天津中医药  2022, Vol. 39 Issue (3): 403-408

文章信息

车思桦, 石贵军
CHE Sihua, SHI Guijun
基于p38MAPK信号通路探讨中医药治疗心肌缺血再灌注损伤的研究进展
Discussion on the research progress of traditional Chinese medicine for myocardial ischemia-reperfusion injury based on p38MAPK signaling
天津中医药, 2022, 39(3): 403-408
Tianjin Journal of Traditional Chinese Medicine, 2022, 39(3): 403-408
http://dx.doi.org/10.11656/j.issn.1672-1519.2022.03.26

文章历史

收稿日期: 2022-01-11
基于p38MAPK信号通路探讨中医药治疗心肌缺血再灌注损伤的研究进展
车思桦1 , 石贵军2     
1. 长春中医药大学,长春 130117;
2. 长春市中医院,长春 130022
摘要:心肌缺血性疾病是导致人类死亡的重要因素,随着经皮冠状动脉介入、搭桥术及溶栓术等介入治疗手段的应用发展,使心肌缺血后能够重新得到血液供应,但是随之而来的再灌注损伤愈加受到临床工作者的重视。p38MAPK信号通路作为丝裂原活化蛋白激酶超家族的重要成员之一,可通过传递细胞内信号参与调控多种胞内应答反应,如炎症反应,细胞应激、凋亡等,在心肌缺血再灌注损伤(MIRI)中发挥重要作用。近年来,中医药以其独特的优势在治疗MIRI方面取得较大进展,日益受到医学界的广泛关注。本文将以p38MAPK信号通路作为切入点,探讨中医药治疗MIRI的作用机制。
关键词心肌缺血再灌注损伤    p38MAPK    中医药    

据报道,全世界每年有超过1 700万人死于心血管疾病,占全因死亡的29%,其中心肌缺血性疾病是导致人类死亡的重要因素[1]。随着经皮冠状动脉介入、冠状动脉搭桥术及溶栓术等介入治疗手段的应用发展,使心肌缺血后能够重新得到血液供应,但是随之而来的再灌注损伤愈加受到临床工作者的重视。心肌缺血再灌注损伤(MIRI)是一种涉及多因素参与的复杂病理生理过程,目前认为其机制主要与氧化应激、炎症反应、钙超载、线粒体功能障碍及细胞凋亡等有关[2]。此外,多种传导通路的信号分子参与调控MIRI的发生发展过程。p38MAPK信号通路作为丝裂原活化蛋白激酶(MAPK)超家族的重要成员之一,可通过传递细胞内信号参与调控多种胞内应答反应,如炎症反应,细胞应激、凋亡等,在MIRI中发挥重要作用[3]

近年来,中医药以其独特的优势在治疗MIRI方面取得较大进展,日益受到医学界的广泛关注。为进一步研究中医药治疗MIRI的作用机制,本文将以p38MAPK信号通路作为切入点,现综述如下。

1 p38MAPK概述

MAPK是一种非常保守的丝氨酸/苏氨酸蛋白激酶,通过三级激酶级联的形式介导细胞外刺激信号转导至细胞内,广泛参与调节细胞的生长、分化、增殖及凋亡等[4]。MAPK家族成员由细胞外信号调节蛋白激酶(ERKs)、c-Jun N末端蛋白激酶(JNK)和p38丝裂原活化蛋白激酶组成,其中p38是MAPK家族调控炎症反应的最主要成员[5]。目前认为p38MAPK家族主要包含4种异构体,分别为p38αMAPK、p38βMAPK、p38γMAPK和p38δMAPK,其分布具有组织特异性,仅有p38α、p38β于心肌中表达,其中p38α是HL-1心肌细胞中主要表达的亚型[6-7]。促炎因子及缺氧等细胞外刺激均可诱导内源性免疫细胞内的p38发生磷酸化而激活,活化下游核转录因子,进而引起信号传导通路的级联反应[8-9]

