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缺氧诱导因子1在高原病中的作用机制的研究进展

周志豪, 孙凡丽, 江秉华

周志豪, 孙凡丽, 江秉华. 缺氧诱导因子1在高原病中的作用机制的研究进展[J]. 四川大学学报(医学版), 2024, 55(6): 1424-1435. DOI: 10.12182/20241160303
引用本文: 周志豪, 孙凡丽, 江秉华. 缺氧诱导因子1在高原病中的作用机制的研究进展[J]. 四川大学学报(医学版), 2024, 55(6): 1424-1435. DOI: 10.12182/20241160303
ZHOU Zhihao, SUN Fanli, JIANG Binghua. Research Progress in the Role of Hypoxia-Inducible Factor 1 in Altitude Sickness and the Mechanisms Involved[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(6): 1424-1435. DOI: 10.12182/20241160303
Citation: ZHOU Zhihao, SUN Fanli, JIANG Binghua. Research Progress in the Role of Hypoxia-Inducible Factor 1 in Altitude Sickness and the Mechanisms Involved[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(6): 1424-1435. DOI: 10.12182/20241160303

缺氧诱导因子1在高原病中的作用机制的研究进展

基金项目: 国家自然科学基金 (No. 82073393)资助
详细信息
    作者简介:

    江秉华,郑州大学特聘教授,国家级领军人才、河南省高层次人才、俄罗斯自然科学院外籍院士。中国抗癌协会肿瘤缺氧生物学和临床应用专委会主任委员。于美国密西西比州立大学获得博士学位,1994–1997年在约翰霍普金斯大学医学院Gregg Semenza教授的实验室从事博士后研究,1997–2000年在美国斯克里普斯研究所Peter Vogt教授从事博士后研究。2000年开始作为PI成立实验室,长期从事肿瘤发生发展以及信号转导的分子机制研究,针对肿瘤和其它血管性疾病的发病机理,运用分子生物学手段进行干预和治疗,在这些领域取得许多重要的研究成果,处于国际领先水平。获得美国癌症学会研究学者奖和国家科技进步奖一等奖等多种奖项。成功申请多项美国专利和中国专利。在Proc Natl Acad Sci USAJ Biol ChemAutophagyCancer ResOncogene等国际学术期刊上发表论文国际学术期刊上发表论文200多篇,被其他科学家引用超过40 000次,H指数为88

    通讯作者:

    江秉华: E-mail:Binghjiang@zzu.edu.cn

Research Progress in the Role of Hypoxia-Inducible Factor 1 in Altitude Sickness and the Mechanisms Involved

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  • 摘要:

    长期居住或短暂进入高原环境的人群大多会出现高原反应,导致一系列生理和病理变化,进而引发高原病。高原环境的显著特征是低氧条件,现有研究表明,缺氧诱导因子1(HIF-1)是人体应对高原低氧环境的关键分子。HIF-1由HIF-1α和HIF-1β两个亚基组成的异源二聚体,作为一种强效转录因子,能够直接调控多种下游靶基因的表达,影响机体的适应性反应。大量研究显示,HIF-1表达异常与多种疾病的发生发展密切相关,包括高原病、心血管疾病、神经系统疾病、炎症性疾病、认知障碍、免疫性疾病及癌症等。本文综述了HIF-1的结构特征、表达调控机制及其下游靶基因,并介绍了已开发的HIF-1抑制剂。此外,文章重点探讨了HIF-1在高原病发生发展中的作用机制,特别是其在高原肺水肿、高原脑水肿及高原肺动脉高压等病理过程中的调控作用。通过深入解析HIF-1的功能,为高原病的防治提供了理论依据和潜在治疗靶点。

     

    Abstract:

    Individuals who reside at high altitudes for extended periods or those who visit these regions briefly frequently experience high-altitude response, which triggers a series of physiological and pathological changes in the body, ultimately causing altitude sickness. One of the most critical features of high-altitude environments is hypoxia. Recent studies have demonstrated that hypoxia-inducible factor 1 (HIF-1) plays a central role in mediating the body's response to hypoxic conditions at high altitudes. HIF-1, a heterodimeric transcription factor composed of an oxygen-sensitive subunit α (HIF-1α) and a constitutively expressed subunit β (HIF-1β), directly regulates the expression of multiple target genes, thereby modulating various physiological processes essential for cellular adaptation to hypoxia. According to a substantial body of research, aberrant expression of HIF-1 is implicated in the pathogenesis and progression of various diseases, including altitude sickness, cardiovascular disorders, neurological conditions, inflammatory diseases, cognitive impairment, immune dysregulation, and cancer. In this review, we provided an in-depth examination of the structural characteristics and regulatory mechanisms governing HIF-1 expression, discussed its downstream target genes, and highlighted the inhibitors currently under development. Additionally, we summarized the pivotal role and underlying mechanisms of HIF-1 in the development of altitude sickness, particularly its regulatory role in the pathophysiological processes of high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE), and high-altitude pulmonary hypertension (HAPH). Through a thorough examination of the role of HIF-1, we aim to provide a theoretical foundation and potential therapeutic targets for the prevention and treatment of altitude sickness.

