Article(id=1208154042870645129, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208154038609228128, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.02.0192, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1620316800000, receivedDateStr=2021-05-07, revisedDate=null, revisedDateStr=null, acceptedDate=1633708800000, acceptedDateStr=2021-10-09, onlineDate=1765975970237, onlineDateStr=2025-12-17, pubDate=1645977600000, pubDateStr=2022-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765975970237, onlineIssueDateStr=2025-12-17, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765975970237, creator=13701087609, updateTime=1765975970237, updator=13701087609, issue=Issue{id=1208154038609228128, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='2', pageStart='107', pageEnd='212', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765975969218, creator=13701087609, updateTime=1765976148463, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208154790459192257, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208154038609228128, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208154790459192258, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208154038609228128, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=192, endPage=196, ext={EN=ArticleExt(id=1208154043684340136, articleId=1208154042870645129, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress on the effect of histone deacetylase on pulmonary arterial hypertension, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Pulmonary arterial hypertension (PAH) is a progressive disease with poor prognosis, which may lead to right heart dysfunction, resulting in a series of clinical symptoms and even death, and there is still a lack of effective treatment. The etiology of PAH is complex, in which epigenetic changes play an important role in its pathogenesis. Histone acetylation modification is one of the most widely and deeply studied epigenetic modifications. The histone acetylation is mainly regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), which play a key role in chromatin and gene regulation, and is closely related to the occurrence of PAH. Targeted histone acetylation pathway has a certain therapeutic potential for PAH. This article reviews the research progress on the effect of HDACs on PAH, in order to further understand the pathogenesis of PAH and provide a new direction of treatment.

, correspAuthors=Yi-Xin Wan, authorNote=null, correspAuthorsNote=
*E-mail:
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肺动脉高压(PAH)是一种预后不良的进展性疾病,可导致右心功能不全,从而引起一系列临床症状,甚至导致死亡,目前尚缺乏有效的治疗方法。表观遗传改变在PAH的发病中起着重要作用。组蛋白乙酰化修饰是目前研究最为广泛和深入的表观遗传修饰之一。组蛋白乙酰化水平主要由组蛋白乙酰基转移酶(HATs)和组蛋白去乙酰化酶(HDACs)调节,在染色质和基因调控中发挥关键作用,与PAH的发生密切相关,且靶向组蛋白乙酰化途径对PAH有一定的治疗潜力。本文就HDACs在PAH中的作用研究进展进行综述,以期加深对PAH发病机制的了解,并为其治疗提供新的方向。

, correspAuthors=万毅新, authorNote=null, correspAuthorsNote=
万毅新,E-mail:
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王丹,硕士研究生,主要从事肺动脉高压等呼吸系统疾病的研究

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组蛋白去乙酰化酶在肺动脉高压中的作用研究进展
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王丹 1, 2 , 李芳伟 1 , 万毅新 1, *
解放军医学杂志 | 综述 2022,47(2): 192-196
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解放军医学杂志 | 综述 2022, 47(2): 192-196
组蛋白去乙酰化酶在肺动脉高压中的作用研究进展
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王丹1, 2, 李芳伟1, 万毅新1, *
作者信息
  • 1兰州大学第二医院呼吸科,兰州 730030
  • 2兰州大学第二临床医学院呼吸科,兰州 730030
  • 王丹,硕士研究生,主要从事肺动脉高压等呼吸系统疾病的研究

通讯作者:

万毅新,E-mail:
Research progress on the effect of histone deacetylase on pulmonary arterial hypertension
Dan Wang1, 2, Fang-Wei Li1, Yi-Xin Wan1, *
Affiliations
  • 1Respiratory Department, the Second Hospital of Lanzhou University, Lanzhou 730030, China
  • 2Respiratory Deparment, the Second Clinical Medical College of Lanzhou University, Lanzhou 730030, China
出版时间: 2022-02-28 doi: 10.11855/j.issn.0577-7402.2022.02.0192
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肺动脉高压(PAH)是一种预后不良的进展性疾病,可导致右心功能不全,从而引起一系列临床症状,甚至导致死亡,目前尚缺乏有效的治疗方法。表观遗传改变在PAH的发病中起着重要作用。组蛋白乙酰化修饰是目前研究最为广泛和深入的表观遗传修饰之一。组蛋白乙酰化水平主要由组蛋白乙酰基转移酶(HATs)和组蛋白去乙酰化酶(HDACs)调节,在染色质和基因调控中发挥关键作用,与PAH的发生密切相关,且靶向组蛋白乙酰化途径对PAH有一定的治疗潜力。本文就HDACs在PAH中的作用研究进展进行综述,以期加深对PAH发病机制的了解,并为其治疗提供新的方向。

