大量致力于提高HDL-C水平的临床研究发现HDL-C水平升高并不能降低心血管事件发生率[9-11]。相关药物公司也停止了升高HDL-C的药物临床试验。证明是HDL功能而不是HDL-C水平起关键作用[12-16]。因此，提出了关于趋炎HDL和HDL功能的学说。

早在1995年，Van Lenten等[17]就发现在急性期反应中，具有抗炎功能的HDL变为趋炎HDL，失去抗LDL氧化的功能。由于载脂蛋白A-I(apolipoptrotein A-I，apoA-I)是HDL含量最高且起主要作用的蛋白质[18]，所以，过去对apoA-I进行了广泛的研究。其中一个设想为是否可以通过模拟apoA-I的特殊结构而合成模拟肽来将趋炎HDL恢复为抗炎HDL，改善HDL功能。因此，Fogelman等[19]基于apoA-I两亲性(亲水性和疏水性)α-螺旋结构的特点设计了一系列模拟apoA-I功能的短肽，这些模拟肽的功能与其结构关系密切，现就apoA-I模拟肽的研究及在心血管疾病、炎症和代谢综合征等方面的作用作一综述。

1 ApoA-I模拟肽结构特点与代谢

Fogelman等[19]首先设计由18个氨基酸组成的apoA-I模拟肽。这种apoA-I模拟肽以苯氨酸(F)占18个氨基酸的个数分别称为1F(只有1个苯氨酸)，2F(有2个苯氨酸), 3F(有3个苯氨酸)，以此类推。基于apoA-I的结构特点，只有当apoA-I模拟肽与脂质的头部基团结合才能发挥作用[20]；而模拟肽的疏水性、电荷、疏水面积、螺旋的连接角和氨基酸组成及其界面方向性是决定其生物特性的主要因素[21-22]。3F-2和3F-14的氨基酸组成一致，但由于3F-2具有膜表面寡聚化程度更高，对氧化磷脂的亲和力更强，以及其芳香族侧链较深地插入胆固醇磷脂膜内等特点，3F-2比3F-14功能更强大[23-24]。模拟肽经脂肪族氨基酸、各类磷脂修饰或以一定方式将多个肽串联起来后，其抗动脉粥样硬化效应可能得以增强[25-28]。最后发现4F可以明显将趋炎HDL恢复为抗炎HDL，改善HDL功能和抑制动脉粥样硬化形成[29]。

氯硝柳胺(本身不抑制胰蛋白酶活性)可与L-4F(由左旋氨基酸组成，所以L表示)紧密结合而使L-4F抵抗胰蛋白酶的消化[30]。尽管相同剂量的D-4F(由右旋氨基酸组成，所以以D表示)在皮下注射时的血药浓度均高于口服，但2者的抗炎及抗主动脉粥样硬化效果相当，其经粪便排泄的总量也是相似的。提示胃肠道可能是apoA-I模拟肽发挥作用的主要位点[31]。考虑到要大剂量的4F才有很好的抗动脉粥样硬化的效果，这样成本很贵。设计出可以通过转基因西红柿扩增的6F，口服给予低密度脂蛋白受体敲除(low density lipoprotein receptor null，LDLr-/-)小鼠6F后，发现完整的6F出现在小肠而不是血浆，并降低小肠的溶血磷脂酸(Lysophosphatidic acid，LPA)水平，再次提示胃肠道可能是apoA-I模拟肽发挥作用的主要位点[32]。另外，也有研究发现模拟肽FAMP可被血管的硬化斑块吸收[33]。

