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Advances in Clinical Medicine
Vol. 13  No. 10 ( 2023 ), Article ID: 73468 , 8 pages
10.12677/ACM.2023.13102195

PCSK9抑制剂在颈动脉狭窄中的应用进展

刘鑫1，刘佳2*

1新疆医科大学第四临床医学院，新疆 乌鲁木齐

2新疆医科大学附属中医医院脑病一科，新疆 乌鲁木齐

收稿日期：2023年9月6日；录用日期：2023年10月1日；发布日期：2023年10月10日

摘要

颈动脉狭窄(Carotid Artery Stenosis, CAS)是急性缺血性脑卒中(Ischemic Stroke, IS)的原因之一，其主要原因是动脉粥样硬化(Atherosclerosis, AS)。低密度脂蛋白胆固醇(Low Density Lipoprotein Cholesterol, LDL-C)异常是导致AS的重要危险因素。近年的研究发现人前蛋白转化酶枯草溶菌素kexin 9型(proprotein convertase subtilisin/kexin type 9, PCSK9)在动脉粥样硬化斑块形成扮演者重要角色。PCSK9抑制剂已被证实可以改善心血管疾病的预后，目前广泛应用于心血管疾病，但是缺乏在CAS中应用的相关报道。本文对PCSK9抑制剂在CAS中的应用做一综述。

关键词

前蛋白转化酶枯草溶菌素Kexin 9型，颈动脉狭窄，PCSK9抑制剂，动脉粥样硬化

Application of PCSK9 Inhibitor in Carotid Stenosis

Xin Liu1, Jia Liu2*

1The Fourth Clinical Medical College of Xinjiang Medical University, Urumqi Xinjiang

2Brain Disease Department 1, Affiliated Traditional Chinese Medicine Hospital of Xinjiang Medical University, Urumqi Xinjiang

Received: Sep. 6th, 2023; accepted: Oct. 1st, 2023; published: Oct. 10th, 2023

ABSTRACT

Carotid Artery Stenosis (CAS) is one of the causes of acute ischemic stroke (IS), and its main cause is atherosclerosis (AS). The abnormality of low density lipoprotein cholesterol (LDL-C) is an important risk factor leading to AS. Recent studies have found that human prothrombin invertase kexin 9 (PCSK9) plays an important role in atherosclerotic plaque formation. PCSK9 inhibitors have been proved to improve the prognosis of cardiovascular diseases. They are widely used in cardiovascular diseases, but there is no relevant report on the application of PCSK9 inhibitors in CAS. This article reviews the application of PCSK9 inhibitors in CAS.

Keywords:Proprotein Convertase Subtilisin/Kexin Type 9, Carotid Stenosis, PCSK9 Inhibitor, Atherosclerosis

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

CAS与动脉粥样硬化斑块发展有关。AS本身是一种慢性的动脉疾病，血脂异常尤其是LDL-C在AS的过程中起着重要作用 [1] [2] [3] 。近年来的研究表明PCSK9在AS形成的每一步都起着重要作用 [1] 。PCSK9抑制剂可以通过抑制PCSK9与低密度脂蛋白受体(Low-Density Lipoprotein Receptor, LDL-R)结合以及PCSK9合成等过程从而降低LDL-C水平，有助于减缓AS的进展，因此可作为CAS的一种新的治疗方案 [4] 。本文对PCSK9抑制剂在CAS中应用的进展进行综述。

2. PCSK9

PCSK9于2003年由Seidah等 [5] 发现。PCSK9基因定位于1号染色体的短臂(chr1p32.3)，长度为22 kb，包含12个外显子和11个内含子 [6] 。PCSK9是一种为分子量为72 kDa的含有692个氨基酸的酶原 [7] [8] ，由N端结构域、信号肽、催化结构域和C端结构域组成 [7] [9] [10] 。主要在肝脏、小肠、血管等器官表达。PCSK9存在功能获得型(Gain Of Function, GOF)和功能缺失型(Loss Of Function, LOF)变异。PCSK9 GOF变异降低循环中LDL-R的减少，与循环中LDL-C水平增加相关 [11] 。相反，PCSK9 LOF变异可降低循环LDL-C水平 [12] 。

3. PCSK9与颈动脉狭窄

CAS的主要原因是动脉粥样硬化 [13] 。AS过程开始于内皮细胞的功能改变，并伴随着动脉壁内层LDL-C的积累、氧化和糖基化，并持续于黏附分子的表达和趋化因子的释放 [1] 。单核细胞和T细胞在血管内膜空间被招募，单核细胞吞噬氧化的低密度脂蛋白(Oxidized low-density lipoprotein, ox-LDL)形成泡沫细胞 [14] 。在动脉粥样硬化的各种危险因素中，血脂异常，尤其是LDL-C异常，在AS的过程中起着重要作用 [15] 。除此之外，PCSK9还能够通过促进炎症、促进斑块及血栓形成等方面加速动脉粥样硬化形成。

