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通讯作者:

田英平(1965-),男,河北石家庄人,博士生导师,主要从事急性中毒和急诊危重病的基础和临床研究。E-mail:tianyingping-jzh@163.com;

姚咏明(1964-),男,湖北黄冈人,博士生导师,主要从事休克、脓毒症和多器官功能障碍综合征发病机制及诊治的转化研究。E-mail:c_ff@sina.com

中图分类号:R542.2,R363.2+1

文献标识码:A

文章编号:2096-8965(2021)04-0027-07

DOI:10.12287/j.issn.2096-8965.20210404

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目录contents

    摘要

    心肌细胞代谢及死亡方式是心肌病的重要病理生理学基础。许多研究提示,铁代谢紊乱是心肌病发生发展的关键环节之一。铁是人体重要生理功能所必需的矿物质,参与细胞呼吸、脂质代谢以及蛋白质合成;在病理条件下,铁蓄积诱导的毒性作用可破坏心肌细胞稳态和活力,导致细胞死亡,即铁死亡。过量的铁则通过芬顿反应诱导过氧化物生成,造成心肌细胞功能损害。因此,铁死亡在调控心肌病的发生及发展过程中具有重要意义。本文总结了铁代谢及铁死亡在心肌病中的病理生理改变及其调控机制,深刻认识铁代谢及铁死亡的调控靶点将为心肌病防治开辟新途径。

    Abstract

    It has been demonstrated that cardiomyocyte metabolism and cell death are the fundamental progresses in the development of cardiomyopathy. Increasing evidences suggest that metabolic imbalance of iron appears to be involved in the pathophysiology of cardiomyopathy. As we well known, iron is an essential mineral required for various functions, including cellular respiration, lipid and oxygen metabolism, as well as protein synthesis. However, cardiomyocyte homeostasis and viability are inclined to be jeopardized by iron-induced toxicity under pathological stress, which is defined as ferroptosis. In the pathogenesis of cardiomyopathy, excessive iron is transported into cells that drives cardiomyocytes more vulnerable to ferroptosis by the accumulation of reactive oxygen species through Fenton reaction. The enhanced induction of reactive oxygen species in ferroptosis leads cardiomyocytes to become more sensitive to oxidative stress under the exposure of excess iron. Thus, ferroptosis might play an important role in the pathogenic progression of cardiomyopathy, and precisely targeting ferroptosis mechanisms may be a promising therapeutic option to revert myocardial remodeling. This review summarizes the pathophysiological alterations from iron homeostasis to ferroptosis together with signaling transduction with regard to ferroptosis in cardiomyopathy.

  • 前言

  • 心肌病是以心脏功能持续性、进行性损伤、心室重塑为特征的心脏病,最终导致心力衰竭,是心源性死亡的主要原因。铁蓄积诱发的毒性作用可破坏心肌细胞的稳态和活力,造成心肌细胞死亡,这种依赖于铁代谢紊乱的脂质过氧化细胞死亡方式称为铁死亡 (Ferroptosis)。随着心肌病的进展,心肌细胞内过量的铁通过芬顿反应诱导活性氧 (Reac⁃ tive Oxygen Species, ROS) 增加,促进心肌细胞对氧化应激敏感性增加[1]。因此,铁死亡在心肌病的发生、发展中扮演着重要角色,可能成为心肌病治疗的潜在靶点。深入探明铁代谢及铁死亡在心肌病中的病理生理特点及分子调节机制将为该疾病的治疗提供理论基础。

  • 1 铁代谢在心肌细胞中的作用及调控机制

  • 事实上,心肌细胞内铁代谢紊乱诱导的ROS过度积累、过氧化损伤以及线粒体通透性转移孔 (mitochondrial Permeability Transition Pore, mPTP) 持续开放,是心肌细胞功能障碍的关键因素[2, 3]。心肌细胞损伤激活缺氧诱导因子 (Hypoxia Inducible Factor,HIF) 并上调转铁蛋白受体1 (Transferrin Receptor 1, TfR1) 以及线粒体铁蛋白 (Mitochon⁃ drial Ferritin, FtMt) 的表达,从而导致细胞内及线粒体中铁过量产生[4, 5]。因此,线粒体在心肌病发生过程中具有连接铁代谢与ROS产生的桥梁作用,抑制线粒体铁相关过氧化反应将为心肌病的诊疗及干预提供理论依据。

