药学学报  2021, Vol. 56 Issue (2): 368-373     DOI: 10.16438/j.0513-4870.2020-1277   PDF    
丹酚酸对缺血性心脏病的作用及作用机制研究进展
达吾提阿瓦古丽, 方莲花, 杜冠华     
中国医学科学院北京协和医学院药物研究所北京市药物靶点研究与新药筛选重点实验室, 北京 100050
摘要: 丹酚酸为唇形科植物丹参的最主要的水溶性活性成分, 具有多种药理作用, 被广泛应用于防治心血管疾病。本文通过查阅国内外最新研究文献, 对丹酚酸防治缺血性心脏病的作用及作用机制进行综述, 并介绍了丹酚酸A和丹酚酸B等丹参的主要水溶性成分通过保护血管内皮、舒张冠状动脉、促进血管再生、抗血小板聚集、抑制炎性反应、抗细胞凋亡和清除自由基等多角度防治缺血性心脏病的作用机制, 为进一步研究丹酚酸对缺血性心脏病的作用及药物研发提供理论依据。
关键词: 丹参    水溶性成分    丹酚酸A    丹酚酸B    缺血性心脏病    
Research advances on the protective effects and mechanism of salvianolic acids against ischemic heart disease
DAWUTI Awaguli, FANG Lian-hua, DU Guan-hua     
Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract: Salvianolic acids are the main water-soluble active compounds of Salvia miltiorrhiza and have been widely used for the treatment of cardiovascular diseases. Based on the latest studies in China and abroad, we summarize the pharmacological effects and mechanism of salvianolic acids on ischemic heart disease by describing how salvianolic acid A and salvianolic acid B protect the vascular endothelium, relax coronary arteries, promote angiogenesis and anti-platelet aggregation, inhibit the inflammatory response, anti-cell apoptosis, and scavenge free radicals. This review provides a theoretical basis for further research on the effects of salvianolic acids on ischemic heart disease and their potential for drug development.
Key words: Salvia miltiorrhiza    water-soluble component    salvianolic acid A    salvianolic acid B    ischemic heart disease    

缺血性心脏病(ischemic heart disease, IHD), 也被称为冠心病, 是指由于冠状动脉粥样硬化使管腔狭窄或梗阻导致心肌缺血、缺氧或坏死而引发的心脏病。临床上包括无症状性心肌缺血、心绞痛、心肌梗死、缺血性心力衰竭和心脏骤停。IHD目前仍然是全世界发病率与死亡率最高的疾病之一[1], 从1990~2017年, 我国IHD发病率上升20.6%, 成为第二大疾病死亡的原因, 严重威胁人们的生命与健康, 并造成巨大的疾病负担[2, 3]

目前, 临床用于治疗IHD的药物包括β受体阻滞剂、硝酸酯类药物、钙通道阻滞剂、抗血小板药物、抗凝药物、他汀类药物、血管紧张素转化酶抑制剂和血管紧张素Ⅱ受体拮抗剂等。虽然用于防治IHD的药物众多, 但是由于IHD的病理生理机制复杂, 单靶点药物治疗效果并不理想, 并且有些药物的毒副作用比较强。而中药具有多成分、多靶点治疗效应和整体调理的作用, 其疗效持久, 不良反应较少, 不仅能改善患者的症状, 而且还能调整患者的体质, 在IHD改善症状以及治疗方面具有不可或缺的补充作用。

丹参为唇形科植物丹参Salvia miltiorrhiza Bge的干燥根及根茎, 是中国传统医学中治疗心脑血管疾病的常用药材。丹参化学成分丰富, 迄今为止, 共发现了201个活性成分[4], 包括酚酸类、二萜类、倍半萜类、生物碱类和黄酮类等成分, 其中脂溶性二萜醌类化合物和水溶性酚酸类化合物共同组成丹参的药效物质基础。脂溶性二萜醌类化合物主要包括丹参酮Ⅰ、丹参酮Ⅱ和隐丹参酮等。水溶性酚酸类化合物主要包括丹参素、迷迭香酸和丹酚酸A、B、C、D等, 其中丹酚酸A和丹酚酸B在治疗心血管疾病方面的药理作用最强。