3.1. PCSK9与脂质代谢

在没有PCSK9干扰的情况下，LDL-R与肝细胞表面的低密度脂蛋白(Low-Density Lipoprotein, LDL)结合形成LDL-R/LDL复合体并将其转移到肝细胞的核内体中，由于PH值的变化导致二者分离，LDL在溶酶体中降解，LDL-R在循环到肝细胞表面继续循环。而PCSK9不仅可以与LDL-R的表皮生长因子同源域A (EGF-A)结合使LDL-R无法结合LDL-C颗粒 [16] ，还可以增强LDL-R的内吞作用和阻断其循环来促进LDL-R降解，通过这两种途径导致LDL-C循环水平增高，导致LDL-C在体内堆积。除了LDL-C之外，PCSK9还可以通过参与甘油三酯(Triglyceride, TG)和脂蛋白a (Lipoprotein-a, Lp(a))来加速AS的发展 [17] [18] 。

3.2. PCSK9与炎症

2019年的一项研究使用多局部正电子发射断层扫描/磁共振成像(Positron emission tomography/magnetic resonance imaging, PET/MRI)揭示了AS早期处于炎症状态 [19] 。欧洲动脉粥样硬化血管内超声(ATHEROREMO-IVUS)研究中的炎症和血管壁重塑合作项目研究表明，血清PCSK9水平与炎症斑块和坏死核心组织的绝对体积有关 [20] 。PCSK9可以通过调节Ly-6Chi [21] 单核细胞导致炎症细胞因子如肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)、白细胞介素-6 (IL-6)等的过量分泌，并减少抗炎细胞因子如白细胞介素-10 (IL-10)和精氨酸酶等的分泌 [22] [23] [24] ；通过诱导核因子Kappa B (NF-KB)易位从而增加促炎细胞因子mRNA水平和toll样受体4 (TLR4)的表达 [23] ；还可以激活血管细胞黏附分子1 (Vascular cell adhesion molecule-1, VCAM-1)的表达以增加单核细胞、淋巴细胞、嗜酸性粒细胞等在血管壁的黏附 [25] 。这些相关研究都表明了PCSK9促进炎症反应从而加速AS的进展。

3.3. PCSK9与斑块形成

斑块形成包括脂蛋白滞留、炎症细胞募集、血管平滑肌细胞(vascular smooth muscle cell, VSMC)增殖、基质合成、钙化、泡沫细胞的形成、凋亡和坏死等一系列复杂的过程。这些过程之间存在复杂的相互作用，并且由于在斑块的发展过程中的作用各不相同，导致不可预测的进展率、不同的斑块形态和不同的临床结果 [26] 。PCSK9增加巨噬细胞的清道夫受体(Scavenger receptor, SR)对LDL的摄取形成更多的泡沫细胞 [27] ；通过诱导黏附分子、趋化剂和炎症细胞因子的表达促进血管壁的炎症 [28] ，促使血管平滑肌细胞凋亡从而降低血管的稳定性 [29] ，加速动脉粥样硬化斑块的形成。一些动物实验和人体研究证实了PCSK9促进小鼠和人类斑块的形成 [30] [31] 。

3.4. PCSK9与血栓形成

血栓形成依赖于血小板的粘附、活化和聚集 [32] 。血小板在止血启动和血栓形成中起着重要作用，并被认为可能是连接血栓和炎症的多功能效应细胞 [33] 。一方面在动物实验模型中证明PCSK9水平与血小板激活标志物糖蛋白Ⅱb/Ⅲa (GP Ⅱb/Ⅲa)和p-选择素(P-selectin)呈正相关 [34] [35] [36] ；另一方面PCSK9已被证明可以显著增强血小板聚集和整合素αⅡbβ3的表达 [34] ，并直接诱导血小板释放颗粒中的ATP和p-选择素，并且在SR的作用下合成血栓素A2 [35] 。其次由于PCSK9可以导致LDL-C水平升高，而LDL-C又可以刺激血小板聚集 [37] 。因此PCSK9通过多种途径导致血小板聚集和活化，促进血栓生成。

4. PCSK9抑制剂

目前多种PCSK9抑制剂已经被开发出来，其机制大致可分为3类：1) LDL-R结合抑制：通过阻止PCSK9与LDL-R结合，允许更多的受体循环到细胞表面以进一步去除LDL-C；2) PCSK9合成抑制：在翻译水平上阻止PCSK9的形成，使PCSK9基因沉默；3) 自催化过程抑制：包括中断PCSK9的自催化过程，从而禁止成熟和细胞分泌 [38] [39] 。依洛尤单抗和阿利西尤单抗都属于单克隆抗体，通过结合PCSK9的相对平坦区域阻断PCSK9与LDL-R的相互作用，降低LDL-C水平，从而抑制PCSK9 [4] 。