  • 1.1 心肌细胞内铁转运及调节机制

  • 早期研究显示,心肌细胞中铁转运主要依赖于铁蛋白,铁离子与TfR1结合后通过受体介导的内吞效应以及二价金属转运体 (Divalent Metal Trans⁃ porter 1, DMT-1) 介导的钙-锌转运受体转移至心肌细胞[6]。生理状态下,铁除了被储存在铁蛋白内,二价铁离子可通过细胞基底外侧的转铁素 (Ferro⁃ portin, FPN) 释放至外周循环[7];进入心肌细胞的铁被转运至不稳定铁池 (Labile Iron Pool,LIP),储存于铁池铁蛋白中[8]。铁蛋白由24个亚基组成,包括铁蛋白重链 (Ferritin Heavy Chain,FTH) 和铁蛋白轻链 (Ferritin Light Chain,FTL),是维持细胞内铁水平稳定的主要因素[9]。当细胞处于应激等病理状态时,细胞通过生物合成途径促进线粒体内血红素及铁硫团簇产生中间体,引起细胞铁离子水平急剧升高[10]。铁的过氧化特性使其易被氧化生成有害的ROS,据此认为,细胞中铁离子转运受到精确的细胞信号通路调控以维持其生物学功能。Had⁃ dad等[11] 研究发现,转录修饰后铁调节蛋白 (Iron Regulatory Proteins,IRPs) 和铁反应元件 (Iron Re⁃ sponsive Elements, IREs) 参与调控细胞内铁稳态,如铁的摄入、储存和释放等生理过程,二者可通过调节铁代谢相关蛋白的合成及功能维持细胞铁离子的稳定。当细胞内铁含量较低时,具有双向调节效应的IRPs通过稳定TfR1和DMT-1的mRNA表达促进铁的吸收,或通过抑制mRNA翻译过程影响铁蛋白的储铁功能[12]。Lakhal-Littleton等[13] 认为,心肌细胞铁调素是影响铁代谢的主要原因,FPN降解与铁调素独立相关,可导致FPN失活,最终减少铁的释放。由此推断,在影响心肌细胞铁转运因素中,仅FPN在铁代谢过程中与铁输出相关,证实心肌细胞对铁超载比其他类型细胞更为敏感。

  • 1.2 心肌细胞线粒体铁代谢的作用及机制

  • 线粒体作为全身能量代谢的细胞器,在心肌病心功能障碍期间对铁稳态和心肌损伤的调节具有重要影响[14-16]。据报道,线粒体为血红素合成及铁硫团簇 (Iron Sulfur Clusters,ISCs) 产生提供重要结合位点,形成血红素及铁硫团簇相关蛋白并将其整合至线粒体氧化磷酸化系统中;进一步通过催化氧化状态下铁的电子传递,为心脏活动提供持续的能量,是维持心脏生理活动的必要条件[17]。已证实,心肌细胞线粒体中铁的水平明显高于其他类型细胞,线粒体内铁缺乏会限制心肌细胞能量输出,而严重的铁超载则通过产生过量ROS引起线粒体破坏及功能障碍[18]。心肌细胞线粒体内铁相关ROS及羟自由基的形成诱发线粒体膜电位 (Mitochondrial Membrane Potential,MMP) 去极化,线粒体通透性孔开放,造成线粒体肿胀及线粒体功能异常[19, 20]。由此可见,线粒体铁浓度与心肌细胞命运密切相关。另据报道,Tf-TfR复合物及溶酶体中铁蛋白降解是铁由细胞质转运至线粒体的主要来源[21];且FtMt是维持心肌细胞线粒体铁稳态的另一主要原因。FtMt表达于心肌细胞上,与FTH具有高度同源序列,通过将铁从细胞质重新分配至线粒体对铁的摄入发挥重要作用[22]。据此推测,心肌细胞FtMt表达升高是线粒体LIP中铁减少的主要原因,进而使机体ROS生成减少[23];FtMt过表达则显著抑制Erastin诱导的铁死亡[24]。由此可见,FtMt可能是维持心肌细胞铁稳态潜在的分子机制及作用靶点。