2 ApoA-I模拟肽对心血管疾病的影响

ApoA-I模拟肽可增强卵磷脂-胆固醇酰基转移酶活性，促进pre-βHDL形成并加速HDL介导的胆固醇逆转运[34-35]。早在2003年，本课题组首先在LDLr-/-和镰状细胞疾病等小鼠模型中开展了一系列研究，发现L-4F可抑制LDL诱导的氧自由基(superoxide anion，O2-)生成以及黄嘌呤氧化酶结合到肺动脉内皮，改善eNOS依赖的血管舒张功能，减少动脉粥样硬化斑块，而对血浆脂蛋白胆固醇水平没有影响[36]。Navab等[37]报道D-4F能在不改变血浆总胆固醇或HDL水平的情况下发挥抗动脉粥样硬化效应，但对已形成的斑块无影响[38]。我们体外证实L-4F预处理可抑制LDL诱导eNOS脱偶联以及一氧化氮(nitric oxide, NO)和O2-的失衡。L-4F本身对O2-没有影响，但增加了NO的产生[39]。随后，我们在LDLr-/-/apoA-I-/-双敲小鼠模型中，证实D-4F只有在apoA-I存在的情况下才能发挥降低血管壁厚度的作用[40]；而代谢谱研究发现D-4F可通过降低血浆磷脂代谢物，尤其是长链溶血磷脂酰胆碱从而抑制动脉粥样硬化[41]。

ApoA-I模拟肽可改善硬皮病Tsk-/+小鼠eNOS依赖的血管舒张和心肌的血管新生潜能[42]，以及抑制心肌细胞的凋亡和降低左室后壁厚度[43]。在新西兰白兔和小鼠主动脉瓣狭窄模型中，apoA-I模拟肽能显著增加主动脉瓣口面积，降低主动脉根部的胶原含量和瓣膜钙化[44-45]。

CER-001是一种新型的重组人apoA-I与磷脂的复合物。在体外细胞和小鼠模型中，CER-001促进了胆固醇清除，并抑制动脉粥样硬化斑块的发展[46]。在临床试验方面，CER-001在家族性高胆固醇血症纯合子患者和家族性低α脂蛋白血症患者中，均显示出促进apoA-I和HDL形成、抗炎、抗动脉粥样硬化的效应[47-48]。但一项在美国、荷兰、加拿大等51个中心进行的RCT试验，发现CER-001对动脉粥样硬化无影响[49]。

3 ApoA-I模拟肽对感染、炎症和氧化损伤的影响

在人肺泡Ⅱ型细胞系A549和LDLr-/-小鼠，D-4F下调了流感病毒感染后血浆炎症指标和肺的病毒滴度，以及抑制了巨噬细胞的迁移、浸润[50-51]。在施行盲肠结扎穿孔的SD大鼠，4F逆转了血浆脂蛋白的紊乱，改善了心肾功能，降低了炎症反应和死亡率[52-53]。

在一组冠心病及其等危症的患者中，口服D-4F可安全有效地改善HDL的抗炎性，从而抑制LDL诱导的单核细胞趋化活性[54]。但在另外的研究中，L-4F虽在体外改善了HDL功能，但并没有降低冠心病患者的HDL炎症指数，相反，增高了高敏C反应蛋白的水平[55]。

在颈动脉结扎小鼠和新西兰白兔中，apoA-I模拟肽可抑制血管内膜增生和局部炎症分子的表达；在体外培养细胞和大鼠中，也可有效抑制脂多糖或TNF-α诱导的炎症反应和血流动力学紊乱[56-60]。模拟肽可改善LDLr-/-、狼疮小鼠的肾组织炎症，减少蛋白尿、氧化脂质和骨质疏松[61-63]。而在肾切除后大鼠，L-4F可抑制促动脉粥样硬化信号通路分子的表达[64]。在体外将血液透析患者血浆与4F孵育，其LDL的趋炎活性下降，HDL抗炎活性升高[65-66]。在胶原诱导性关节炎大鼠中，D-4F+普伐他汀可显著改善关节炎的临床严重程度评分和关节的破坏性表现，降低血浆细胞因子/趋化因子水平和增强HDL的抗炎活性[67]。在LDLr-/-、APP/PS1双转基因敲除小鼠中，D-4F通过抑制炎症和β淀粉样蛋白沉积，从而改善认知功能[68-69]。L-4F可降低高脂喂养的小鼠血浆的氧化标志物，并改善了颈动脉内皮的愈合能力[70]。