依洛尤单抗(AMG-145)于2015年上市，用于经过饮食调脂和药物治疗无法达到LDL-C目标水平的患者 [40] 。OSLER-1和OSLER-2实验以及FOURIER实验证实了依洛尤单抗能够有效降低LDL-C、胆固醇、TG、apoB、Lp(a)水平，除注射部位不良反应高于安慰剂组之外，两组间在不良事件(包括新发糖尿病和神经认知事件)方面无显著差异，而且并未观察到严重不良事件 [41] 。阿利西尤单抗在ODYSSEY LONG TERM试验以及ODYSSEY OUTCOMES试验中能够显著的长期降低LDL-C水平，且不良事件与依洛尤单抗相似 [42] [43] 。尽管两种药物疗效及不良事件相似，但有研究表明依洛尤单抗较阿利西尤单抗能更有效地降低LDL-C [44] 。

Inclisiran (Leqvio®)是一种基于siRNA(小干扰RNA)的治疗药物，由诺华公司开发，是一种合成的长效siRNA，靶向于PCSK9 mRNA以阻止其表达，于2020年12月在欧盟上市，相关研究证实了其安全性和有效性 [45] [46] ，但该药在我国尚未被批准上市。其它的PCSK9抑制剂如小分子药物(small molecules)以及PCSK9疫苗等药物目前仍处于研发中，如果研发成功，未来可能会提供更多的治疗方案。

5. PCSK9抑制剂在CAS中的应用

CAS根据6个月内有无短暂性脑缺血发作和缺血性卒中发生可分为症状性(Symptomatic carotid artery stenosis)和无症状性(Asymptomatic carotid artery stenosis)。目前其主要治疗包括颈动脉内膜剥脱术(carotid endarterectomy, CEA)、颈动脉支架成形术(carotid artery stenting, CAS)以及最佳药物治疗(best medical therapy, BMT) [47] 。经颈动脉支架成形术(transcarotid artery revAScularization, TCAR)由于其良好的成功率以及低卒中发生率和低颈动脉损伤率也逐渐进入了人们的视野 [48] 。指南推荐在CAS的药物治疗中使用他汀类药物以降低胆固醇和LDL-C [13] 。但是，由于他汀类药物个体差异，以及部分接受他汀类药物治疗的患者出现肌痛、抽筋甚至横纹肌溶解症等不良反应，因此在这些患者中如何选择降脂药物，以及如何强化降脂治疗是目前关注的焦点。

大量的研究证实了PCSK9抑制剂在在降脂、抗炎及抗血小板聚集等方面的功能。Alessandro等人在家族性高胆固醇血症(FH)患者接受PCSK9抑制剂治疗12周后观察到炎症和血小板激活代谢物同时减少 [49] 。Marcin等人观察到在在不稳定动脉粥样硬化斑块患者中，接受阿利西尤单抗治疗3个月后，炎症因子如IL-6、IL-8、TNF-α等影响动脉粥样硬化斑块稳定性的因素明显降低 [50] 。Nathaniel等人观察到高胆固醇血症患者接受依洛尤单抗治疗后Lp(a)水平显著下降 [51] ，还证实了PCSK9抑制剂具有稳定斑块等作用。Atsushi等人在一份病例汇报中描述了3例拒绝接受手术的CAS患者，在接受阿利西尤单抗治疗6个月后，观察到纤维冒形成以及富含脂质坏死核的消退，首次证明了PCSK9抑制剂可以稳定颈动脉斑块 [52] 。Norman等人在颈动脉MRI上观察到接受阿利西尤单抗治疗后斑块组成和新生血管的退化 [53] 。Matteo等人观察到接受依洛尤单抗治疗12周后，颈动脉硬度和颈动脉膨胀性均有改善 [54] 。Nicholas在FOURIER试验中观察到PCSK9抑制显著降低了静脉血栓栓塞(Venous thromboembolism, VTE)的风险 [55] 。此外，根据FOURIER试验中的数据显示，依洛尤单抗在亚洲人群中显著降低了LDL-C，在降低心血管事件风险和在其它地区具有相同的安全性和有效性 [56] 。

虽然PCSK9抑制剂尚未进入国内的颈动脉狭窄指南，但是《缺血性脑卒中强化血脂管理上海专家建议》 [57] 以及《中国缺血性卒中和短暂性脑缺血发作二级预防指南(2022)》 [58] 都推荐在接受他汀治疗后LDL-C未达标的患者可使用PCSK9抑制剂，为临床治疗提供了依据。

6. 未来与展望

PCSK9自2003年被发现至2015年PCSK9抑制剂获得FDA批准上市，越来越多的研究挖掘出PCSK9的多种作用机制及功能，也开发出来越来越多的PCSK9抑制剂，对于他汀药物部耐受的患者提供了更多的选择，使降脂治疗进入了一个新的时代。但是仍有相当数量的高危患者LDL-C仍未达标。目前对于PCSK9基因的仍处于不断研究的状态，未来可能开发出的PCSK9抑制剂的口服制剂或疫苗等药物，能够为高LDL-C患者的治疗方案提供了更有价值的补充。

文章引用

刘 鑫,刘 佳. PCSK9抑制剂在颈动脉狭窄中的应用进展
Application of PCSK9 Inhibitor in Carotid Stenosis[J]. 临床医学进展, 2023, 13(10): 15693-15700. https://doi.org/10.12677/ACM.2023.13102195

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    59. NOTES

    *通讯作者。

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