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血管紧张素II在衰老中的新作用
1.血管紧张素II介绍控制体液容量平衡对生命至关重要,而人类专门用于这一任务的复杂系统是由生存反应形成的进化过程的结果[4]。例如,在对创伤做出反应时,交感神经系统的激活会促进肾素、血管紧张素、醛固酮、儿茶酚胺和钠尿肽的释放,这些物质的作用使血液循环中的体液压力得以维持,尽管大出血会导致体液流失[22][72]。维持容积平衡使动物得以从海水中的盐分迁移到淡水和干燥的陆地上[59]。在人类进化过程中,肾素-血管紧张素系统(RAS)发挥了重要作用,因为它能够控制盐的摄入并刺激口渴。对当代原始部落的研究表明,狩猎采集者的祖先靠少量盐生存,这可能得益于肾素-血管紧张素系统的激活,而没有患上高血压[33]。随着饮食习惯的改变,盐的摄入量也随之增加,从而使RAS介导的血压升高变成了一个负面因素。因此,自然选择在很大程度上影响了高血压的发展,不同地域和种族的人群高血压发病率差异很大[70]。生活在炎热潮湿地区(如热带地区)的古人类,为了适应低盐供应和电解质失衡的风险,进化出了保留盐分的倾向[19]。相比之下,温带等气候较凉爽、干燥地区的人口则适应了钠供应较多、钠流失较少的条件[19]。在这种情况下,人类RAS 基因的变异可能是造成高血压易感性地区差异的部分原因[41]。除了盐潴留和高血压之外,最近的研究还阐明了RAS,特别是其主要效应分子血管紧张素II(AngII)在炎症、自身免疫和衰老中的作用。本文旨在强调血管紧张素II的新作用及其可能的临床意义。2.肾素-血管紧张素系统成分的影响1898年,罗伯特-泰格斯特(RobertTigerstedt)和他的学生佩尔-贡纳尔-伯格曼(PerGunnarBergman)发现兔肾皮质提取物中存在一种加压物质,并将其命名为肾素[64]。1934年,亨利-戈德布拉特(HenryGoldblatt)证实,用银夹收缩狗的肾动脉可产生慢性高血压[20]。随后,布劳恩-梅内德斯等人以及佩奇和赫尔默使用同样的技术证明了肾脏分泌另一种具有快速加压作用且持续时间极短的化合物--血管紧张素[7][6][45]。自这些早期研究以来,我们对AngII的生理学和病理生理学的认识有了很大提高。2.1血管紧张素肽AngII是一种八肽,由底物血管紧张素原通过肾素和血管紧张素转换酶(ACE)的顺序酶解形成。具体来说,肾素分解血管紧张素原形成血管紧张素Ⅰ,血管紧张素Ⅰ又被血管紧张素转换酶转换成血管紧张素Ⅱ。底物血管紧张素原在肝脏中产生,肾素在肾脏中产生,而 AngII在血管组织中产生[65]。ACE是一种循环酶,它还能将缓激肽降解为非活性片段,从而降低血清中内源性血管扩张剂的水平[8][17]。可以想象,对于心血管疾病或脑部功能逐渐衰退的患者(包括老年痴呆症和阿尔茨海默氏症)来说,情况可能也是如此,但目前尚无此类研究。ACE2是另一种羧肽酶,能从AngII中裂解出一种氨基酸,生成七肽血管扩张剂Ang1-7[11][16],ACE和ACE2之间的平衡对控制AngII水平至关重要[20]。在心脏中,肥大细胞、内皮细胞和间质间质细胞都能表达这种酶[66],在肾脏中,间质细胞和血管平滑肌细胞也能表达这种酶[23]。在心脏、血管和肾脏组织中,尤其是在疾病状态下,消解酶介导的AngII生成已成为ACE的替代途径[3][23][38](图1)。AngII可在血液循环中被其他氨肽酶分解,形成Ang(2-8)(AngIII)和Ang(3-8)(AngIV)。AngIII在增加血压和血管加压素释放[10][51]以及刺激培养肾细胞中促炎介质的表达[54]方面的作用与AngII相似,但效力较弱。