组蛋白去乙酰化酶  /  肺动脉高压  /  组蛋白去乙酰化酶抑制剂  /  表观遗传改变  /  组蛋白修饰

Pulmonary arterial hypertension (PAH) is a progressive disease with poor prognosis, which may lead to right heart dysfunction, resulting in a series of clinical symptoms and even death, and there is still a lack of effective treatment. The etiology of PAH is complex, in which epigenetic changes play an important role in its pathogenesis. Histone acetylation modification is one of the most widely and deeply studied epigenetic modifications. The histone acetylation is mainly regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), which play a key role in chromatin and gene regulation, and is closely related to the occurrence of PAH. Targeted histone acetylation pathway has a certain therapeutic potential for PAH. This article reviews the research progress on the effect of HDACs on PAH, in order to further understand the pathogenesis of PAH and provide a new direction of treatment.

histone deacetylases  /  pulmonary arterial hypertension  /  histone deacetylase inhibitor  /  epigenetic change  /  histone modification
王丹, 李芳伟, 万毅新. 组蛋白去乙酰化酶在肺动脉高压中的作用研究进展. 解放军医学杂志, 2022 , 47 (2) : 192 -196 . DOI: 10.11855/j.issn.0577-7402.2022.02.0192
Dan Wang, Fang-Wei Li, Yi-Xin Wan. Research progress on the effect of histone deacetylase on pulmonary arterial hypertension[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (2) : 192 -196 . DOI: 10.11855/j.issn.0577-7402.2022.02.0192
肺动脉高压(pulmonary arterial hypertension,PAH)是指在海平面、静息状态下右心导管测得的平均肺动脉压(mPAP)≥25 mmHg、肺小动脉楔压(PAWP)≤15 mmHg及肺血管阻力>3 Wood单位的血流动力学状态,可导致右心室肥厚及右心衰竭,甚至引起患者死亡[1],其特征性的病理改变包括肺动脉中膜肥厚、内膜向心性或偏心性增殖和纤维化、外膜增厚纤维化、细胞外基质沉积、血管周围炎性细胞浸润及管腔内原位血栓形成等[2]。PAH病因复杂,目前认为其由遗传背景、表观遗传改变、损伤等多种因素作用导致,其中表观遗传改变尤其是组蛋白乙酰化修饰在PAH发病中起着重要作用。组蛋白的乙酰化是由组蛋白乙酰基转移酶(histone acetyltransferases,HATs)和组蛋白去乙酰化酶(histone deacetylases,HDACs)两个酶家族控制的动态过程[3]。组蛋白乙酰化水平可调节PAH相关关键基因的转录状态,与病理性血管重构过程中的细胞增殖、炎症和纤维化表型密切相关。由于翻译后组蛋白乙酰化的可逆性,许多HDAC抑制剂在不同PAH临床前模型中的治疗效果已被评估[4]。多项研究发现,Ⅲ类HDAC亚型(主要是SIRT1、SIRT3)在PAH发病中具有保护作用,其激活剂可预防甚至逆转PAH[5-7]。本文就HDACs及其抑制剂(Ⅲ类HDACs激活剂)在PAH中的作用研究进展进行综述。