  • 2 铁死亡的主要调控途径

  • 铁死亡作为新发现的不同于凋亡的程序性细胞死亡方式,与谷胱甘肽合成耗竭及抗氧化酶失活密切相关,其特征是铁超载相关ROS依赖性脂质过氧化反应。谷胱甘肽过氧化物酶4 (Glutathione Peroxidase4, GPX4) 失活以及多不饱和脂肪酸 (Poly-Unsaturated Fatty Acids, PUFAs) 过氧化是导致细胞氧化还原稳态破坏的重要原因[25]。研究证实,铁死亡参与心肌病发病过程,在小鼠心肌病模型中给予铁死亡抑制剂如利普司他汀-1 (Liprox⁃ statin-1,Lip-1) 能有效保护心肌细胞,提示铁死亡可能为治疗心肌病提供新策略[26]。铁死亡在心肌病中相关分子调控通路主要包括铁代谢通路、谷胱甘肽代谢通路、脂质过氧化通路、NADPH氧化酶4 (NADPH Oxidase4, NOX4) 通路、活化转录因子4 (Activating Transcription Factor, ATF4) 信号通路、核因子转录相关因子2 (Nuclear Factor Erythroid 2-Related Factor,NRF2) 信号通路等。

  • 2.1 铁代谢通路

  • 铁超载是由细胞内铁失衡或线粒体内铁代谢紊乱所致,进而影响铁死亡的发生及进展。细胞内铁调节核受体激动剂 (Nuclear Receptor Coactivator, NCOA4) 可通过调节噬铁蛋白进一步抑制细胞内铁蛋白释放铁离子[27];另一个关键编码蛋白为铁响应元件结合蛋白2 (Iron Responsive ElementBinding Protein 2, IREB2) 则主要影响铁蛋白表达及铁离子转运[28]。铁在线粒体膜上的跨膜转运依赖于位于线粒体外膜的电压依赖性阴离子通道 (Voltage-Dependent Anion Channel, VDAC)。当线粒体铁离子超载时,VDAC2/3处于开放状态,通过调控FtMt上游蛋白启动铁死亡。过表达FtMt可抑制线粒体铁过量,从而保护细胞免受铁死亡[29]

  • 2.2 谷胱甘肽代谢通路

  • 细胞内还原型谷胱甘肽 (Glutathione,GSH) 是机体重要的抗氧化缓冲系统,可通过向GPX4提供电子从而抑制铁依赖性ROS形成;并将脂质氢过氧化物转化为脂质醇,发挥对脂质过氧化的保护作用。内源性谷胱甘肽的生物合成依赖于Xc-系统,其由跨膜蛋白转运载体家族7成员11 (Trans⁃ porter Solute Carrier Family 7Member 11,SLC7A11) 和单通道跨膜调控蛋白家族3成员2 (Solute Carrier Family 3Member 2,SLC3A2) 组成;Xc-系统可通过1∶1交换谷氨酸和胱氨酸来调节铁死亡[30]。 Hayano等[31] 研究证实,铁死亡诱导剂Erastin能直接抑制Xc-系统功能,导致GPX4失活,且抑制GPX4加重脂质过氧化介导的铁死亡,提示GPX4介导的铁死亡途径可能成为心肌病的潜在干预靶点。

  • 2.3 脂质过氧化代谢通路

  • 尽管细胞抗氧化作用在酶联反应中占主导地位,但长期处于氧化应激状态下,细胞可激活脂质代谢相关酶包括酰基辅酶长链家族成员4 (AcylCoA synthetase Long-Chain Family Member4,ACSL4) 和溶血磷脂酰胆碱酰基转移酶3 (Lysophosphatidyl⁃ Choline Acyltransferase3,LPCAT3) 进而诱导脂质过氧化反应。PUFAs被催化生成脂质过氧化物,破坏细胞形态及功能,如细胞膜缺陷及线粒体收缩功能障碍,最终诱发铁死亡[32]。进一步观察提示,外源性不饱和脂肪酸不仅降低细胞对铁死亡的易感性,而且抑制细胞膜脂质双分子层的过氧化损伤[33]

  • 2.4 NOX4信号通路

  • NOX4是心肌细胞氧化应激的主要分子介质,可将NADPH中电子转移至氧原子,甚至产生超氧化物,诱导过氧化反应。抑制NOX4介导的氧化应激反应则缓解心肌细胞毒性及细胞内自由基诱导的线粒体损伤。同样,在心力衰竭模型中,敲除NOX4基因可明显改善铁超载,显著逆转心室重构。凋亡诱导线粒体相关因子2 (ApoptosisInducing Factor Mitochondrial-Associated 2,AIFM2) 作为另一类脂溶性电子载体,不依赖于GPX4发挥抗氧化作用。AIFM2是NADPH依赖的氧化还原酶辅酶Q (Coenzyme Q,CoQ) 的重要调控因子,通过直接调节CoQ抗氧化系统抑制铁死亡[34]