2 p38MAPK在MIRI中的作用

p38 MAPK作为细胞内的重要信号通路之一,可通过调节氧化应激、炎症反应、细胞凋亡及钙超载等机制,在MIRI病理生理过程中发挥关键调节作用。

2.1 p38MAPK调节氧化应激反应

氧化应激反应是导致MIRI的重要机制之一。当大量活性氧(ROS)过表达时,线粒体清除氧自由基的能力降低,使机体氧化还原状态紊乱,从而出现氧化应激反应[10]。心肌组织在缺血再灌注阶段会累积大量ROS,通过促进细胞凋亡信号调节激酶1(ASK1)的活化因而激活p38 MAPK通路,导致线粒体损伤并加剧代谢紊乱[11]。有研究显示[7],p38MAPK是诱导线粒体ROS升高的上游,心肌缺血再灌注后p38MAPK活性升高,而p38MAPK抑制剂BIRB796能够减少氧化应激和细胞凋亡,以发挥缺血再灌注损伤保护作用。此外,另有研究发现p38 MAPK抑制剂SB239063能够抑制可入肺颗粒物(PM2.5)诱导的心肌细胞凋亡及ROS生成,说明p38MAPK在参与调节心肌细胞的氧化应激反应方面具有重要作用[12]

2.2 p38MAPK调节炎症反应

心肌缺血再灌注期间所恢复的血液供应可诱导大量中性粒细胞进入缺血组织,并释放炎症因子,如白细胞介素-4(IL-4)、白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)等,引发炎症反应,使心肌组织发生新的损伤。p38MAPK是参与调控机体炎症反应的重要信号通路,心肌再灌注时激活的p38MAPK能够促使黏附分子和炎症因子的表达增加,而核转录因子(NF-κB)作为p38MAPK信号通路的下游因子,游离并进入细胞核发生转录,诱导炎性因子增加,最终造成心肌损伤[13-14]。有研究显示[15]p38MAPK在心肌再灌注的炎性反应中,对白细胞富集的起始无影响,而是通过影响白细胞的迁移,促使白细胞在心肌缺血再灌注区域大量聚集,以加剧炎症反应。Song等[16]研究发现,p38 MAPK抑制剂SB203580能够显著减少炎性因子的表达,对心肌细胞具有保护作用。

2.3 p38MAPK调控细胞凋亡

越来越多的研究显示,在心肌缺血再灌注过程中存在明显的细胞凋亡,其损伤产生的钙离子(Ca2+)超载、大量ROS及线粒体能量代谢障碍等诱因可单独启动或联合作用加剧引起细胞凋亡,其中p38MAPK在心肌细胞凋亡中起重要作用[17-18]。心肌缺血再灌注可诱导p38MAPK激活并促使下游底物磷酸化,释放大量炎症细胞因子,参与心肌细胞凋亡过程[19]。Hang等[20]研究发现,在阿霉素诱导的H9C2心肌细胞凋亡模型中p38MAPK的表达、磷酸化p38 MAPK/p38MAPK比值均显著增加,提示p38MAPK参与由阿霉素诱导的H9C2心肌细胞凋亡过程。有研究表明,通过降低磷酸化p38MAPK的表达,能够明显抑制细胞凋亡,进而对心肌缺血再灌注后损伤的心肌细胞发挥保护作用[21]

2.4 p38MAPK调控细胞自噬

自噬又被称为Ⅱ型程序性细胞死亡,当受到外界刺激时真核生物通过与溶酶体结合,并在细胞内部自身降解产生适应性反应,以维持细胞内环境稳态,属于一种细胞内部的自我保护机制。目前普遍认为,自噬具有双重性,其无论在心肌缺血还是再灌注期间均扮演重要角色。研究证实[22-23],在心肌缺血期间,自噬水平的上调可及时清除错误折叠蛋白或损伤线粒体等,作为一种防御机制对心肌细胞起保护作用;然而在再灌注期间自噬水平过度激活处于高水平状态,则引起自噬小体清除障碍,最终诱使细胞启动死亡程序,进而对心肌造成损伤。相关研究表明[24],在心肌缺血再灌注阶段某些诱导自噬的因素能够通过调控p38MAPK信号通路而影响细胞的自噬反应,如B淋巴细胞瘤-2基因(Bcl-2)蛋白水平、Ca2+浓度增高等。

2.5 p38MAPK与钙超载

心肌缺血时,Na+/K+-ATP酶的活性降低,胞浆内Na+增多而激活Na+/Ca2+交换蛋白,使细胞内Ca2+浓度异常升高,最终出现钙超载现象[25]。在再灌注阶段,钙超载可使恢复血液供应的心肌纤维发生过度收缩,甚至造成心肌断裂[26]。因此,心肌细胞内钙稳态的调控对维持正常心功能至关重要,钙稳态的破坏还会引起内质网应激,加剧缺血性损伤[27]。研究发现[28],减轻细胞内钙超载能明显缩小MIRI后的心肌梗死面积,减少心律失常的发生率。马焦[29]采用大鼠心肌细胞氧糖剥夺-复氧(OGD/R)模型发现,p38MAPK通路激活能够介导OGD/R损伤后心肌细胞的钙超载,其机制可能与抑制磷酸化信号传导子及转录激活子3(p-STAT3)和肌浆网钙泵(SERCA2)表达有关;当给予p38MAPK抑制剂SB203580后,细胞内Ca2+浓度显著减少,提示p38MAPK的激活可能参与了MIRI钙超载过程。