丹酚酸具有抗氧化、抗炎、抗血栓、抗细胞凋亡、保护血管内皮、保护线粒体功能等多种生物活性[5], 被广泛用于治疗心肌缺血、心肌梗死、心绞痛、心力衰竭、高血压、糖尿病和高血脂等心血管疾病[6]。本文将着重综述丹酚酸A和丹酚酸B在防治IHD的作用及作用机制, 为进一步研究丹酚酸对IHD的作用及药物研发提供理论依据。

1 减少缺血诱因, 改善血液循环 1.1 保护血管内皮, 舒张冠状动脉

冠状动脉是给心脏提供血液的主要血管, 其正常的收缩-舒张功能是保证心肌细胞充足的供血供氧的前提。若冠状动脉堵塞或痉挛, 则心肌供血供氧减少, 就会诱发心肌梗死、心绞痛、甚至猝死等IHD。内皮细胞(endothelial cells, EC)是一层扁平细胞, 位于血管的最内层。内皮细胞作为组织与血液物质交换的重要场所, 它不仅参与血浆和组织液的物质代谢交换, 并且合成和分泌多种活性物质, 保证血管的正常收缩和舒张功能。研究证明, 改善内皮细胞功能可以降低IHD的风险, 内皮细胞释放的一氧化氮(nitric oxide, NO)激活鸟苷酸环化酶, 从而增加细胞内单磷酸鸟苷的水平, 导致血管舒张、血小板分解和防止血小板黏附[7]

有研究采用连二亚硫酸钠体外诱导的人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVEC)缺氧损伤模型, 探讨丹酚酸组分对缺氧损伤的保护作用, 结果显示, 丹酚酸A和丹酚酸B给药组在5×10-4 g·mL-1剂量下, 通过调节NO、乳酸脱氢酶(lactate dehydrogenase, LDH)、丙二醛(malondialdehyde, MDA)、肿瘤坏死因子α(tumor necrosis factorα, TNFα)和白细胞介素6(interleukin 6, IL-6)含量, 对缺氧损伤的HUVEC发挥保护作用[8]。丹酚酸A还通过有效抑制缺血再灌注[9]和缺氧[10]诱导的极低密度脂蛋白(very low-density lipoprotein, VLDL)受体的过表达, 保护血管内皮、减轻缺血再灌注和缺氧导致的心肌损伤。此外, 在KCl、CaCl2和组胺刺激的大鼠和猪离体冠状动脉环收缩模型中, 10 g·L-1丹酚酸B通过抑制血管平滑肌细胞外钙内流和内钙释放, 扩张冠状动脉[11]。研究还发现, 丹酚酸B促进内皮型一氧化氮合成酶(endothelial nitric oxide synthase, e NOS)的磷酸化, L-精氨酸(L-arginine, L-Arg)的摄取, 增加NO的生成, 扩张冠状动脉, 减轻小鼠心肌缺血损伤[12]。丹酚酸B还可通过阻断受体依赖性钙通道和电压依赖性钙通道引起的外钙内流和阻断三磷酸肌醇受体引起的内钙释放, 非内皮依赖性地舒张血管, 但其舒张血管作用与血管平滑肌上的钾离子通道和β受体无关[13]。以上研究表明, 丹酚酸通过多条信号通路保护血管内皮, 舒张冠状动脉。

1.2 促进血管再生

IHD治疗的关键在于解除心肌组织的缺血缺氧状态, 恢复缺血区的血液供应。血管新生是一种生理病理过程, 其形成需要基底膜的降解、内皮细胞的迁移和内皮细胞的增殖, 最终在已有的毛细血管中发展出新的血管。虽然缺血和炎症等病理生理过程会刺激心肌细胞, 自发产生新的血管, 但这种生理性侧支血管不够丰富, 不能纠正缺血的症状, 而治疗性血管新生通过促进缺血心肌周围的血管生长, 建立侧支循环, 能改善患者的缺血缺氧症状, 抑制心肌细胞的坏死[14]

