第二军医大学学报  2019, Vol. 40 Issue (4): 430-434   PDF    
微粒在动脉粥样硬化发生和发展中的作用
徐汝明1, 顾颖1, 杨帆2, 王国坤2     
1. 海军军医大学(第二军医大学)长海医院心血管内科, 上海 200433;
2. 海军军医大学(第二军医大学)长海医院心血管外科, 上海 200433
摘要: 微粒是细胞激活或凋亡时细胞膜通过出芽形式脱落的直径约为0.1~1 μm的小囊泡,载有蛋白质、细胞因子、mRNA、微RNA等物质,发挥多种生物学效应。在动脉粥样硬化的发生和发展中,微粒在内皮细胞损伤、炎症反应、平滑肌细胞增殖和迁移等过程中发挥重要作用。循环中高水平的微粒不仅是动脉粥样硬化患者血管损伤的生物标志物,也是动脉粥样硬化的潜在诊断指标和治疗靶点。本文立足于微粒在动脉粥样硬化发生和发展中的作用,从细胞水平对相关研究进展作一综述。
关键词: 微粒    动脉粥样硬化    内皮细胞    炎症    平滑肌细胞    
Role of microparticles in development and progression of atherosclerosis
XU Ru-ming1, GU Ying1, YANG Fan2, WANG Guo-kun2     
1. Department of Cardiovasology, Changhai Hospital, Naval Medical University(Second Military Medical University), Shanghai 200433, China;
2. Department of Cardiovascular Surgery, Changhai Hospital, Naval Medical University(Second Military Medical University), Shanghai 200433, China
Abstract: Microparticles are small vesicles with a diameter ranging from 0.1 to 1 μm that fall off from cell membranes through germination when cells are activated or apoptotic. Microparticle contains proteins, cytokines, mRNA, microRNA and other substances, and exerts a variety of biological functions. Microparticle plays an important role in endothelial cell dysfunction, inflammation, and smooth muscle cell proliferation and migration in the development and progression of atherosclerosis. High-level microparticles in circulation are not only biomarkers of vascular injury in atherosclerosis patients, but also potential diagnostic and therapeutic targets of atherosclerosis. This review focuses on the role of microparticle in the development and progression of atherosclerosis, and sums up the related research progresses at the cellular level.
Key words: microparticles    atherosclerosis    endothelial cells    inflammation    smooth muscle myocytes    

动脉粥样硬化是冠心病、周围动脉性疾病和卒中等心脑血管疾病发生和发展的病理基础,其主要病理变化包括内皮细胞通透性增加,低密度脂蛋白(low-density lipoprotein,LDL)在内皮下的沉积,白细胞渗出和泡沫细胞形成,平滑肌细胞的迁移和增殖,以及新生血管的形成等[1]。微粒(microparticle)是细胞激活或凋亡时细胞膜通过出芽形式脱落的直径约为0.1~1 μm的小囊泡,可以作为载体将蛋白质、细胞因子、微RNA(microRNA,miRNA)、mRNA等物质转运到靶细胞,发挥多种生物学效应。微粒在动脉粥样硬化的发生和发展中起重要作用,根据细胞来源及诱导微粒产生的刺激不同、微粒表面成分尤其是功能性miRNA的表达不同,微粒对动脉粥样硬化的发生和发展可表现出不同甚至完全相反的功能[2]。本文从细胞水平对微粒在动脉粥样硬化发生和发展过程中作用的相关研究进展作一综述。

1 微粒调节血管内皮细胞功能

微粒影响血管内皮细胞的正常生理功能。Densmore等[3]将内皮细胞微粒(endothelial microparticle,EMP)注射给予C57BL/6小鼠,发现小鼠肺血管内皮通透性增加,氧化低密度脂蛋白(oxygenized low-density lipoprotein,oxLDL)等生物大分子通过内皮细胞连接处并扩散和沉积,促进动脉粥样硬化的发生。此外,微粒能够通过抑制一氧化氮合酶活性,抑制内皮细胞合成及分泌一氧化氮,导致内皮细胞功能障碍和血管舒张功能障碍[4]。Ishida等[5]发现将分离自糖尿病大鼠循环中的微粒与健康鼠颈动脉共培养能够损伤血管内皮。Bammert等[6]将人脐静脉内皮细胞在高糖培养基中诱导产生微粒,该微粒可诱导内皮细胞Caspase-3表达增加约50%,miRNA-Let-7a表达减少近60%,Caspase-3表达增加和miRNA-Let-7a表达减少均可促进内皮细胞凋亡。还有研究发现终末期肾病患者循环微粒中miRNA-92a表达增加,并损伤内皮功能[7]。Jansen等[8]对小鼠注射给予饥饿诱导产生的EMP,发现EMP通过向内皮细胞转移miRNA-126,能够抑制SPRED1表达,促进内皮细胞的增殖和血管内皮的修复。然而,Schober等[9]发现内源性微粒中miRNA-126-5p可促进血管内皮增殖和修复,而miRNA-126-3p并无这一作用,提示内源性与外源性微粒表达的miRNA-126功能有所不同。同时有研究显示,健康小鼠来源的EMP可通过向内皮祖细胞转移功能性miRNA促进细胞的迁移和增殖,促进血管修复,抑制动脉粥样硬化进展[10]。Aday等[11]将血管内皮生长因子165(vascular endothelial growth factor 165,VEGF165)整合入微粒制成缓释微粒,该缓释微粒可促进脐血来源的晚期内皮祖细胞中血管内皮生长因子受体2(vascular endothelial growth factor receptor 2,VEGFR-2)和蛋白激酶B的磷酸化,进一步体内研究显示VEGF165缓释微粒可通过抑制miRNA-17提高内皮祖细胞的存活率。上述研究表明,病理状态诱导产生的微粒可以抑制一氧化氮合成,增加内皮通透性,影响内皮功能;但微粒亦可作为载体,健康来源或携带特殊组分的微粒可起到改善内皮功能的作用。