     

  • 长时间持续的地壳抬升运动形成了低山、丘陵和宽谷盆地的组合体,即高原。中国拥有世界上最大的高原面积和最多的高原居住人口。由于高原地区特有的高海拔、低气压和低氧环境,平原居民进入高原或高原居民进入更高海拔地区时,人体会经历一系列复杂的生理适应过程,这一现象被称为“高原习服”[1]。若个体不能有效适应这种低氧低压环境,可能会引发多种急性和慢性高原病,严重者甚至危及生命[2]

    高原病的发病机制复杂,主要与个体的高原习服能力密切相关。而个体的高原习服能力差异显著,这取决于人体对氧气的利用和调节能力。氧气是维持细胞正常功能的关键物质,所有细胞通过线粒体进行有氧呼吸,产生ATP以供能,并参与细胞修复、免疫应答等多种生理过程,是许多生化代谢途径中的重要电子受体[3]。缺氧诱导因子-1(hypoxia-inducible factor-1, HIF-1)是细胞应对缺氧环境的关键转录因子,具有广泛的靶基因谱,包括与缺氧适应、炎症反应和肿瘤生长相关的基因[4]

    HIF-1在多种生理和病理过程中发挥重要作用,涵盖肿瘤发生发展、炎症反应、免疫调节以及高原病等[2, 5-6]。研究表明,HIF-1不仅在缺氧条件下发挥作用,还在其他应激条件下(如炎症、氧化应激等)参与细胞的适应性反应[7]。因此,HIF-1不仅是高原病发生发展的关键调控因子,也是多种疾病病理过程中的重要参与者。

    本文就HIF-1的结构和功能以及在高原环境下HIF-1参与高原病发生发展的机制进行阐释,为高原病的治疗与预防提供新的思路。

    1991年,GREGG L. SEMENZA团队和PETER J. RATCLIFFE团队在研究氧调节人类促红细胞生成素(erythropoietin, EPO)基因表达时,发现了一段位于EPO基因3'端120-256个碱基处的顺式作用DNA序列,并将其命名为缺氧反应元件(hypoxia response element, HRE)[8]。随后, SEMENZA团队进一步鉴定出一种转录因子能够与HRE序列结合,激活EPO基因在缺氧条件下的转录,该转录因子被命名为缺氧诱导因子1(hypoxia-inducible factor 1, HIF-1)[7]。HIF-1及其识别序列是哺乳动物细胞响应缺氧环境的关键组分,通过亲和纯化与蛋白质测序,证实其由两个亚基组成:120 kDa的HIF-1α和94 kDa的HIF-1β[9]

    WANG等[9-10]基于HIF-1α氨基酸测序的寡核苷酸序列,经过大量筛选,排除了假阳性cDNA克隆和仅编码部分HIF-1α的克隆,最终成功克隆了编码完整HIF-1α蛋白的全长cDNA,同时证明了HIF-1α作为活性亚基,与结构性亚基HIF-1β共同介导HIF-1复合体的形成,并与其DNA结合位点相互作用。进一步研究表明,HIF-1α包含826个氨基酸,它含有basic helix-loop-helix (bHLH) 和 Per-ARNT-Sim (PAS) 结构域,这些结构域对于HIF-1α的转录活性至关重要[11]

    1999年,WILLIAM G. KAELIN团队在研究Von Hippel-Lindau (VHL)时,发现缺乏功能性VHL基因的细胞会显著高水平表达缺氧相关基因。引入野生型VHL基因后,细胞的正常生理调节得以恢复[12]。与此同时,RATCLIFFE团队发现脯氨酸羟化酶(prolyl hydroxylase domain, PHD)家族成员PHD1、PHD2和PHD3通过不同的机制协同调节HIF-1α的稳定性,维持细胞内的氧气平衡 [13] 。简单来说,在常氧条件下,PHD2使HIF-1α发生脯氨酸羟基化修饰,促使其与VHL蛋白结合,进而被泛素化降解;而在缺氧条件下,PHD2的活性降低,导致HIF-1α的转录活性和稳定性增强。KAELIN和RATCLIFFE的研究为理解细胞氧感知机制提供了重要线索。