AngIV通过增加肾脏[21]和大脑[32]的血流量发挥保护作用。图片1:肾素血管紧张素系统(RAS)血管紧张素I被ACE或糜蛋白酶裂解后产生活性八肽AngII,通过AT1和AT2受体发挥作用。血管紧张素II的水平还受ACE2的调节,ACE2可将血管紧张素II 分解,生成具有血管扩张作用的七肽Ang1-7。AGT,血管紧张素原;ACE,血管紧张素转换酶;AT1R,血管紧张素1型受体;AT2R,血管紧张素2型受体;ACEi,血管紧张素转换酶抑制剂;ARB,血管紧张素II受体阻滞剂。循环中的AngII会导致血压升高,并影响肾小管→肾小管保留钠和水分[8][29]。在过去二十年中,该领域最重要的进展之一是发现了局部或组织RAS。局部系统的特点是在多个器官中存在RAS成分,包括心脏[67]、肾脏[30]、大脑[39]和胰腺[18],以及生殖组织[63]、淋巴组织[26]和脂肪组织[27]。局部RAS在每个器官中发挥不同的功能,它可以独立运行功能,如在肾上腺和大脑中,也可以与循环RAS密切互动,如在心脏和肾脏中。此外,人们还发现了一种功能性细胞内RAS[14][50]。局部和细胞内RAS的发现凸显了AngII的几种突出的非血流动力学效应,包括促炎、增殖和促纤维化活性。AngII可促进活性氧(ROS)生成、细胞生长、细胞凋亡、细胞迁移和分化、细胞外基质重塑、调节基因表达,并可激活多种细胞内信号通路,导致组织损伤[55]。在肾脏、心脏和血管等组织中,AngII通过促进促炎趋化因子的表达来诱导炎症反应,导致组织中免疫细胞的聚集[61]。在高血压中,肾脏中出现了一种有害的放大机制,其中AngII会诱导肾脏血管紧张素原的表达,从而诱导其自身的合成[31]。2.2血管紧张素受体血管紧张素II通过两种不同的G蛋白偶联受体(即血管紧张素1型和2型(AT1和AT2)受体)发挥作用[24][48]。单一的AT1受体在人体细胞中表达,而在大鼠和小鼠中存在两种同工型AT1A和AT1B,它们的序列相似度为95%。技术术语缩写在首次使用时均有解释。文章遵循客观性、可理解性和逻辑结构、清晰客观的语言、常规结构和格式、正式语域、均衡表达、精确选词和语法正确性等原则。AT1A受体是与人类AT1受体最接近的鼠类受体,在肾、心、脑、肾上腺、血管平滑肌、肝脏和其他一些组织中均有表达[9]。相反,AT1B主要表达于垂体前叶和肾上腺肾小球上区[43]。AT1A能产生AngII的大多数常规效应,如血压升高[25]、肾上腺肾小球上皮细胞释放醛固酮[1]、近端肾小管细胞盐潴留[62]以及通过大脑中的受体刺激交感神经系统[12]。AT1B可在AT1A受体缺失的情况下调节血压[43]。血管紧张素II型受体在发育中的胎儿组织中普遍表达。然而,在出生后,该受体的表达量会下降,在肾上腺髓质、子宫、卵巢、血管内皮和不同脑区等各种成人组织中的表达量仍然很低[60]。在心血管和肾脏系统中,AT1和AT2受体具有反调节作用[58]。血管紧张素II与AT2受体结合会导致阻力动脉和导管动脉的血管扩张,进而改善人类和小鼠的动脉重塑。AT2受体在心血管损伤中上调,并在防止缺血再灌注损伤和急性心肌梗塞中发挥重要作用[58]。此外,AT2受体对肾脏纤维化和缺血性肾损伤也有保护作用,因为在肾脏消融的小鼠模型中,该受体的缺失会加重肾损伤并降低存活率[5]。在对血管紧张素II的反应中,AT2受体通过刺激NF-κB通路也被认为具有促炎功能[15][53][69]。AT1和AT2受体是AngIII的结合位点,而AT4受体是AngIV的特异性受体,在大脑、肾脏、心脏和血管中都有表达[13]。