  • 2.5 ATF4信号通路

  • ATF4是参与细胞自噬、氧化应激和炎症反应调控的关键转录因子,在生理状态下处于低表达水平,而在缺氧或内质网应激 (Endoplasmic Reticu⁃ lum Stress,ERS) 刺激下表达水平显著升高。新近资料显示,激活ATF4-C/EBP同源蛋白 (C/EBP Homologous Protein,CHOP) 信号通路可靶向诱导GSH降解,表明ATF4-CHOP信号通路与心肌病所致心肌细胞铁死亡密切相关。此外,热休克蛋白5 (Heat Shock Protein 5,HSPA5) 可通过介导内质网折叠负向调控GPX4活性,而HSPA5高表达能反馈性诱导ATF4活化,从而提高GPX4水平,最终抑制铁死亡[35]。因此,ATF4-HSPA5-GPX4级联信号转导参与氧化应激及代谢过程,进而调控铁死亡。

  • 2.6 NRF2信号通路

  • NRF2可通过促进铁的储存、减少铁积累以及上调SLC7A11活性增加谷氨酸含量,对铁死亡反应进行调节。NRF2受上游信号分子P62调控,P62抑制NRF降解及转录功能,下调SLC7A11表达,从而有效抑制铁死亡的发生[36]。另据报道,NRF2能调控血红素加氧酶1 (Heme Oxygenase1,HO-1) 及铁蛋白,进一步影响铁死亡进程;在小鼠心肌病模型中,敲除HO-1基因可加重Erastin诱导的铁死亡,而NRF2激活则反馈性促进HO-1表达[37]。据此推断,NRF作为铁死亡负向调控分子,在心肌病中发挥重要调控作用。然而,NRF在心脏其他疾病中的确切调控机制有待进一步探索。

  • 3 铁死亡与心肌病

  • 心肌病与心力衰竭的进展密切相关,尤其是致命性心力衰竭,如缺血性心肌病、扩张型心肌病、肥厚型心肌病等。终末分化的心肌细胞功能丧失被认为是多发性心肌病发生发展的重要危险因素。然而,心肌细胞死亡的机制尚未澄清。研究证实,铁死亡与多种心肌病有关,包括缺血性心肌病、阿霉素诱导的心肌病、铁超载心肌病、感染性心肌病等。

  • 3.1 铁死亡与缺血性心肌病

  • 铁死亡是缺血性心肌病发病机制的重要因素之一,在小鼠心肌细胞缺血模型中给予铁死亡抑制剂如Lip-1可有效保护心肌细胞,提示铁死亡可能为治疗缺血性心肌病提供新的策略。当心肌细胞长期暴露于缺血状态时,铁代谢失衡特别是铁超载促进氧化系统中过量ROS及氧自由基生成,从而加重氧化应激并伴有心肌细胞膜损伤、心血管内皮细胞功能障碍[38]。研究显示,在缺血早期,心肌细胞中铁在酸性环境下易于释放,铁介导的芬顿反应增强,促使低活性的过氧化氢转变为高反应性羟自由基,因此在心肌缺血期给予铁抑制剂可能有助于减少自由基产生并缓解心肌细胞缺血损伤[39]。有报道认为,多种铁代谢相关因素在心肌细胞缺血损伤中发挥重要调控作用,包括HIF、FTH信号转导通路以及线粒体铁蛋白调控途径。例如,心肌缺血状态下,HIF过度激活可通过上调TfR1表达引起铁超载,最终加剧ROS诱导的过氧化损伤[40]。另有研究证实,心肌细胞在发生缺血损伤后给予铁螯合剂有利于心功能障碍的逆转[41];在小鼠心肌缺血模型中观察到FTH呈表达下调趋势,明显抑制心肌细胞结合游离铁的能力,引发氧化应激增强甚至细胞死亡[42]。此外,线粒体铁蛋白能抑制ROS产生,在调节缺血性心肌病生存和预后中具有重要意义。线粒体铁摄入受线粒体铁转换蛋白2 (Mitoferrin2, MFRN2)以及线粒体钙单胞体 (Mitochondrial Cal⁃ cium Unipiter,MCU) 调控,且线粒体铁输出受ATP结合亚族B (ATP-Binding Cassette Subfamily B,ABCB) 蛋白影响[43]。因此,线粒体铁调节可能成为改善缺血性心肌病的有效靶标。