    SEMENZA、RATCLIFFE和KAELIN三位科学家及其团队的工作揭示了细胞如何通过HIF-1感知和应对不同氧浓度的变化,阐明了缺氧调节机制在生理和病理过程中的重要作用。这些发现不仅为医学发展奠定了基础,也为HIF-1作为调节人类病理生理功能的重要分子提供了理论依据。因此,SEMENZA、RATCLIFFE和KAELIN因在缺氧领域的突破性贡献,荣获2019年诺贝尔生理学或医学奖。

    HIF-1作为细胞感知外界环境中氧气水平的关键分子,其表达和功能受多种因素调控。除了氧气浓度外,活性氧(reactive oxygen species, ROS)、生长因子、重金属及非编码RNA等也在转录和蛋白质水平上对其产生影响,进而参与疾病的发生与发展。

    HIF-1的活性最早由SEMENZA和WANG等人发现受缺氧调控。随后,SEMENZA研究团队克隆了HIF-1α,并进一步证实HIF-1是由HIF-1α和HIF-1β两个亚基组成的二聚体转录因子,并首次证明HIF-1α亚基包含两个转录激活域(transcription activation domain, TAD),分别位于531-575和786-826氨基酸区域[11]。当这两个TAD以GAL4融合蛋白形式表达时,其转录活性在缺氧条件下显著增强;而位于这两个TAD之间的576-785氨基酸序列则具有抑制转录激活的作用。

    在此基础上,RATCLIFFE和KAELIN进一步揭示了VHL蛋白在氧气感知中的关键调节机制。在常氧水平下,HIF-1α的第402和564位脯氨酸残基被PHD羟基化,促进其与VHL蛋白结合。VHL作为一种E3泛素连接酶,特异性识别并结合HIF-1α的第532和538位赖氨酸残基,导致HIF-1α发生泛素化修饰,最终通过蛋白酶体途径降解[14]。而在缺氧条件下,PHD活性受到抑制,HIF-1α的羟基化减少,导致其在细胞内积累并转移至细胞核,与HIF-1β结合形成有活性的HIF-1复合体[15]。该复合体能够结合到靶基因上的HRE,调控一系列基因的转录,这些基因参与红细胞生成、血管生成、能量代谢、细胞存活、凋亡及糖酵解等过程[16-17]图1)。

    图  1  HIF-1α感知氧气的机制
    Figure  1.  Mechanism of HIF-1α expression in response to oxygen
    HIF-1α: hypoxia-inducible factor 1 alpha; HIF-1β: hypoxia-inducible factor 1 beta; bHLH: basic helix-loop-helix; PAS-1/2: Per-ARNT-Sim domain-1/2; TAD: transcription activation domain; PHD: prolyl hydroxylase domain; VHL: Von Hippel-Lindau; HRE: hypoxia response element.

    HIF-1的调控不仅依赖于氧气水平,还受到多种信号通路的影响。1997年,JIANG等[18]首次发现V-SRC(virus-Sarcoma)癌基因能够以非氧依赖的形式诱导HIF-1的表达与活化,从而促进血管内皮生长因子(VEGF)和烯醇化酶1(ENO1)等基因的转录表达,促进肿瘤的血管生成和代谢重编程,推动肿瘤的进展。该研究首次从病理的角度出发,将癌基因与HIF-1的诱导表达联系起来,为理解肿瘤的发生发展提供了新的见解。后续研究又发现表皮生长因子(EGF)可通过激活磷脂酰肌醇3-激酶(PI3K)信号通路增强HIF-1α的转录活性,进而促进糖酵解[19]。另外,还有研究表明,NF-κB是HIF-1α的关键转录激活因子,缺氧条件下,NF-κB的活性对于HIF-1α的累积至关重要 [20]

    因此,HIF-1不仅在缺氧应答中发挥核心作用,还与其他信号通路相互作用,共同调控细胞的代谢和生存反应。

    重金属对环境和人类健康的多方面影响已得到广泛研究。它们不仅通过污染环境直接威胁生态系统,还可能通过食物链或吸入等途径在人体内累积,对健康构成潜在威胁。早在1999年,SALNIKOW等[21]就报道了镍诱导的细胞转化会改变HIF-1α与p53之间的平衡,进而影响VEGF的表达。此外,六价铬与重金属镉都是常见的环境污染物,已被证明能够通过抑制PHD的活性,阻止HIF-1α在正常氧条件下的降解,使其稳定并进入细胞核,激活下游靶基因[22-23]。砷酸盐是一种广泛存在于水、食物和空气中的环境毒物,可通过激活PI3K/Akt/mTOR信号通路,诱导人前列腺癌细胞中HIF-1α的表达[24]。重金属锌可以协同HIF-1α,促进金属响应转录因子-1(MTF-1)与金属硫蛋白基因(Mt)的结合活性,促进其表达[25]。同时,锌离子还可以诱导产生一种新的HIF-1α亚型——HIF-1(Z),该亚型能够抑制HIF-1α的活性,降低缺氧诱导的基因的mRNA表达[26]。另外,还有数据表明,铀矿工人肺组织中HIF-1α的表达水平与其职业暴露和肺癌亚型密切相关[27]