评估丹酚酸A和丹酚酸B对心肌梗死大鼠血管新生影响的Meta分析结果表明[15], 丹酚酸A和丹酚酸B均能增加心肌梗死大鼠的血管密度, 改善心功能。灌胃给药丹酚酸A (5.0和10 mg·kg-1)通过上调血管内皮生长因子(vascular endothelial growth factor, VEGF)、血管内皮生长因子受体-2 (vascular endothelial growth factor receptor 2, VEGFR-2)和基质金属蛋白酶9 (matrix metalloprotein 9, MMP-9)的表达及促进内皮细胞数量和功能, 来诱导心肌梗死大鼠缺血区的血管新生, 缩小梗死范围[16]。通过结扎冠状动脉左前降支建立的心肌梗死大鼠模型中, 丹酚酸B增加心肌组织VEGF[17]、核因子E2相关因子2 (nuclear factor E2-related factor 2, Nrf2)和血红素加氧酶1 (heme oxygenase isozyme-1, HO-1)的表达, 促进血管再生, 显著减少心肌梗死面积[18]。丹酚酸B还可通过干预内皮祖细胞提高骨髓间充质干细胞移植后大鼠心肌VEGF和碱性成纤维细胞生长因子(basic fibroblast growth factor, b FGF)蛋白表达, 促进血管新生, 改善心肌梗死大鼠的心功能[19, 20]

2 抑制血小板聚集和血栓生成

动脉粥样硬化斑块破裂形成的血栓被认为是IHD发病的触发因素, 而血小板聚集是血栓形成的重要环节。研究发现, 丹酚酸A体内外均能够剂量依赖性地抑制二磷酸腺苷(adenosine diphosphate, ADP)、花生四烯酸(arachidonic acid, AA)和凝血酶(thrombin, THR)诱导的血小板聚集, 并且丹酚酸A和阿司匹林对正常凝血系统的作用类似[21]。磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase, PI3K)是血小板激活过程中细胞内信号的关键传递因素。研究发现, 在光化学损伤引起的动脉血栓模型中, 丹酚酸A通过抑制PI3K信号通路, 抑制血小板的分泌和聚集, 以及胶原涂层表面上的血小板黏附, 降低动脉血栓的形成[22]。在体外实验中, 丹酚酸A剂量依赖性地抑制ADP、THR和胶原诱导的血小板聚集[22, 23]。丹酚酸A的抗血栓作用可能与其抗血小板作用及在不影响凝血系统的情况下调节血液流变学的能力有关。

此外, 动静脉分流大鼠模型中, 静脉注射丹酚酸A(2.5~10 mg·kg-1)抑制ADP诱导的血小板聚集, 显著降低血栓重量, 增加最强的血小板功能抑制剂之一环磷酸腺苷(cyclic adenosine monophosphate, c AMP)的水平, 但丹酚酸A对大鼠的凝血参数没有影响[23]。研究还发现, 颈静脉给药10 mg·kg-1丹酚酸A通过抑制血小板活化, 保护心肌缺血再灌注损伤[24]。丹酚酸A拮抗嘌呤能受体P2Y1 (purinergic P2Y1 receptor, P2Y1R)和嘌呤能受体P2Y12 (purinergic P2Y12 receptor, P2Y12R)活性[25], 而丹酚酸B只拮抗P2Y12受体活性[25, 26], 抑制血小板聚集, 防止血栓形成。丹酚酸B在正常流动剪应力情况下, 促进血管内皮细胞分泌前列环素(prostacyclin, PGI2), 抗ADP诱导的血小板聚集[27]。这些数据提示, 丹酚酸可能被研发为预防血栓性疾病的一种新的治疗药物。

3 减轻心肌损伤 3.1 抑制炎性反应

IHD的主要诱因是动脉粥样硬化, 是一种进行性的动脉壁增厚的慢性炎症过程。慢性炎症导致循环C反应蛋白、趋化因子和细胞因子水平升高、凝血异常、内皮功能障碍和具有斑块易损特征的过早动脉粥样硬化[28]。越来越多的研究结果表明, 炎症是IHD发病机制的关键因素[29]。冠状动脉左前降支结扎所致的心肌梗死模型和H2O2诱导的H9c2细胞损伤模型中, 丹酚酸A通过调节硫氧还蛋白(thioredoxin, Trx)/c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)信号通路, 抑制炎症反应, 改善心功能[30]。尾静脉注射给药丹酚酸A (0.5~1 mg·kg -1)在高脂肪饮食和维生素D3注射诱导的动脉粥样硬化动物模型中, 通过调节白细胞介素1β(interleukin 1β, IL-1β)和核因子κB (nuclear factor kappa-B, NF-κB)蛋白表达来抑制炎症[31]。研究还发现, 丹酚酸B通过抑制Toll样受体4(toll like receptor 4, TLR4)-NF-κB-TNFα炎性反应损伤通路, 保护缺氧[32]和脂多糖[33]损伤的心肌细胞。