  • 3.2 铁死亡与阿霉素诱导的心肌病

  • 阿霉素是临床常用的抗肿瘤药物,但具有较强的心脏毒副作用,可引起心功能障碍甚至心力衰竭。在小鼠模型中,注射阿霉素后导致核周相关因子2 (Nuckear factor-E2related Factor 2,Nfr2) 依赖性HO-1表达明显增强,引发铁超载及脂质过氧化反应,从而导致铁死亡[44]。进一步观察显示,给予铁死亡抑制剂处理则显著缓解阿霉素所致心脏毒性作用,提高小鼠生存率,同时铁超载现象减轻,发挥心脏保护作用[45]。因此,靶向干预铁死亡可能成为阿霉素诱导心肌病的潜在治疗措施。

  • 3.3 铁死亡与铁超载性心肌病

  • 铁超载性心肌病是一种以铁过量导致左心室舒张功能障碍为特征的心肌病。许多资料显示,铁超载可诱发心肌细胞线粒体功能异常,干扰线粒体动力学反应,从而导致心肌细胞发生铁死亡。游离铁被心肌细胞摄取后通过芬顿反应介导线粒体氧化应激,造成线粒体呼吸下降、线粒体膜电位去极化损伤、线粒体肿胀以及线粒体膜受损[46]。研究显示,铁螯合剂可有效降低心肌细胞线粒体中的铁含量,减少活性氧的产生,从而缓解线粒体功能紊乱[47]。值得指出的是,关于铁死亡在铁超载性心肌病中的确切意义仍有待深入探究。

  • 3.4 铁死亡与糖尿病心肌病

  • 糖尿病心肌病是长期、严重糖尿病患者并发的以左心室收缩功能障碍为特征的心肌病,其发病机制主要与氧化应激损伤相关。氧化应激反应过程中产生多种活性氧及自由基,导致心肌细胞损伤及功能障碍。糖尿病患者线粒体功能异常、内质网应激及多种活性氧酶的激活均可造成心肌细胞活性氧蓄积,促进铁死亡发生,引起糖尿病心肌病[48]。因此,通过抑制氧化应激缓解铁死亡将为糖尿病心肌病的治疗奠定基础。

  • 3.5 铁死亡与脓毒性心肌病

  • 脓毒性心肌病是重症脓毒症患者感染所致急性心功能障碍,是可逆性的并发症,也是脓毒症患者高死亡率的主要原因之一。据报道,严重感染患者合并脓毒性心肌病可使其病死率增加65%[49]。脂多糖 (Lipopolysaccharide,LPS) 攻击与脓毒症所致心功能障碍密切相关,常引起心肌细胞凋亡、焦亡及铁死亡等。在脓毒症小鼠模型中,铁死亡过氧化反应标志物环氧化酶-2(Cyclooxygenase-2,COX-2) 表达显著上调[50];且LPS诱导心肌细胞线粒体损伤中的形态学异常与铁死亡线粒体改变相符[51]。进一步分析发现,在LPS诱导的脓毒症心肌病中, NCOA4表达增加,而铁蛋白水平通过铁吞噬作用降解,导致铁蓄积,从而引发铁死亡[52];采用铁死亡抑制剂处理则可以显著降低脓毒症心肌病动物的死亡率。

  • 4 问题与展望

  • 综上所述,铁死亡作为依赖于铁代谢紊乱的重要调控细胞程序性死亡方式之一,参与了心肌病的发生与发展过程。与细胞凋亡等细胞死亡方式不同,目前对于心肌病状态下铁代谢紊乱及铁死亡的探索和认识仍处于起步阶段,许多重要科学问题亟待解决,新的防治策略需要探索。例如,对铁代谢的关键调控靶点、主要细胞死亡途径及信号转导通路的干预是治疗心肌病的潜在治疗方法,这样不仅可通过抑制铁死亡的方式来减轻心肌病所致内皮功能异常,而且能有效地抑制心室重构,进而针对性地改善心功能障碍。总之,深刻认识铁代谢在心肌细胞铁死亡中的科学意义、铁死亡核心调控环节以及设计针对性临床试验将有助于多种心肌病的精准治疗。

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