2 微粒与炎症反应对动脉粥样硬化的影响 2.1 微粒与单核巨噬细胞

内皮下LDL的氧化修饰被认为是动脉粥样硬化的核心病变,局部内皮下脂质沉积过多和巨噬细胞表面清道夫受体介导的脂质过度摄取共同促进了泡沫细胞的形成,巨噬细胞和泡沫细胞死亡导致胞外脂质不断沉积,形成动脉粥样硬化的脂质核心[12]。微粒表面富有P-选择素、组织因子、趋化因子、miRNA,并能促进单核细胞肿瘤坏死因子α(tumor necrosis factor α,TNF-α)、白细胞介素(interleukin,IL)-1β和白细胞介素1受体拮抗剂(interleukin-1 receptor antagonist,IL-1Ra)的表达,共同促进单核细胞和血小板在内皮细胞损伤部位的黏附和炎症反应[13]。血小板源性微粒(platelet-derived microparticle,PMP)还可通过分泌花生四烯酸促进单核细胞环氧化酶(cyclooxygenase 2,COX-2)表达,加强COX-2和内皮细胞上细胞间黏附分子1(intercellular cell adhesion molecule-1,ICAM-1)的结合,促进炎症反应[14]。然而,中性粒细胞源性微粒可诱导巨噬细胞分泌抗炎因子转化生长因子β1(transforming growth factor-β1,TGF-β1),抑制炎症反应[15]。Li等[16]研究发现,携带miRNA-19b的EMP能够促进血管周围脂肪组织炎症,使大量促炎组织因子被释放出来,诱导单核细胞聚集,miRNA-19b的促炎作用与细胞因子信号抑制剂3(suppressor of cytokine signaling 3,SOCS3)表达被抑制有关。Ceolotto等[17]研究发现,在动脉粥样硬化患者中,miRNA-30c-5p与总胆固醇、低密度脂蛋白胆固醇和颈动脉内膜中层厚度均呈负相关;在体外,oxLDL可抑制miRNA-30c-5p的表达,促进IL-1β释放和Caspase-3表达,促进巨噬细胞凋亡;与miRNA-30c-5p结合的微粒能够被巨噬细胞摄取,从转录水平调控靶基因表达,提示miRNA-30c-5p是抗动脉粥样硬化治疗的潜在靶点。

单核细胞在血管内皮的黏附和沉积是促进炎症发生和动脉粥样硬化发展的始动因素,微粒在此过程中可发挥不同的作用。一方面,斑块微粒、PMP及内皮细胞活化产生的微粒能使ICAM-1水平明显升高,促进单核细胞黏附和炎症反应[18-19];微粒还能够促进内皮细胞中IL-6、人单核细胞趋化蛋白1(monocyte chemotactic protein-1,MCP-1)、COX-2等炎症因子的合成与释放,活化c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)和核因子κB(nuclear factor-κB,NF-κB)通路,促进炎症反应[20-21]。另一方面,诱导内皮细胞凋亡产生的微粒可以抑制ICAM-1的表达,抑制炎症反应[22-23]。上述研究表明病理状态下的微粒富含组织因子和趋化因子等物质,能够促进单核细胞的趋化和黏附,以及局部炎症因子的释放,促进动脉粥样硬化的发生发展。微粒携带了抑制动脉粥样硬化的miRNA后可改善动脉粥样硬化,从而对动脉粥样硬化进行早期干预。