    在细胞代谢过程中,ROS作为重要的信号分子,能够通过多种机制调控HIF-1α的表达。这些机制包括信号通路激活、蛋白稳定性调节、转录调控和翻译调控等,构成了HIF-1α在缺氧应答中的重要调控网络。例如,研究发现,卵巢癌细胞中高水平的ROS能够诱导NADPH氧化酶4(NADPH oxidase 4, NOX4)过表达,进而促进HIF-1α和VEGF的表达,从而增强血管生成和肿瘤生长[28]。此外,ROS还可以通过上调还原因子-1(reduction-oxidation factor 1, Ref-1)的表达来增强HIF-1α的稳定性和转录活性[29]。然而,ROS对HIF-1α的调控并非单一方向,在某些情况下,ROS可以抑制HIF-1α的活性。例如,在人骨肉瘤细胞中,缺氧条件下ROS通过调节PHD2的活性,抑制HIF-1α的稳定性[30]。同样,在NCI-60癌细胞群中,抗坏血酸(维生素C)产生的ROS能够在缺氧条件下抑制HIF-1α的活性,表明ROS对HIF-1α的调控具有双重作用,具体效应取决于细胞类型和微环境条件[31]

    非编码RNA(non-coding RNA, ncRNA)在HIF-1α的调控中也发挥了重要作用。多项研究表明,miRNA可以直接或间接调控HIF-1α信号通路。例如,在乳腺癌中,miR-148a/152通过激活胰岛素样生长因子受体1(IGF-1R)和胰岛素受体底物1(IRS1),促进HIF-1α的表达,进而调控细胞转化和肿瘤血管生成[32]。在肺癌中,miR-214通过靶向抑制生长抑制因子4(ING4),促进HIF-1α的表达,增强肿瘤细胞的存活能力[33]。另外,除了miRNA,其他类型的非编码RNA也参与了HIF-1α的调控。例如,长链非编码RNA(lncRNA)HIF1A-AS2与MYC形成正反馈回路,促进KRAS驱动的非小细胞肺癌的增殖和转移[34]。PAARH 可以通过激活 HIF-1α/VEGF 信号促进肝细胞性肝癌进展和血管生成[35]

    综上所述,HIF-1除了受到氧气调控以外,PI3K基因与生长因子、重金属、ROS和非编码RNA等因素也可通过多种机制调控HIF-1的表达和活性,揭示了HIF-1在缺氧应答中的复杂调控网络(图2)。

    图  2  HIF-1的表达调控机制
    Figure  2.  Regulatory mechanism of HIF-1 expression
    Ni: nickel; Cr: chromium; Cd: cadmium; As: arsenic; Zn: zinc; U: uranium; PHD: prolyl hydroxylase domain; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; EGF: epidermal growth factor; V-SRC: virus-sarcoma;NF-κB: nuclear factor kappa-B; NOX4: nicotinamide adenine dinucleotide oxidase 4; Ref-1: redox factor-1;IGF-1R: insulin-like growth factor 1; IRS1: insulin receptor substrate 1; ING4: inhibitor of growth-4; HIF1A-AS2: HIF1A antisense RNA 2; PKA-AS1: PKA antisense RNA 1.

    HIF-1是应对缺氧环境的关键转录因子,在高原病的病理机制中发挥重要作用[36]。高原病,亦称高山病,是指人体在高海拔地区因适应不良或失调引发的一系列临床综合征,主要包括高原肺动脉高压(high-altitude pulmonary hypertension, HAPH)、高原性肺水肿(high-altitude pulmonary edema, HAPE)、高原性脑水肿(high-altitude cerebral edema, HACE)及慢性高山病(chronic mountain sickness, CMS)[2]。高原病发病率较高,尤其是急性高原病的发生率可达53%,严重影响高原地区居民的健康(图3)。

    图  3  HIF-1参与多种高原病的发生
    Figure  3.  HIF-1 is involved in the pathogenesis of many types of high-altitude diseases
    PDGF: platelet-derived growth factor; NOX4: nicotinamide adenine dinucleotide oxidase 4; PPAR-γ: peroxisome proliferator-activated receptor γ; Nur77: orphan nuclear receptor; VEGF: vascular endothelial growth factor; ET-1: endothelin 1; TRPC1: classical transient receptor potential channel 1; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase 1; IL-1: interleukin 1; IL-6: interleukin 6; LDH: lactate dehydrogenase; EGLN1: egl-9 family hypoxia inducible factor 1; ENaC: epithelial sodium channel; GSH: glutathione; SOD: superoxide dismutase; ERK: extracellular regulated protein kinases; TGF-β: transforming growth factor beta; MMPs: matrix metalloproteinases; CLDN: claudin; OCLN: occludin; EPO: erythropoietin; GATA1: GATA binding protein 1.