M1巨噬细胞迅速浸润损伤部位并表现出强烈的炎症表型。研究结果显示, 丹酚酸B通过抑制哺乳动物雷帕霉素靶蛋白复合物1 (mammalian target of rapamycin complex 1, mTORC1)依赖的糖酵解途径, 降低缺血再灌注心脏中M1巨噬细胞的数量, 减轻炎症反应, 改善心肌功能障碍[34]。此外, 丹酚酸B预处理给药有效抑制黏附分子, 减少中性粒细胞的浸润, 下调炎性细胞因子, 改善心肌组织的炎症反应, 保护心肌缺血再灌注损伤的心肌组织[35]。丹酚酸B还能通过调控Nod样受体蛋白3[nucleotide-binding domain (Nod)-like receptor protein 3, NLRP3]炎症小体预激活阶段, 减轻缺氧诱导的大鼠心肌细胞损伤[36]

3.2 减轻氧化应激

氧化应激是指活性氧(reactive oxygen species, ROS)自由基过量产生或累积和抗氧化酶的减少, 造成体内氧化系统与抗氧化防御系统之间的平衡紊乱, 从而对细胞产生多种毒性作用的病理状态。在生理状态下, ROS在调节基因表达、诱导细胞凋亡、生长信号转导和免疫应答等方面发挥重要作用。然而, ROS具有高反应性和毒性, 可因缺血而增加, 并加重心肌损伤。当心肌细胞处于缺血和缺氧状态时, 自由基的过度生成可能会超出抗氧化剂的清除作用而诱发氧化应激。越来越多的证据表明, 抗氧化剂能够逆转氧化应激, 可有效改善活性氧引起的心肌损伤[37]

氧化应激破坏细胞膜, 导致钙超载、细胞凋亡, 产生炎性介质, 损伤内皮细胞和血小板功能, 继而导致IHD的发生和发展。由于丹酚酸A和丹酚酸B都具有多酚类结构, 被认为是自由基清除剂[38]。研究发现, 丹酚酸B通过增加清除氧自由基[39], 减少MDA的形成, 增加超氧化物歧化酶(superoxide dismutase, SOD)的活性[40], 发挥抗脂质过氧化作用, 进而提高心肌细胞的抗氧化损伤能力。丹酚酸B可以降低人主动脉内皮细胞的氧化应激, 抑制Cu2+和内皮细胞诱导的低密度脂蛋白(low density lipoprotein, LDL)氧化, 降低内皮细胞中ROS的产生和细胞毒性[41]。H2O2诱导的骨髓间充质干细胞氧化应激损伤模型中, 发现丹酚酸B可以通过调节Nrf2/Kelch样环氧氯丙烷相关蛋白-1 (Kelchlike ECH associated protein 1, Keap 1)、B淋巴细胞瘤-2(B-cell lymphoma 2, Bcl-2)与B细胞淋巴瘤-2相关X蛋白(Bcl-2 associated X protein, Bax)表达, 降低氧化损伤并促进骨髓间充质干细胞的存活, 还可以提高骨髓间充质干细胞向心肌样细胞分化的能力[42]。丹酚酸B还通过激活Keap1-Nrf2-ARE信号通路, 发挥抗血管内皮细胞氧化损伤的作用[43]。此外, 丹酚酸A通过抗氧化, 抑制炎症因子的生成, 以及调节凋亡蛋白的表达, 减轻异丙肾上腺素诱导的心肌缺血损伤[44]

