Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (35): 5735-5740.doi: 10.12307/2021.308
Wen Miaomiao1, Fan Junbai2
Received:
2020-10-21
Revised:
2020-10-24
Accepted:
2020-11-21
Online:
2021-12-18
Published:
2021-08-06
Contact:
Fan Junbai, Chief physician, the Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
About author:
Wen Miaomiao, Master candidate, Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
Supported by:
CLC Number:
Wen Miaomiao, Fan Junbai. Relationship between biological activities of Apelin and Elabela and diseases[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(35): 5735-5740.
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2.1 Apelin的结构和功能 Apelin在机体内分布广泛,如脂肪组织、心脏、血管内皮、胃肠道、中枢神经系统、乳腺和胎盘[3]。其前体是由11号X染色体q26-26.1编码的77个氨基酸组成,血管紧张素转化酶2将其水解为不同长度的活性多肽。依据其氨基酸数目分为Apelin-12,13,17,36,55,77等多个亚型,分子结构越短,与APJ受体结合与分离越高效,活性越强[4]。Apelin可抑制由血管紧张素Ⅱ诱导的细胞内Ca2+ 增加和血管收缩的作用,进而拮抗血管紧张素Ⅱ[5]。 2.2 疾病与Apelin的生物活性 2.2.1 神经系统疾病 Apelin/APJ在神经系统中广泛分布,包括脊髓、背根神经节、中脑导水管的周围灰质等疼痛相关的结构,因此认为Apelin参与了疼痛的形成[6]。神经损伤时,脊髓Apelin/APJ系统被激活,参与神经性疼痛的启动与维持。使用抑制APJ受体的药物可明确减轻热痛觉及机械性痛觉过敏[7]。研究者在炎性疼痛的大鼠模型中发现其脊髓中Apelin表达量下降,通过电针刺激可使Apelin恢复正常表达量,大鼠疼痛明显减轻[8]。由此推测Apelin/APJ具有镇痛作用,可用于临床疼痛治疗。 除此之外,近年研究发现Apelin有神经保护作用。在大鼠脑缺血再灌注模型中,外源性给予Apelin-13可大幅减少梗死体积和神经系统的损伤[9],其机制是:Apelin-13通过降低血脑屏障的通透性、增加血管内皮生长因子、上调血管内皮的一氧化氮合酶等途径,保护了血脑屏障不被损伤[10]。在此基础上,可以使用APJ拮抗剂MM54(cyclo [1-6] CRPRLC-KH-cyclo [9-14] CRPRLC)观察Apelin的作用:在患有恶性胶质瘤的小鼠模型中,使用MM54可发现肿瘤生长速度显著下降,与肿瘤相关的神经症状的扩展也被阻断[11]。在创伤性脑损伤的小鼠模型中,向脑室内外源性注入Apelin-13,发现其自噬作用被抑制,脑损伤程度减轻,提示Apelin-13有抑制自噬的作用[12]。在帕金森大鼠模型中,把Apelin-13注入黑质中,研究者发现大鼠的认知障碍症状明显缓解[13]。在上述研究基础上,已有Apelin用于临床神经系统疾病的治疗,成为新的研究热点。 2.2.2 呼吸系统疾病 Apelin是近年发现的呼吸系统疾病治疗的新靶点,能够通过激活AMPK-KLF2-eNOS-NO 信号通路以及 miR-424/503-FGF 轴来有效缓解肺动脉高压的严重程度[14]。