表观遗传改变是由染色体改变但不改变脱氧核糖核酸序列导致的稳定的可遗传表型,目前PAH相关表观遗传机制包括DNA甲基化、组蛋白修饰和通过microRNA进行的RNA干扰,其中组蛋白修饰研究最为广泛和深入[8-9]。四种不同的组蛋白组成一个八聚体,DNA盘绕在组蛋白八聚体构成的核心结构外面形成了核小体的核心颗粒,组蛋白与DNA的密切相互作用表明组蛋白修饰在核小体结构的调节中起重要作用,可以改变基因转录位点的暴露情况,调节转录因子的活性而影响基因的转录;组蛋白的修饰方式有多种,最常见的是组蛋白乙酰化[3]。组蛋白乙酰化水平主要由HATs和HDACs调节,前者催化乙酰辅酶A上的乙酰基结合到组蛋白尾部的赖氨酸残基上,通过中和赖氨酸的正电荷降低DNA与组蛋白的亲和力并放松染色质的结构,使其更容易与转录因子结合;HDACs的作用与HATs相反,通过去除组蛋白尾部赖氨酸残基上的乙酰基而使染色质的结构更加紧密,阻止其与转录因子结合,导致转录沉默[3]。两个酶家族作用的平衡状态是调控基因表达的关键,控制着多种发育过程和疾病状态,其中HDACs家族在PAH中的作用研究较多。
HDACs在所有真核细胞中均有表达,目前已确认18种HDACs,其在结构、酶功能、亚细胞定位和表达模式等方面存在差异。HDACs可分为4类:Ⅰ类(HDAC1、2、3、8)、Ⅱ类(Ⅱa类:HDAC4、5、7、9;Ⅱb类:HDAC6、10)、Ⅲ类(SIRT1、2、3、4、5、6、7)和Ⅳ类(HDAC11),其中Ⅰ、Ⅱ、Ⅳ类为Zn2+依赖型去乙酰化酶,Ⅲ类活性依赖于烟酰胺腺嘌呤二核苷酸[3]。Ⅰ类与酵母Rpd3具有同源性,Ⅱ类与酵母Hda1具有同源性,Ⅳ类与酵母Rpd3和Hda1具有相似的同源性,Ⅲ类与酵母sir2同源,又称为sirtuin亚型[10-11]
Ⅰ类HDACs由保守的脱乙酰基酶结构域、短的氨基和羧基末端延伸组成,是多蛋白核复合体的亚单位,对转录抑制和表观遗传修饰至关重要[12]。Ⅱa类HDACs含有3个保守的14-3-3蛋白结合位点,可以磷酸化依赖的方式刺激Ⅱa类HDACs的胞质滞留或核输出,调节转录因子如肌细胞增强因子-2(MEF2)的活性[13]。Ⅱb类HDAC6含有两个串联脱乙酰酶结构域和一个C端锌指,可脱乙酰化抗微管蛋白而调节细胞的运动、黏附功能,还可通过锌指结构域与泛素结合调节热休克因子-1(HSF-1)和血小板衍生生长因子(PDGF)的功能[13]。HDAC10对N8-乙酰亚精胺的催化活性最强,为自噬诱导剂,由两个保守的结构基序决定了其底物特异性:一个310螺旋含有P(E,A)CE基序,立体地限制了活性位点;一个静电守门人E274为阳离子多胺底物提供了选择性[14]。Ⅲ类HDACs具有NAD+依赖的脱乙酰酶和ADP核糖基转移酶活性,是细胞增殖、分化、凋亡、线粒体生物合成、新陈代谢和炎症反应等多种过程所必需的[15]。HDAC11具有脱乙酰酶和脱脂-酰基转移酶活性,其中脱脂-酰基转移酶活性较高,其催化核心区与Ⅰ类和Ⅱ类HDACs蛋白具有序列相似性[16]
Li等[17]首次报道了从缺氧诱导的PAH模型中分离出活化的肺动脉外膜成纤维细胞(PAAF)所表现出的持久性促炎表型与Ⅰ类HDACs异常活性的关系,主要表现为Ⅰ类HDACs的表达和活性增加,Apicidin(一种特异性的Ⅰ类HDAC抑制剂)明显降低了PAH促炎介质的表达,并导致PAAF诱导单核细胞迁移和激活的能力明显降低。有研究发现,特发性肺动脉高压(IPAH)患者肺组织中Ⅰ类HDACs的表达及活性增加;HDAC抑制剂丙戊酸和琥珀酰异羟肟酸可抑制PAH牛血管成纤维细胞和R细胞的增殖,并抑制PDGF刺激的人血管平滑肌细胞的增殖[18]