3 中药通过p38MAPK通路对MIRI的干预作用

目前,如何开拓中医药在心血管疾病领域的应用已成为近年来的研究热点之一,这些研究为临床上防治心肌缺血再灌注损伤奠定了实验基础。

3.1 中药单体及有效组分

汉防己乙素是中药汉防己的主要活性成分之一,李昌等[30]研究发现,汉防己乙素可显著上调谷胱甘肽(GSH)、超氧化物歧化酶(SOD)、Bcl-2及c-myc蛋白表达水平,下调胱天蛋白酶3、MDA和Bax/Bcl-2蛋白表达水平,降低心肌细胞凋亡率,抑制p38MAPK和ERK1/2磷酸化水平,进而减轻MIRI大鼠心肌细胞凋亡和线粒体损伤。见表 1

表 1 中药单体基于p38 MAPK信号通路对MIRI的保护作用 Tab. 1 Protective effect of traditional Chinese medicine monomer on MIRI based on p38 MAPK signaling pathway

天麻素是中药材天麻发挥药效作用的物质基础,张玲等[31]采用天麻素干预大鼠血清剥夺/复灌H9C2心肌细胞模型,发现凋亡相关蛋白cleaved Caspase-3、p-p38MAPK表达降低,Bcl-2/Bax、p-Akt蛋白表达增加,通过激活Akt/p38MAPK信号通路,以抑制细胞凋亡,从而达到抗MIRI的保护作用。

雷公藤内酯醇是从中药雷公藤的根中提取的环氧二萜内酯化合物,于海杰[32]通过实验证实,雷公藤内酯醇可显著降低MIRI大鼠模型炎性因子IL-1β、TNF-α、白细胞介素-6(IL-6)表达含量,升高p-p38蛋白表达水平,能够有效抑制炎症反应,提示雷公藤内酯醇抗MIRI的炎症反应与激活p38 MAPK信号通路密切相关。

人参皂苷Rb1来源于五加科植物人参Panax ginseng C. A. Mey的根,王逸等[33]研究结果显示,人参皂苷Rb1可以通过下调p38α水平而抑制p38α磷酸化,同时下调Caspase-3和TNF-α水平,以抑制TNF-α细胞受体途径凋亡,使缺血再灌注损伤心肌的梗死面积缩小,进而通过p38MAPK信号通路发挥心脏保护作用。

黄芪多糖为豆科植物中药黄芪的提取物,赵启明等[34]通过建立未成年大鼠MIRI模型,探讨黄芪多糖对缺血/再灌注心肌的保护机制,给予黄芪多糖干预后大鼠心肌TNF-α、NF-κB、p-p38MAPK表达水平显著降低,表明黄芪多糖是通过抑制p38MAPK信号通路,改善缺血再灌注损伤时的炎症反应,进而减轻缺血再灌注所致的心肌损伤。

葱白是一种常见的辛温通阳中药,杨剑锋等[35]研究发现葱白提取物可以减少p-p38、p53蛋白及mRNA表达水平,降低心肌细胞凋亡率,具有改善缺血/再灌注模型大鼠心功能的作用,其机制可能与抑制p38 MAPK信号通路活性。

青蒿素是从传统中药青蒿中分离出的活性成分,马瑞松等[36]通过实验研究发现青蒿素能够显著降低TNF-α、HMGB1、INF-γ、IL-17A、IL-6炎症因子的表达,下调p-p38表达,提示青蒿素可能通过抑制p38MAPK通路,减轻I/R中炎症反应,从而减轻心肌缺血再灌注损伤。

3.2 中药复方

芪桂益脉灵由党参、黄芪、炒酸枣仁、三七、桂枝、苦参、龙齿、麦冬、黄连、五味子组成,具有益气活血,化瘀通脉的作用,赵龙等[37]应用芪桂益脉灵干预急性MIRI大鼠模型,实验结果显示该方能够降低VCAM-1、ICAM-1在内皮细胞膜上的蛋白表达,降低p-p38蛋白表达,通过减轻炎症反应,抑制p38MAPK信号通路的激活,从而保护损伤心肌。见表 2