2.2 微粒与树突状细胞和淋巴细胞

树突状细胞是人体内主要的抗原提呈细胞。EMP可以诱导血浆中树突状细胞成熟,成熟的树突状细胞不仅能分泌炎性细胞因子(如IL-6、IL-8),还可促进CD4+T淋巴细胞增殖和向辅助性T淋巴细胞1(helper T cell 1,Th1)分化;但PMP、T淋巴细胞来源的微粒促树突状细胞成熟作用不明显[24]。Th1分泌Th1因子,如γ干扰素(interferon-γ,IFN-γ)、IL-2、TNF-α,加速动脉粥样硬化的发展;IFN-γ还可抑制平滑肌细胞增殖,诱导产生胶原酶,降解斑块纤维帽,破坏斑块稳定性[24]。但也有研究发现,多核中性粒细胞分泌的微粒可抑制树突状细胞的活化,降低其吞噬活性,促进抗炎因子TGF-β1的释放[25]。Lu等[26]研究显示,心肌梗死患者循环中的微粒可以上调Th1的分化和功能,提高Th1因子IFN-γ和TNF-α的产生,抑制动脉粥样硬化进展。这些研究表明,不同来源的微粒对树突状细胞和淋巴细胞作用不同,通过不同机制调控其在动脉粥样硬化中的炎症反应。

3 微粒与平滑肌细胞增殖和迁移对动脉粥样硬化的影响

平滑肌细胞从血管壁中膜迁移到内膜,并在内膜增殖,吞噬脂质形成泡沫细胞,在动脉粥样硬化的起始和进展阶段均有重要作用。微粒对平滑肌细胞增殖的影响与其细胞来源有关[1]。Niu等[27]研究显示动脉粥样硬化患者循环中存在高浓度的白细胞源性微粒,这些白细胞源性微粒能够促进平滑肌细胞黏附和增殖,其机制可能涉及细胞外调节蛋白激酶(extracellular regulated protein kinase,ERK)和蛋白激酶B通路的激活。在体外,内皮细胞源性miRNA-126可通过旁分泌形式转移至平滑肌细胞,促进平滑肌增殖。然而,Jansen等[28]发现通过EMP向平滑肌细胞转移功能性miRNA-126-3p,可以抑制低密度脂蛋白受体相关蛋白6(low-density lipoprotein receptor-related protein 6,LRP6)的表达,进而抑制血管平滑肌细胞增殖和迁移。此外,在剪切力或Krüppel样转录因子2(Krüppel-like factor 2,KLF2)基因过表达刺激作用下,内皮细胞产生的微粒能够向平滑肌细胞传递miRNA-143和miRNA-145,影响血管平滑肌细胞的基因表达,抑制动脉粥样硬化[29]。在体外,血清素和血栓素A2刺激血小板产生的微粒通过血小板源性生长因子依赖的机制促进平滑肌细胞的增殖,但促迁移效果比较局限[30]。内毒素刺激单核细胞微粒携带功能性Caspase-1,可以诱导平滑肌细胞死亡[31]。关于微粒对平滑肌细胞功能影响的研究报道较少,且不同来源微粒携带的miRNA对平滑肌细胞可能表现出相反的调控作用,因此微粒对平滑肌迁移和增殖的作用有待进一步研究。

4 展望

越来越多的研究揭示了微粒在动脉粥样硬化性疾病中可能的作用。微粒被认为是血管损伤和炎症反应的生物标志物,在广泛内膜损伤病变(如高血压、糖尿病、冠心病)中,循环微粒水平明显升高[32-33]。Niu等[27]发现动脉粥样硬化患者和健康人微粒成分不同,动脉粥样硬化患者循环中白细胞源性微粒水平更高。微粒也是早期心血管风险的预测因子,在亚临床粥样动脉硬化患者体内即可检测到循环微粒水平升高[34]。一些药物,如阿司匹林、他汀类药物、抗凝剂、血管紧张素受体阻滞剂、钙通道阻滞剂等,能够降低患者循环中微粒水平,提示这些药物可能在一定程度上通过降低微粒水平而发挥临床疗效,降低微粒水平可能是血管损伤疾病潜在的治疗靶点[35]

微粒的检测对预测心血管疾病风险、及早发现亚临床病变、评价药物疗效方面有广阔前景,也为动脉粥样硬化提供了新的治疗靶点。然而,目前有关微粒在临床上的应用研究尚不成熟。首先,由于微粒携带的蛋白质及miRNA等对其功能的发挥至关重要,不同病理状态、不同刺激产生的微粒区别较大,需要进一步探究与动脉粥样硬化发生发展相关的微粒亚型。其次,微粒制备和检测流程复杂,尚无稳定方便的制备和检测流程,且检测成本较高[33]。第三,微粒在正常人循环中普遍存在,对动脉粥样硬化等心血管病的诊断,微粒阈值尚无统一的标准[35]。微粒在临床上的应用仍需要进一步的探索。

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