    深入探讨 HIF-1 在高原病中的分子机制,有助于开发新的防治策略,提升高原病的诊疗水平。例如,通过抑制HIF-1的过度激活,可以减少其对靶基因的异常调控,从而缓解高原病的症状。此外,针对HIF-1下游信号通路的研究也可能为药物研发提供新的靶点。未来科学家们有望通过基因编辑、小分子抑制剂等手段,精准调控HIF-1的活性,帮助患者更好地适应高原环境,降低高原病的发生率和严重程度。

    HAPH是由长期暴露于高海拔环境引起的慢性疾病,其特征为持续的低氧状态导致的肺血管收缩、重塑及肺循环阻力增加。在严重情况下,患者可能发展为右心衰竭,甚至面临生命危险[37]。当人体暴露于高海拔地区时,大气中的氧气含量急剧下降,导致机体进入低氧状态。这种低氧环境会迅速激活HIF-1α的表达,进而引发一系列复杂的分子和细胞反应。在HAPH的早期阶段,HIF-1α的激活可以作为一种适应性反应,帮助机体应对低氧环境,但随着时间的推移,这种适应性反应逐渐转变为病理性的重塑过程[38]

    在缺氧条件下,HIF-1α的稳定性显著增强,通过与其他转录因子的相互作用,进一步放大了其对下游基因的调控作用。例如,HIF-1α可以与NF-κB等炎症相关转录因子形成复合物,共同调控促炎因子的表达[39],从而加剧HAPH的发展。此外,HIF-1α还可以通过调控线粒体功能,影响细胞的能量代谢。在缺氧条件下,HIF-1α会诱导糖酵解相关酶的表达,促使细胞从有氧呼吸转向无氧代谢,以维持能量供应[40]。然而,这种代谢转换虽然能在短期内满足细胞的能量需求,但从长远来看,却会导致线粒体功能障碍和氧化应激的增加,进一步损害肺血管内皮细胞的功能,加速HAPH的进展[41]

    有研究表明,在HAPH患者的肺组织中,HIF-1α表达显著上调,其下游靶基因如VEGF、PDGF等也呈现上调趋势,且这些变化与疾病的严重程度密切相关[42]。例如,一项研究通过构建HIF-基因敲除小鼠模型并进行缺氧暴露,发现HIF-1α在肺血管内皮细胞中的上调可诱导PDGF-B的表达,促进远端肺动脉的病理性肌化,并维持病理性远端小动脉平滑肌细胞(SMC)的生存和稳态[43]。进一步的体外实验表明,缺氧条件下,HIF-1α在SMC祖细胞中的稳定性增强,促进了其增殖和分化,强调了HIF-1α在肺血管重塑中的重要作用[44]

    类似的研究显示,使用模拟高海拔低氧环境的大鼠模型和低氧培养的肺动脉平滑肌细胞(pulmonary artery smooth muscle cells, PASMCs),结合间歇性短期复氧化处理,可以减弱缺氧诱导的PASMCs增殖,并逆转HIF-1α/NOX4/PPAR-γ轴的激活,从而减轻HAPH的进展[45]。此外,NLRC3在HAPH患者肺血管SMC中的表达下调,通过利用NLRC3基因敲除小鼠模型的进一步研究揭示,NLRC3缺失可激活IKK/NF-κB p65/HIF-1α信号通路,促进了PASMCs的增殖、人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVECs)的凋亡、迁移和炎症反应,进而加剧了血管重塑和HAPH的进展[46]

    在另一项研究中,将基因敲除小鼠模型暴露于10%氧气环境中,结合体外人类肺动脉内皮细胞(human pulmonary artery endothelial cells, HPAECs)和人类肺动脉平滑肌细胞(human pulmonary artery smooth muscle cells, HPASMCs)的缺氧培养,利用蛋白质组学分析发现,Otud6b的表达增加可激活HIF-1α。Otud6b是一种去泛素化酶,能够通过去除HIF-1α的泛素标记,增强其稳定性,从而延长其在细胞内的存在时间。在缺氧条件下,Otud6b的表达增加,导致HIF-1α的积累和活化,进而促进了内皮素-1(ET-1)和VEGF的表达,加剧了内皮细胞的损伤和血管重塑,推动HAPH的发展[47]。同时,另有研究表明,RhoA/ROCK信号通路的激活与HAPH的发生和发展密切相关,RhoA/ROCK信号通路是调节细胞骨架重排和细胞收缩的重要途径,能够通过激活肌球蛋白轻链激酶(MLCK)和肌球蛋白磷酸酶靶向亚基1(MYPT1),促进肌动蛋白纤维的聚合和收缩蛋白的磷酸化,导致血管平滑肌细胞的收缩和血管壁的增厚[48]。在慢性缺氧条件下,小鼠肺动脉中RhoA和ROCK的表达上调,而抑制RhoA/ROCK信号通路可显著降低HIF-1α的表达,减少TRPC1和TRPC6通道蛋白的表达和功能,进而减少细胞内Ca2+流入,抑制肺动脉重塑和血管收缩,减缓HAPH的进展[49]