3.3 改善线粒体功能, 抑制细胞凋亡

在IHD中, 冠状动脉血管阻塞会造成不可逆的细胞损伤甚至死亡。线粒体作为心肌细胞的“发电站”和“凋亡中心”, 在IHD中发挥重要的作用。心肌细胞的坏死和细胞凋亡是导致心肌缺血缺氧损伤的主要原因之一。研究发现, 丹酚酸A通过激活蛋白激酶B (protein kinase B, Akt)信号通路, 抑制糖原合成酶激酶-3β(glycogen synthase kinase-3β, GSK-3β)、半胱氨酸天冬氨酸特异性蛋白3(cysteinylaspartatespecificproteinase-3, caspase-3)和Bax/Bcl-2蛋白表达, 减少缺氧/复氧损伤所导致的心肌细胞凋亡, 改善线粒体功能[45]。丹酚酸A还可通过JNK/PI3K/Akt信号通路[46]、双特异性磷酸酶2 (dual specificity phosphatase 2, DUSP2)介导的细胞外调节蛋白激酶1/2 (extracellular regulated protein kinases1/2, ERK1/2)/JNK通路[47], 在心肌缺血再灌注损伤的大鼠模型中发挥抗凋亡作用。此外, 在脂多糖(lipopolysaccharide, LPS)诱导的H9c2心肌细胞氧化应激损伤模型中, 丹酚酸A通过激活Akt/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)/起始因子4E结合蛋白1 (e IF4E-binding protein 1, 4EBP1)通路, 减少心肌细胞凋亡并降低心肌细胞线粒体膜电位的下降速度, 减缓LPS诱导的H9c2心肌细胞凋亡和氧化应激[48]

丹酚酸B通过抑制Bax、切割的caspase-9和切割的PARP的表达, 促进Bcl-2、微管相关蛋白1轻链3-II(microtubule-associated protein 1 light chain 3-II, LC3-II)、酵母ATG6的哺乳动物同源物(Beclin1)和VEGF的表达, 抑制细胞凋亡, 减轻急性心肌梗死导致的心肌损伤[49]。此外, 丹酚酸B通过激活PI3K/Akt通路, 抑制细胞凋亡, 改善心功能, 减轻心肌缺血再灌注损伤[50], 减少缺氧/复氧诱导的H9c2心肌细胞损伤[51]。丹酚酸B还能抑制类NIP3蛋白X (nip3-like protein X, NIX)介导的线粒体自噬激活, 从而升高线粒体膜电位, 降低切割的caspase-3和LC3-II蛋白表达, 升高细胞活力, 对H9c2心肌细胞发挥缺氧/复氧损伤的保护作用[52]

4 结语与展望

综上所述, 丹酚酸为唇形科植物丹参的最主要的水溶性活性成分, 其通过影响多靶点多通路, 从多角度发挥防治IHD的作用(图 1)。了解丹酚酸抗IHD的分子机制, 为丹酚酸的临床合理应用和药物研发提供理论依据。虽然丹酚酸对IHD的研究诸多, 但主要集中在丹酚酸对心肌梗死和心肌缺血再灌注损伤的治疗方面, 而丹酚酸对缺血性心力衰竭和心绞痛等IHD的作用及作用机制相关的研究仍然有限, 需要进一步深入研究。目前, 丹酚酸的真正药物作用靶点尚未找到和确认, 这是本领域最大的挑战也是最大的希望所在。相信随着科学技术的不断进步和临床研究的全面开展, 更多、更深层的有关丹酚酸对IHD的机制将会不断被阐明, 为丹酚酸治疗IHD提供有用的参考。

Figure 1 The major signaling pathways involved in the salvianolic acid A (SAA) and salvianolic acid B (SAB) against ischemic heart disease.VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; TLR4:Toll like receptor 4;NOX: Non-phagocytic cell oxidase; IκK: Inhibitor kappa B kinase; NF-κB: Nuclear factor kappa-B; TNF-α: Tumor necrosis factor α; IL-1β: Interleukin 1β; IL-6:Interleukin 6;Trx: Thioredoxin; JNK: c-Jun N-terminal kinase; PI3K: Phosphatidylinositol-3-kinase; Akt: Protein kinase B; Bax: Bcl-2 associated X protein; Bcl-2:B-cell lymphoma 2;ROS: Reactive oxygen species; e NOS: Endothelial nitric oxide synthases; NO: Nitric oxide; SOD: Superoxide dismutase; GSH-Px: Glutathione peroxidase; CAT: Catalase; Nrf2:Nuclear factor E2-related factor 2;ARE: Antioxidant response element; OH-1:Heme oxygenase isozyme-1;NQO1:NAD(P) H: quinone oxidoreductase 1

作者贡献: 阿瓦古丽·达吾提查阅文献、撰写文章、修改文章; 方莲花指导撰写思路和文章修改; 杜冠华指导撰写思路。

利益冲突: 所有作者均声明不存在利益冲突。

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