Apelin在缓解急性肺水肿的过程中也起积极作用,Apelin-13能够抑制由脂多糖引起的活性氧的形成过程,进而抑制核因子κB 通路以及炎性蛋白体NLRP3的活化,最终减轻肺损 伤[15]。除上述作用外,Apelin还具有抗急性呼吸窘迫征的作用,在急性呼吸窘迫征大鼠模型肺组织中Apelin水平和APJ受体的表达升高,通过促进炎性因子水平的降低来减轻肺损伤的程度[16]。另外,睡眠呼吸暂停综合征、肺栓塞、哮喘等肺部疾病与Apelin的关系将成为未来几年的研究热点,有望将Apelin应用于临床中肺部疾病的治疗。 2.2.3 循环系统疾病 高血压与血管内皮功能障碍、动脉硬化密切相关。因Apelin可作用于血管内皮,其与高血压的关系密不可分,在Apelin各分型中,Apelin-12降血压作用最 强[17]。Apelin除通过依赖一氧化氮扩张血管来降低动脉血压外,还可促进内皮细胞增殖,在血管生成过程中还可参与调控血管直径。但是,上述Apelin的血管舒张作用依赖于血管内皮完整的前提;在血管内皮完整情况下,Apelin促进内皮细胞释放一氧化氮舒张血管;当血管内皮缺失时,Apelin与APJ受体结合,激活磷脂酶C,刺激二酰甘油和三磷酸肌醇的生成,使细胞内Ca2+浓度增加,进而促进激球蛋白磷酸化,最终导致血管收缩[18]。在关于高血压与Apelin的相关性研究中发现,在高加索人群中,血清中Apelin低水平可能是导致高血压发生的原因[19]。与此结果相同,黄扬等[20]的实验研究发现老年高血压患者血清Apelin表达水平显著低于正常对照组,血清水平与血压变异系数呈反比。综上可得出Apelin是高血压患者保护因子的结论。 Apelin在血管平滑肌细胞中大量表达,通过激活肌球蛋白轻链促使血管平滑肌收缩[21]。Apelin通过激活一些能够促进血管平滑肌向合成表型转化的信号通路,如PI3K/Akt、细胞外信号调节激酶通路等,促进血管平滑肌细胞表型转换和增殖[22]。与之相应,发现在动脉粥样硬化斑块的形成过程,Apelin起促进血管平滑肌细胞从中膜向内膜的迁移的作用[23]。F13是Apelin的拮抗剂,能够显著减弱肾性高血压中Apelin诱导的降压反应[24],在离体的大鼠脑动脉中发现,F13能够消除一氧化氮的血管舒张作用[25]。Apelin的另一种拮抗剂是ML-221,能够抑制Apelin 对微血管内皮的促增殖作用。有小鼠实验证明,缺血性视网膜病变时视网膜血管病理性增加,经腹腔注射ML-221可明显抑制此过程[26]。因此可通过使用Apelin拮抗剂,减慢由Apelin诱导的对机体有害的进程。 2.2.4 消化系统疾病 Apelin在胃肠道广泛分布,如胃底区、十二指肠上皮细胞、胰腺组织。Apelin不仅能够通过影响胃迷走信号的传入而增加胃酸分泌,还可通过介导蛋白激酶刺激胆囊收缩素的分泌[27-28]。这与ANTUSCHEVICH等[29]发现Apelin可增加胃、胰腺酶活性,促进胆囊收缩素分泌的结果一致。在消化系统运动功能方面,Bulbul等[30]和Birsen等[31]发现Apelin-13可通过激活胆囊收缩素1受体抑制迷走神经的传入,进而起抑制胃酸分泌的作用。除此之外,Apelin还可通过阻断迷走神经中的胆碱能通路抑制胃肠道运动[32]。在BIRSEN等[31]的研究中还发现Apelin可缩短应激性胃损伤的愈合时间。上述发现对于治疗人体应激性胃溃疡具有重要意义。 肝纤维化是指肝内结缔组织异常增生,是由病毒、酒精、胆汁淤积等病因引起的慢性肝损伤,在此过程中,肌成纤维细胞是造成肝纤维化的主要细胞。近期研究发现,Apelin系统是肝星状细胞转化为肌成纤维细胞的信号通路之一,通过介导血管紧张素Ⅱ和内皮素1激活肝星状细胞引发纤维化效应,成为肝纤维化的促进剂[33]。此外,缺氧、炎症、促纤维化因子这些促进肝纤维化的因素也能够上调肝细胞和肝星状细胞中的APJ表达,使纤维永久化[34-36]。因此,在建立肝硬化的大鼠模型中,不难发现大鼠血浆中Apelin含量比对照组明显增加;使用Apelin的拮抗剂F13,可发现肝纤维化程度显著减轻。在切除部分肝脏的小鼠实验中,发现Kupffer细胞中APJ大量表达,其抑制了肝脏再生,使用拮抗剂F13可促进肝细胞再生[37]。