表 2 中药复方基于p38 MAPK信号通路对MIRI的保护作用 Tab. 2 Proteetive effect of traditional Chinese medine copound on MIRI hased on p38 MAPK signaling

加味丹参饮是由《时方歌括》中丹参饮加减而成,方中包括丹参、檀香、黄芪、当归、赤芍、川芎、生地黄、红花,陈聪等[38]研究发现,加味丹参饮可降低致炎因子ICAM-1、COX-2蛋白表达水平,降低p38MAPK蛋白表达,通过抑制p38MAPK信号通路,减轻MIRI大鼠的炎症反应,从而发挥保护心肌作用。

通心脉方由川芎、黄芪、血竭等中药组成,郑晓丹等[39]采用Langendorff离体心脏灌流方法建立MIRI模型,发现通心脉方可显著降低TNF-α、Caspase-8、Caspase-3及MDA含量,升高SOD、CAT含量,下调p-p38αMAPK蛋白表达,具有改善心肌缺血再灌注损伤的作用,其机制可能与通过减轻心肌细胞脂质过氧化反应,抑制p38MAPK活性,阻断TNF-α受体依赖性死亡级联反应和抑制细胞凋亡有关。

王峰等[40]用参附注射液预处理干预MIRI大鼠模型,结果表明参附注射液可明显升高SOD、GSH-Px活性,增强HSP70表达,减弱p38 MAPK蛋白表达,通过清除自由基,减轻炎症反应,抑制p38MAPK信号通路,从而拮抗心肌缺血再灌注损伤。

鹿红方由鹿角、淫羊藿、山茱萸、红花、补骨脂、沉香和女贞子组成,具有补肾、活血、强心之功。郭洪琳[41]通过H9C2心肌细胞缺氧/复氧实验,探讨鹿红方抗心肌缺血再灌注损伤机制,结果显示鹿红方预处理可降低细胞中MDA含量,抑制Caspase-3、p-p38MAPK表达水平,增加SOD含量,提示其作用机制可能与抑制p38MAPK信号通路激活,减少氧化应激损伤及细胞凋亡有关。

4 小结

MIRI发病机制较为复杂,目前西医尚未发现疗效确切且安全的治疗药物,而中医药因其多靶点、多途径、多环节及毒副作用小、价格低廉等独特优势,在防治MIRI领域具有较大潜力尚待进一步挖掘。综前所述,无论中药单体或复方均可基于调控p38 MAPK信号通路对MIRI发挥一定的心肌保护作用,其机制大多与抑制细胞凋亡、减轻炎症反应以及改善氧化应激损伤等方面有关。但是,现阶段的中医药研究仍存有一系列问题,如选用的实验模型并不能做到统一和标准化;研究方法不够系统和深入;不能排除细胞内各信号通路之间的相互影响作用等。在未来的研究工作中,应着重探索如何运用中医药预处理以诱导细胞产生内源性保护物质,减轻因缺血再灌注而带来的心肌组织损伤,并明确阐明其对抗MIRI的具体作用机制,将实验研究成果转化并应用于临床实践,使其对MIRI产生积极治疗意义。

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Discussion on the research progress of traditional Chinese medicine for myocardial ischemia-reperfusion injury based on p38MAPK signaling
CHE Sihua1 , SHI Guijun2     
1. Changchun University of Chinese Medicine, Changchun 130117, China;
2. Changchun Hospital of Traditional Chinese Medicine, Changchun 130022, China
Abstract: Myocardial ischemic disease is an important factor leading to human death. With the application and development of interventional treatments such as percutaneous coronary intervention, bypass surgery, and thrombolysis, blood supply can be restored after myocardial ischemia. The reperfusion injury that comes has received more and more attention from clinicians. As one of the important members of the mitogen-activated protein kinase superfamily, the p38MAPK signaling pathway can participate in the regulation of a variety of intracellular responses by transmitting intracellular signals, such as inflammation, cellular stress, and apoptosis. This signaling pathway plays an important role in perfusion injury(MIRI). In recent years, traditional Chinese medicine has made great progress in the treatment of MIRI with its unique advantages, and has received widespread attention from the medical community. In order to further study the mechanism of action of Chinese medicine in the treatment of MIRI, this article will use the p38MAPK signaling pathway as an entry point.
Key words: myocardial ischemia-reperfusion injury    p38MAPK    traditional Chinese medicine