3.大脑老化会影响认知功能吗?由于发现了一种独立于循环系统RAS,人们开始研究大脑RAS的作用,特别是它在阿尔茨海默病(最常见的痴呆症)的病理生理学中的作用。阿尔茨海默病的主要风险因素是年龄、老化大脑中错误折叠蛋白的积累和心血管系统的恶化。淀粉样蛋白(α-β)肽的积累会导致氧化和炎症损伤,造成能量衰竭和突触功能障碍[36][49]。在阿尔茨海默病患者死后脑组织的匀浆中观察到ACE活性增加,并与A-beta斑块负担和淀粉样血管病变的严重程度相关[2]。有报告称,患者大脑顶叶和额叶皮质血管周围的神经元和血管周围的ACE和AngII免疫反应性增加[37][56]。ACE活性的增加可能会通过增加AngII的产生来减少脑灌注特征[28]。在Tg2576阿尔茨海默氏症小鼠模型中,使用AT1受体阻滞剂进行预防性治疗可减少阿尔茨海默氏症样神经病理学,并减轻A-beta肽在大脑中聚集成细胞外淀粉样斑块沉积[68]。在阿尔茨海默病患者中,使用能通过血脑屏障(BBB)的ACEi(如培哚普利和卡托普利)治疗对认知能力下降的速度有好处[42]。一项对819491名被诊断患有痴呆症或阿尔茨海默氏症的患者(主要为男性)进行的队列分析表明,与ACEi或其他治疗高血压或血管疾病的药物相比,ARB治疗可显著降低以入住疗养院为衡量标准的痴呆症或阿尔茨海默氏症的发病率和病情进展。此外,联合使用抗逆转录酶抑制剂和ACEi还能降低阿尔茨海默氏症或痴呆症恶化的风险[34]。抗血管紧张素转换酶抑制剂的保护作用能持久且稳定的减慢老年大脑认知功能退化。阻断AT1受体还可能促进内源性AngII向AngIII和AngIV的转化。在这种情况下,AT4受体被AngIV激活可能会产生增强记忆的效果[71]。帕金森病的发病机制和进展涉及大脑RAS的激活[37]。这主要是由于减少了氧化应激,而氧化应激是导致帕金森病的一个关键因素[35][40]。ARB对缺血性损伤的神经保护作用已在临床和实验研究中得到证实,并被发现可预防中风[57]。4.临床意义第一种口服活性ACEi--卡托普利的合成[44]刺激了新治疗模式的发展,并开启了了解RAS系统临床意义的研究新纪元,RAS阻断剂在治疗高血压、心力衰竭和肾脏疾病方面的疗效已逐渐显现出来[46]。随后发现的AngII拮抗剂也使高血压的治疗受益匪浅,它可以选择性地阻断AT1受体的激活,而不影响血管舒张激肽,从而降低血压,即使在AngII没有增加的患者中也是如此。使用ACEi或ARB抑制RAS活性对左心室功能障碍或收缩性心力衰竭患者具有有益作用。使用ACEi或ARB治疗可降低冠心病高危患者的死亡率和不良心血管后果的风险,与血压控制无关[73]。对有微量白蛋白尿的糖尿病患者进行ACEi强化治疗,可起到肾脏保护和心脏保护的作用。对非糖尿病慢性肾病患者进行综合干预,包括使用剂量高于血压控制建议剂量的。未来几年的挑战将是确定这些药物能否转化为新的医疗应用。单独选择性阻断AT1受体或与ACEi联用更能保护脑血管免受损伤,这为认知功能减退患者的健康带来了新的前景。根据最近在转基因动物和长期接受ACEi或ARB治疗的老年大鼠身上进行的研究,干扰AngII合成和/或生物活性的药物可能是调节衰老信号级联和延长寿命的有希望的候选药物。数百万高血压、心脏和肾功能衰竭患者长期使用ACEi和ARB,其良好的安全记录表明,长期使用这些药物可能会有效防止与衰老相关的器官功能逐渐退化,而不会产生明显的副作用。至于这是否有助于健康老龄化和长寿,目前还只是一个猜测。参考文献1. 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