    HAPE是一种由过度缺氧性肺血管收缩引起的非心源性肺水肿,是高原病中致死率较高的一种,其病理机制复杂,与HIF-1α的异常表达密切相关[50]。研究表明,血液中HIF-1α水平的升高是HAPE风险的重要生物标志物,具有出色的诊断性能(AUC=0.87),当阈值设定为86.45 pg/mL时,其敏感性和特异性分别为80%和81.45%[51]

    在体外实验中,将HUVECs暴露于缺氧条件下,内皮细胞通过NF-κB依赖的过程自分泌产生肿瘤坏死因子-α(TNF-α),进而激活HIF-1α,最终导致VEGF的产生,促进血管生成 [52] 。在另一项研究中,大鼠被放置在一个特殊的低压舱内,模拟7620 m的海拔高度,发现低氧环境激活HIF-1α信号传导,促进了促炎细胞因子如IL-1β、IL-6、TNF-α和VEGF的产生,这些细胞因子的大量释放,导致了肺部血管通透性的增加,液体开始渗入肺泡,最终引发了HAPE的形成和加重[53-54]

    网络药理学和分子对接研究表明,藏药高原安胶囊通过调控多种靶基因改善缺氧耐受性,主要作用于HIF-1信号通路,在HAPE的防治中显示出广泛应用前景[55]。研究人员利用计算机模拟技术,详细分析了高原安胶囊中的有效成分与HIF-1α及其下游靶点的结合模式。结果显示,高原安胶囊中的某些活性成分能够特异性地抑制HIF-1α的表达,减少促炎细胞因子的释放,从而降低HAPE的发生风险。此外,动物实验也表明接受高原安胶囊治疗的大鼠在模拟高海拔环境中表现出更低的HIF-1α水平,肺部炎症反应明显减轻,肺泡液清除率显著提高。研究人员通过对HAPE患者的肺组织样本进行RNA测序,转录组分析显示,HIF-1α在HAPE中通过影响BNIP3LVEGFAANGPTL4EGLN1等低氧相关基因的表达,发挥核心作用[56]。特别是EGLN1基因,其编码的蛋白PHD2是HIF-1α的主要调节因子之一。在HAPE患者中,EGLN1的表达水平显著下降,导致HIF-1α的稳定性和活性增强,进而加剧了肺部损伤。此外,研究人员通过对HAPE患者的血液样本进行全基因组甲基化分析,发现了多个与HIF-1α信号通路相关的CpG位点的异常甲基化。这些位点的甲基化状态不仅影响了HIF-1α的表达水平,还与其他关键基因的表达调控密切相关。深度测序研究揭示,EGLN1的CpG位点甲基化分布降低和HIF-1α的CpG位点甲基化分布升高会增加HAPE的风险,两者CpG位点的差异甲基化分布与血浆PHD2水平和外周血氧饱和度(SpO2)水平相关,并参与HIF-1α的信号传导[57]

    体外实验中,原代肺泡上皮细胞(AEC)暴露于低氧环境(1.5%O2)24 h,结果显示缺氧诱导的HIF-1α通过抑制上皮钠通道(ENaC)的活性,显著降低ENaC通道的开放频率,减少钠离子的重吸收,与此同时,细胞内的水分积聚增多,肺泡液清除率下降,这使得肺泡内的液体无法及时排出,进一步加重了肺泡的充水现象,影响肺泡气体交换。严重的低氧血症可能进一步增强缺氧性肺血管收缩,导致HAPE的发生[58]。类似地,雄性Sprague Dawley大鼠暴露于模拟7620 m海拔高度6 h,缺氧诱导的HIF-1α/VEGF表达增加了脂质过氧化,降低了抗氧化剂(GSH、GPX和SOD)、Nrf2和HO-1的水平,导致肺表面活性物质氧化及肺泡结构破坏,使得肺泡更容易塌陷。通过对大鼠进行抗氧化剂预处理,研究人员发现,抗氧化剂能够有效减轻肺组织的氧化损伤,降低HAPE的发生率,提示抗氧化治疗可能是HAPE防治的一个重要方向[59]