HDAC1可通过增加组蛋白H3的赖氨酸9(H3K9ac)在铁硫生物发生蛋白BOLA家族成员3(BOLA3)启动子上的脱乙酰化来抑制BOLA3的转录,从而增加低氧诱导因子-2α的活性,进而引起线粒体电子传递、糖酵解等,促进内皮细胞增殖[19]。基质金属蛋白酶(MMP)属于内肽酶家族,具有降解细胞外基质的功能,MMP抑制剂(TIMP)可以抑制MMP的活性。本团队对PAH大鼠进行研究发现,HDAC1通过抑制miR-34a而增高MMP-9/TIMP-1和MMP-2/TIMP-2的比值,参与野百合碱(monocrotaline,MCT)诱导的大鼠PAH的发生和发展,而应用HDAC抑制剂MS-275抑制HDAC1可逆转上述表现,减少细胞外基质沉积,减轻肺动脉重塑和PAH[20]。在IPAH患者肺动脉平滑肌细胞(PASMCs)的体外实验中发现,HDAC2可通过上调转录调节因子YES相关蛋白1(YAP1)、淋巴增强因子-1(LEF1)而促进IPAH肺血管重塑的发展[21]。YAP1通常与特发性肺纤维化和肺血管疾病中血管硬化和纤维化表型的进展有关[22];LEF1是Wnt/β-catenin信号通路下游的核效应因子,与上皮-间质转化有关[23]。Krüppel样因子2(KLF2)信号的降低与PAH发病有关[24],HDAC8可通过下调KLF2而参与PAH的发病,且HDAC8 siRNA和HDAC抑制剂可使体外IPAH-PAAFs中KLF2的转录水平增高,不同程度地减弱IPAH相关的细胞过度增殖和病理性血管重构表型[21]。活性氧(ROS)增加和超氧化物歧化酶(SOD)活性降低与PAH有关[25],应用Ⅰ类HDAC选择性抑制剂MGCD0103或HDAC3 siRNA处理IPAH-PASMCs后,SOD3 mRNA水平恢复,表明组蛋白去乙酰化可使IPAH-PASMCs中SOD3的表达减低,进而增强PASMCs的增殖能力,而选择性HDAC抑制剂可恢复IPAH中SOD3的表达[26]。Ⅰ类HDACs的RNA干扰实验表明,沉默HDAC1HDAC2能明显降低PDGF诱导的CycD1蛋白表达,从而抑制PASMCs的增殖和迁移[27]
PAH动物模型中HDAC4、HDAC5、HDAC7以及NADPH氧化酶(ROS的主要来源)和ROS增加,而HDAC抑制剂丙戊酸可有效抑制NADPH氧化酶基因的表达,抑制ROS的过量产生,减轻PAH的血管重塑和右心室肥厚[28]。Ⅱa类HDACs与肌细胞增强因子2(MEF2)密切相关,可维持MEF2处于转录不活跃状态[29]。MEF2是一个转录因子家族,在心血管发育和分化中起重要作用[29]。在IPAH患者肺动脉内皮细胞(PAECs)的体外实验和PAH大鼠模型中发现,HDAC4和HDAC5的核积聚增加,从而导致MEF2下调及涉及肺血管完整性和稳态的基因(包括KLF2、KLF4及连接蛋白37、40等)表达减少,且使miR-424miR-503水平降低,进而促进PAECs的增殖;而Ⅱa类HDAC抑制剂MC1568可恢复PAECs中MEF2的活性,表现为MEF2转录靶点表达增加,细胞迁移和增殖减少,从而缓解PAH[30]。HDAC4可通过上调血小板源性生长因子-BB(PDGF-BB)而诱导PASMCs的增殖和迁移,miR-1281可通过降低HDAC4的表达及活性而拮抗上述作用[31]。HDAC4可通过上调MMP-2和MMP-9的表达而调节PAECs的增殖和迁移,并导致血管生成细胞的细胞周期发生改变,从而参与PAH的发病[32]。IPAH-PAECs体外实验发现HDAC7表达增加,其可能通过促进PAECs的增殖和迁移而促进PAH的发生[33]。目前关于HDAC9与PAH的研究报道较少。
PAH患者的远端肺动脉、PASMCs、PAECs以及PAH模型大鼠右心室中HDAC6蛋白表达上调,而HDAC6可使Ku70处于低乙酰化状态,阻止Bax转位到线粒体,促进PAH-PASMCs增殖并抑制其凋亡,特异性HDAC6抑制剂Tubasatin A可拮抗上述作用,缓解PAH[34]。目前关于HDAC10与PAH的研究报道较少。
有研究发现,SIRT1在PAH中具有潜在的保护作用,非特异性SIRT1激活剂白藜芦醇可预防甚至逆转PAH动物模型的相关表现,如血管重塑及右心室肥大[5-7]。最近,在IPAH患者PASMCs的体外实验和PDGF刺激的大鼠PASMCs中发现,SIRT1通过去乙酰化组蛋白H1和叉头框蛋白O1(FOXO1)抑制PASMCs的增殖,抑制或特异性下调SIRT1可促进IPAH患者和PAH大鼠PASMCs的增殖,SIRT1基因缺失加剧了慢性缺氧诱导的小鼠肺动脉肌化;使用SIRT1特异性激活剂STAC-3可抑制PDGF诱导的PASMCs增殖[35]。过氧化物酶体增殖物激活受体α(PPARα)和过氧化物酶体增殖物激活受体γ共激活剂α(PGC-1α)信号失活与氧化酶和抗氧化酶能力失衡有关[36]。PAH动物模型研究发现,SIRT1是PPARα/PGC-1α介导的氧化应激及线粒体损伤和功能障碍的关键保护因子,有助于改善PASMCs的增殖和肺动脉重塑[35]。MCT诱导的PAH模型大鼠中SIRT1蛋白表达下降,p53和p21表达上调,从而促进了PAH的发展[37]。Xi等[38]的研究发现,缺氧诱导的人PAECs中SIRT1表达增加,从而激活Akt信号通路,上调Bcl-2和缺氧诱导因子-1(HIF-1)的表达,促进PAECs增殖,抑制PAECs凋亡,最终促进PAH的发生。