另外,Apelin对胆管疾病的治疗也有重要作用,通过检测原发性胆管炎患者的血清及胆汁发现,Apelin及APJ表达水平均升高。在胆汁淤积小鼠模型中发现Apelin能够通过Nox4/ROS/ERK通路诱导胆管细胞的增殖,并通过细胞内活性氧途径激活肝星状细胞[38]。因此,Apelin对于肝脏纤维化的预测及胆管疾病治疗方面具有重要意义。 Apelin及APJ在消化系统疾病状态下表达增加:克罗恩病患者的肠系膜脂肪组织中Apelin高表达;食管静脉曲张严重程度与Apelin水平呈正相关;在消化道肿瘤中Apelin表达增加[39-40]。因此,Apelin具有作为消化道肿瘤预测因子的潜力。 2.2.5 泌尿系统疾病 Apelin/APJ在肾外髓质、收集小管、肾血管内皮细胞中广泛表达,可改善肾纤维化、肾缺血再灌注损伤、糖尿病肾病等病情进展[41]。除此之外,Apelin及APJ在加压素能神经元中也大量表达。当在大鼠脑室外源性注射Apelin,发现精氨酸加压素的神经元电活动受到抑制,大鼠尿量增加。然而,Apelin在肾脏的作用并非如此复杂,其直接调节集合管上的水通道调节蛋白2的含量,发挥利尿作用[42]。 2.2.6 内分泌系统疾病 内分泌功能的调节轴是由下丘脑与垂体和其他性腺共同构成,以往研究表明Apelin/APJ系统对这些轴所介导的内分泌功能起重要作用,如类固醇的释放、食物摄入、急性应激等[43]。RAK等[44]研究发现,Apelin通过AMPK/ERK和Akt/PI3信号通路促进卵巢细胞的增殖,不仅如此,Apelin还可抑制类胰岛素生长因子1和卵泡刺激素诱导的类固醇分泌。 在糖代谢中,Apelin可提高葡萄糖利用率和增加胰岛素敏感性[45],由此Apelin被认为是治疗临床中的胰岛素抵抗和2型糖尿病的新型治疗靶点。在超重男性的临床研究中,静脉给予30 nmol/kg的(Pyr1)-Apelin-13可发现葡萄糖输注速率显著提高,胰岛素敏感性也得到了显著改善[46]。WANG等[47]发现Apelin具有促进胰岛素分泌作用,即抗糖尿病的作用,可明显减轻与2型糖尿病相关的并发症。因此,Apelin/APJ系统可明显使与糖尿病相关的糖耐量异常和胰岛素敏感性失调得到一定程度的改善。 Apelin除了上述作用外,近年被发现其可作为脂肪因子参与能量代谢,可与瘦素、脂联素共同作用于葡萄糖代谢、脂质代谢、胰岛素的调节分泌等[48]。对胰岛素抵抗的小鼠进行腹腔注射Apelin(0.1 μmol/kg)治疗,28 d后观察到小鼠肝脏中三酰甘油的含量以及与脂肪生成相关的基因表达大幅下降,显示Apelin能够抵抗小鼠的肝脂质代谢[49]。在饮食与Apelin基因表达的研究中发现,低热量饮食能够降低肥胖患者Apelin的基因表达及血浆浓度,高热量饮食则与之相反[50]。上述表明了Apelin在脂肪代谢过程中有着关键的作用。 2.2.7 免疫系统疾病 免疫功能的正常是机体维持健康的前提,近年越来越多的研究开始转向Apelin与免疫功能的研究。对免疫治疗无效患者的肿瘤细胞进行研究时发现,编码Apelin的基因大多发生缺失突变。因此,推测Apelin的基因突变能够改变癌细胞对T细胞免疫疗法的易感性[51]。为了探讨Apelin对腹腔巨噬细胞的影响,将大鼠腹腔巨噬细胞与Apelin-13共同孵育,发现巨噬细胞的吞噬及趋化活性明显降低,进而得出Apelin对巨噬细胞功能活性具有抑制作用的结论[52]。除此之外,Apelin在淋巴管的生成过程中也有促进作用。克罗恩病患者就是通过不断提升Apelin水平,进而促进肠淋巴功能来改善结肠的炎症症状[53]。Apelin与免疫系统疾病的相关报道较少,仍需要进一步的研究。 2.2.8 妊娠期疾病 Apelin能够参与调节胎儿及新生儿的葡萄糖稳态:当外源性静脉给予Apelin时,大鼠胎盘中的葡萄糖转运明显增加;当向母体腹腔注射Apelin时,新生儿的肺部组织及肌肉的葡萄糖摄取功能显著增强[54]。VAN MIEGHEM 等[55]发现那些胎儿发育迟缓的妊娠妇女的血清以及胎盘组织中Apelin水平均下降,进而推测Apelin的下降与妊娠期心血管疾病的发病显著相关。