    HACE是一种潜在致命的脑病,与长时间暴露于高原低压缺氧环境密切相关。HACE的发生机制涉及血管源性水肿和细胞毒性水肿的协同作用,导致脑内液体积聚,进而引发脑水肿[60-61]。研究表明,HIF-1在HACE中扮演了关键角色。通过构建特异性敲除血管周细胞中HIF-1α的小鼠模型,并使其暴露于8% O₂低氧环境96 h,研究发现HIF-1α的激活显著上调了VEGF、TGF-β和MMPs的表达,这些分子共同作用增加了血脑屏障(blood-brain barrier, BBB)的通透性,促进了脑水肿的发生[62]

    脑血管内皮细胞是BBB的重要组成部分,其高表达的紧密连接蛋白(如claudin、occludin)和黏附连接蛋白(如cadherin),以及多种转运蛋白,赋予了其“看门人”的功能,严格调控物质的跨膜运输[63]。在一项实验中,研究人员将大鼠脑微血管内皮细胞暴露于1%O₂的低氧环境中,模拟高原条件,结果表明低氧迅速诱导了HIF-1α的稳定表达,破坏了紧密连接蛋白的完整性,并增加了酪氨酸磷酸化水平,最终导致BBB通透性增加[64]。此外,有研究表明,使用模拟高海拔条件的低压低氧舱构建HACE动物模型时,人类脱落乳牙来源的间充质干细胞(stem cells from human exfoliated deciduous teeth, SHED)治疗可以通过抑制HIF-1α介导的ERK信号通路,抑制小胶质细胞的M1型极化并促进M2型极化,从而有效缓解HACE的症状[65]

    还有多种其他的高原病的发生可能与HIF-1的表达水平相关。其中最常见的是慢性高山病(CMS),是由长期高海拔低氧环境引发的疾病。HIF-1表达和CMS的发生紧密相关,其主要特征为红细胞过度增生,导致血细胞比容显著升高,对高原居民健康构成严重威胁[66]。研究表明,黄芪可缓解低氧诱导的CMS症状,在小鼠模型中表现出显著疗效。网络药理学分析显示,黄芪中的活性成分可以通过下调HIF-1α的表达水平,影响EPO、VEGF以及Gata-1的表达,导致外周血中红细胞和血红蛋白的数量减少,从而抑制造血干细胞向红细胞系分化[67],黄芪可能成为缓解CMS症状的有效手段。

    另一项针对藏族人群的研究进一步揭示了CMS的分子机制。该研究招募了141名参与者,包括70名CMS患者和71名健康对照,通过对529个与氧气代谢和红细胞调节相关的基因进行靶向测序,发现PI3K-AKT、JAK-STAT和HIF-1信号通路在CMS的发生发展中起关键作用。这些通路的异常激活可能与红细胞过度增生及CMS的病理过程密切相关[68]。这些研究结果为理解CMS的遗传基础提供了重要线索,并为开发新的治疗策略奠定了理论基础。

    高原病的预防和治疗是一个综合性过程,涉及逐渐适应海拔、健康教育、心理干预、生活方式调整以及药物治疗等多个方面。预防措施包括逐渐增加海拔高度以避免急性高原反应,保持充足的水分和营养摄入,避免剧烈运动和酒精摄入,以及在必要时使用药物如乙酰唑胺和地塞米松来预防或减轻症状 [69] 。对于急性高原病的治疗,降低海拔、吸氧和药物治疗是关键,而慢性高原病则可能需要长期氧疗和生活方式的调整[70-71]。紧急情况下,快速降低海拔至低地是挽救生命的重要措施[72]。总体而言,高原病的防治需要个体化的策略,结合非药物和药物疗法,以及在不同严重程度下的适当处理。

    在高原病的治疗中,缺氧是一个重要的生理挑战,而HIF-1在调节身体对缺氧反应中扮演着关键角色。目前,已开发出多种HIF-1抑制剂,通过多靶点、多机制的联合应用,显著提高了对HIF-1的抑制效果,并在肿瘤、缺氧性疾病等领域展现出潜在的临床应用价值。主要类型的HIF-1抑制剂包括:

    如吖啶黄(Acriflavine)、拓扑替康(Topotecan)、棘霉素(Echinomycin)、YC-1、PX-478和HI-102等,这些化合物可以直接抑制HIF-1α蛋白的表达或活性,有效的阻断HIF-1介导的转录过程,进而抑制下游靶基因的表达,减少细胞在缺氧条件下的适应性反应[73-77]

    如姜黄素(curcumin)、白藜芦醇(resveratrol)、表没食子儿茶素没食子酸酯(EGCG)和槲皮素(quercetin)等,这些天然化合物不仅具有抗氧化和抗炎作用,还能通过调节HIF-1α的上游信号通路,如PI3K/Akt、MAPK等,间接抑制其转录功能,从而抑制HIF-1的活性[78-81]