4 ApoA-I模拟肽对代谢综合征的影响

在Ⅰ型糖尿病模型中，D-4F降低了链脲霉素诱导的SD大鼠的氧化蛋白和氧化LDL的含量，抑制了循环内皮细胞脱落和O2-产生，增强了血管的保护功能[71-72]。而在链脲霉素诱导的ApoE敲除小鼠中，D-4F抑制了动脉粥样硬化斑块形成，并降低了血浆类花生四烯酸物质水平[73]。在Ⅱ型糖尿病模型方面，L-4F在不改变ob/ob小鼠食物摄入的情况下，可减少内脏和皮下的脂肪含量，降低血浆炎症因子水平和增加胰岛素的敏感性，从而降低了葡萄糖和胰岛素的水平。其左心室功能也得到改善[74-75]。而在转基因小鼠模型中，D-4F可取得与过表达人apoA-I基因相当的效果，均显著减少了白色脂肪含量和略提高了胰岛素敏感性；其机制可能在于促进解偶联蛋白-1的表达和腺苷酸活化蛋白激酶的磷酸化[76]。

5 ApoA-I模拟肽对肿瘤的影响

D-4F抑制了卵巢癌细胞系(小鼠和人)的活性和增殖，改善其抗氧化状态，并在C57BL/6J小鼠移植肿瘤模型中得以证实，这可能是通过上调锰超氧化物歧化酶的表达和降低LPA、低氧诱导因子-1α的水平实现的[77-79]。在诱导性和自发性结肠癌中，L-4F和G*(apoJ模拟肽)均有效抑制了小鼠结肠腺癌细胞的活性和增殖，降低了LPA的水平，以及息肉的大小和数目[80]。

6 总结

综上所述，apoA-I模拟肽基于其结构特点而发挥一系列保护效应，主要包括抗心血管疾病，抗感染、炎症和氧化损伤，改善代谢综合征和抗癌。但apoA-I模拟肽由于其高昂的成本而极大地限制了它的实际应用。未来若能降低其成本，可有望推动其生产和进一步的临床研究，并最终使靶标人群受益。

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(编校：吴茜)

Research advances on the apolipoptrotein A-I mimetic peptides

LIU Xiang1,2,4, OU Zhi-jun3,4, LI Yan1,2,4, OU Jing-song1,2,4,5

(1.Division of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 2.The key Laboratory of Assisted Circulation, Ministry of Health, Zhongshan School of Medicine, SYSU, Guangzhou 510275, China; 3.Division of Hypertension and Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 4.National and Guangdong Province Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, China; 5.Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine of Sun Yat-sent University, Guangzhou 510080, China)

High density lipoprotein cholesterol (HDL-C) has

extensive attention because of its cardiovascular protective effects. Recent studies showed that HDL could promote reverse cholesterol transport (RCT), be anti-inflammatory and antioxidant, and induce angiogenesis. Apolipoptrotein A-I (apoA-I), the most abundant protein of HDL, plays a pivotal role in the HDL mediated-functional activities. Short peptides based on the amphiphilic alpha helix structure of apoA-I have been designed and aimed at imitating the function of apoA-I. The function and metabolism of these mimetic peptides depend on their amino acids component and sequence, and have been proved to exert protection in against cardiovascular disease, infection, inflammation and oxidative damage, metabolic syndrome and tumor. Clinical trials confirmed their benefits, but high cost put them out of the practical applications..

apolipoptroteinA-I; cardiovascular disease; inflammation; metabolic syndrome

10.3969/j.issn.1005-1678.2016.12.005

教育部长江学者奖励计划项目；国家杰出青年科学基金(81325001)；国家自然科学基金(81170271, 81370370)；广东省高等学校高层次人才项目(珠江学者计划)；国家临床重点专科建设项目；科技部国际合作专项(2015DFA31070)；广东省自然科学基金研究团队项目(2015A030312009)。

刘湘，博士在读，研究方向：心血管，E-mail：liux69@mail2.sysu.edu.cn；区景松，通信作者，男，博士，教授、主任医师，研究方向：心血管，E-mail：oujs@mail.sysu.edu.cn。

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