除此之外,Apelin/APJ还有调节体液平衡的作用,子痫前期中Apelin的低表达加速了妊娠期高血压的发生发展[56]。因此,Apelin可作为诊断和治疗子痫前期的一种新的潜在介质。 2.2.9 抗衰老 衰老是由于机体细胞线粒体数量下降、酶活性降低引起代谢速率下降所导致。在Apelin和APJ基因敲除的小鼠模型中,其衰老速度有一定的加速趋势。当恢复Apelin则发现小鼠不仅活力增强,行为与昼夜节律表型也得到了恢复。Apelin抗衰老的机制还包括促进自噬、降解受损细胞器、阻止细胞衰老以及通过干细胞作用促进细胞增殖和分化[57]。因此,从一定程度讲,Apelin起抗衰老的作用。 2.3 Elabela的结构和功能 近年来发现APJ的另一配体Elabela,是a类(视紫红质)G蛋白偶联受体,位于4号染色体。CHNG等[58]和PAULI等[59]的研究表明,Elabela的前体由54个氨基酸组成,经加工成为Elabela32、Elabela21、Elabela11等亚型。Elabela表达于心脏内皮、血管内皮、肾脏、前列腺和胎盘,与促进细胞运动、更新胚胎干细胞和胚胎干细胞的凋亡以及内胚层的分化相关。人类胚胎干细胞中可测到Elabela表达,却没有APJ表达,由此推断,Elabela还有其他受体[60]。在肺动脉高压大鼠模型中,下调血浆Apelin的基础上外源性给予Elabela,发现右心室肥厚及肺血管重构被改善[61]。因此推测,Elabela在心血管疾病中可补偿Apelin的功能下调。 2.4 疾病与Elabela的生物活性 2.4.1 循环系统疾病 Elabela与Apelin具有相似的心血管作用,如增加心肌收缩力和心输出量、舒张血管,在人类和小鼠肺动脉高压模型中血浆浓度均表现为下降[62]。Elabela可通过降低转录因子FoxM1和血管紧张素转化酶的表达来抑制肾素-血管紧张素系统,进而抑制血管紧张素Ⅱ的升压作用[61]。 Elabela也有抗凋亡作用,通过抑制凋亡蛋白和激活抗凋亡蛋白两种方式。慢性淋巴细胞癌患者血浆中Elabela水平明显高于正常人[63]。也有研究表明,在卵巢癌中Elabela表达水平升高,以及Elabela水平的升高与愈后不良有关[64]。在YI等[65]的研究中发现,胶质母细胞瘤中Elabela水平升高,抑制了细胞迁移和增殖。在依赖p53发生凋亡的细胞中,Elabela通过影响细胞的增殖及生长周期发挥抑制凋亡的作用,此作用独立于Apelin。 2.4.2 泌尿系统疾病 Elabela还可使大鼠的尿流率和水摄入增加,进而影响体液平衡,其作用效果是Apelin的5倍。若静脉给予Elabela,尿液检测发现尿渗透压降低,Na+、K+排出量增多[66]。Elabela的利尿作用还能间接影响血压,如XU等[67]在小鼠远端肾单位中发现,其通过与肾素-血管紧张素系统对抗的方式来参与血压调节。除此之外,还有研究报道Elabela与肾纤维化的关系,例如Elabela在糖尿病肾病中可抑制与肾纤维化相关的基因表达,减慢肾小球结构改变,由此可作为糖尿病肾病潜在的治疗方式[68]。 2.4.3 妊娠期疾病 Elabela对胚胎心血管的形成和早期胚胎发育至关重要。Elabela在早孕时检测到,参与内胚层分化和心脏形态发生[58,69]。Elabela不仅通过激活PI3k/Akt/mTOPC1通路来参与蛋白翻译和细胞周期进展,还通过促进中胚层细胞的迁移和分化来推进早期心脏形态发生和原始血管网络形成[60]。怀孕小鼠实验中Elabela基因敲除者出现蛋白尿及血压升高现象,类似于子痫前期的症状,当外源性给予Elabela时,子痫前期样症状则被改善[70]。同样的,DENG等[71]发现,Elabela通过旁分泌方式激活APJ受体促进血管舒张和增加利尿,以缓解子痫的高血压及蛋白尿症状。然而,在重度子痫前期和正常妊娠妇女的研究中发现,两者血清Elabela并没有差异性,说明Elabela不能作为子痫前期可靠的生物标志物[72]。因此,Elabela对子痫前期的作用具有争议性,仍需进一步探索。"
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