SIRT3基因敲除小鼠发生PAH后,PASMCs中HIF-1α、信号转导和转录激活因子3(STAT3)、活化T细胞核因子(NFAT)等与PAH相关的转录因子激活,从而促进PAH-PASMCs的增殖并抑制其凋亡[39]。该研究还发现,在人PAH-PASMCs和PAH模型大鼠中,SIRT3表达下调,而腺病毒基因治疗可恢复SIRT3的表达并逆转疾病表型;一项纳入162例PAH患者和49名健康对照的无偏见队列研究发现,与代谢综合征相关的SIRT3多态性功能丧失与PAH相关[39]。最近的一项大鼠体内外实验发现,在缺氧条件下可通过上调miR-874-5p而下调SIRT3的表达,miR-874-5p缺失后SIRT3呈过表达,进而抑制自噬及异常平滑肌细胞的增殖,而自噬是缺氧性PAH病理性血管重构的主要原因[6]。目前关于其他sirtuin亚型与PAH的研究报道较少。
HDAC11是最新发现的HDAC,也是唯一的Ⅳ类成员。目前很少有关于HDAC11与PAH的研究报道。
目前关于PAH与表观遗传学的研究越来越深入,组蛋白去乙酰化修饰与PAH的发生密切相关,其中Ⅰ、Ⅱ、Ⅲ类HDACs在PAH发病中起着重要作用。关于PAH动物模型实验及PAH患者的体外实验研究证实,在PAH中Ⅰ类和Ⅱ类HDACs表达增加、活性增强(Ⅲ类HDACs在PAH中表达减低、活性减弱),从而促进了PASMCs、PAECs、成纤维细胞的增殖,并可促进细胞外基质异常沉积、上皮-间质转化、炎症反应等,导致肺血管重塑,进而参与PAH的发生发展,但其具体作用机制尚需更多的研究证实。抑制Ⅰ、Ⅱ类HDACs可不同程度地逆转上述表现,而激活Ⅲ类HDACs可逆转PAH,表明Ⅰ、Ⅱ类HDAC抑制剂在PAH的治疗中可能具有潜在的应用价值,而Ⅲ类HDAC可能对PAH有保护作用,其激活剂对PAH有一定的治疗潜力。最近有研究发现,HDAC抑制剂有可能作为一种治疗干预手段逆转心室舒张功能障碍,并阻断细胞外基质重塑[40]。在人和动物PAH成纤维细胞的体外实验中发现,HDAC抑制剂可通过上调miRNA的表达而逆转PAH的表型[20,41]。但目前相关研究偏少,各亚型HDACs及其抑制剂(sirtuin激活剂)在PAH中的具体作用机制仍不完全明确,甚至部分研究结论相反,且目前对于Ⅰ、Ⅱ类HDAC抑制剂及Ⅲ类HDACs激活剂在PAH治疗中的研究仅限于动物模型和PAH患者的PASMCs、PAECs体外实验,对于其不良反应相关研究较少。因此尚需进一步研究证实各亚型HDACs在PAH中的作用机制,探讨其相关抑制剂或激活剂的治疗作用及不良反应,并研究出相对安全的药物进行临床试验,以靶向组蛋白乙酰化途径或其下游通路,为PAH患者提供一种更有针对性、更有效和经济的治疗策略。
  • 国家自然科学基金(81960014)
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2022年第47卷第2期
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doi: 10.11855/j.issn.0577-7402.2022.02.0192
  • 接收时间:2021-05-07
  • 首发时间:2025-12-17
  • 出版时间:2022-02-28
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  • 收稿日期:2021-05-07
  • 录用日期:2021-10-09
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National Natural Science Foundation of China(81960014)
国家自然科学基金(81960014)
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    1兰州大学第二医院呼吸科,兰州 730030
    2兰州大学第二临床医学院呼吸科,兰州 730030

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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