    如雷帕霉素(rapamycin)和LY294002(PI3K/Akt/mTOR通路抑制剂)、U0126和PD98059(MEK抑制剂)、格尔德霉素(Geldanamycin)和17-AAG(HSP90抑制剂)等,这些药物通过特异性靶向HIF-1α的上游信号分子,阻止其磷酸化,从而抑制HIF-1的激活和功能[76,82-83]。这类抑制剂在多种肿瘤模型中表现出良好的抗增殖和抗血管生成效果。

    如2-甲氧基雌二醇(2ME2),这是一种内源性雌二醇代谢物,能够通过抑制HIF-1α的积累和转录活性,降低与血管生成和细胞存活相关的HIF-1靶基因的表达。此外,切托明(Chetomin)可通过干扰HIF-1α与辅激活因子p300的结合,抑制其转录功能;博雷佐米布(Bortezomib)则通过促进HIF-1α的泛素化降解,进一步增强其抑制效果[84-85]

    综上所述,高原病的防治不仅需要关注非药物和药物疗法的个体化策略,还应考虑HIF-1抑制剂等新兴治疗方法的潜力,这些治疗方法可能为高原病的治疗提供新的治疗途径。

    HIF-1是维持氧气稳态的关键调控因子,在高海拔适应中发挥重要作用。在缺氧条件下,HIF-1α亚基得以稳定并转移到细胞核内,与HIF-1β结合形成异二聚体,进而结合到HRE,激活一系列靶基因的表达。这些靶基因包括EPOVEGFGLUT和糖酵解酶等,它们共同促进氧供给和代谢适应。HIF-1在高原病的发生发展中扮演核心角色,成为研究和预防该类疾病的重要靶点。研究表明,HIF-1在不同人群中的表达和功能存在显著差异,尤其是在对缺氧敏感的亚群中。深入探讨这些差异,有助于揭示高原病的发病机制,并为个性化防治提供理论依据。此外,开发天然或合成的无毒化合物以抑制HIF-1活性,可能为预防缺氧诱导的高原病提供新的策略。这些化合物不仅可以调节HIF-1的过度激活,还能通过影响其下游信号通路,减轻高原病的症状。未来的研究应聚焦于HIF-1信号通路的精细调控机制,特别是其在不同组织和细胞类型中的动态变化。这将有助于理解HIF-1如何在复杂生理环境中协调多种生物学过程。同时,针对特定亚群的个性化防治措施也应成为研究的重点。例如,通过对高原居住者和短期暴露者的比较研究,可以更好地了解HIF-1在不同时间尺度上的作用,从而优化预防和治疗方案。

    此外,HIF-1与其他信号通路之间的相互作用也是值得深入探讨的领域。HIF-1不仅参与缺氧应答,还与炎症、免疫反应和细胞凋亡等多种生物学过程密切相关。因此,解析HIF-1与其他通路的交叉调控机制,可能为高原病的综合防治提供新的思路。例如,HIF-1与NF-κB通路的相互作用可能在HAPE和HACE的病理过程中起到关键作用,进一步研究这一机制有望为临床治疗提供新的靶点。总之,HIF-1在高海拔适应和高原病发生发展中的重要性不容忽视。未来的研究应继续深化对其调控机制的理解,并探索基于HIF-1的个性化防治策略,以期为高原病的预防和治疗提供更为有效的手段。

    *    *    *

    作者贡献声明 周志豪与孙凡丽负责论文构思、数据审编、调查研究和初稿写作,江秉华负责论文构思、数据审编、调查研究、经费获取和审读与编辑写作。所有作者已经同意将文章提交给本刊,且对将要发表的版本进行最终定稿,并同意对工作的所有方面负责。

    Author Contribution  ZHOU Zhihao and SUN Fanli are responsible for conceptualization, data curation, investigation, and writing--original draft. JIANG Binghua is responsible for conceptualization, data curation, investigation, funding acquisition, and writing--review and editing. All authors consented to the submission of the article to the Journal. All authors approved the final version to be published and agreed to take responsibility for all aspects of the work.

    利益冲突  所有作者均声明不存在利益冲突

    Declaration of Conflicting Interests All authors declare no competing interests.

  • 图  1   HIF-1α感知氧气的机制

    Figure  1.   Mechanism of HIF-1α expression in response to oxygen

    HIF-1α: hypoxia-inducible factor 1 alpha; HIF-1β: hypoxia-inducible factor 1 beta; bHLH: basic helix-loop-helix; PAS-1/2: Per-ARNT-Sim domain-1/2; TAD: transcription activation domain; PHD: prolyl hydroxylase domain; VHL: Von Hippel-Lindau; HRE: hypoxia response element.

    图  2   HIF-1的表达调控机制

    Figure  2.   Regulatory mechanism of HIF-1 expression

    Ni: nickel; Cr: chromium; Cd: cadmium; As: arsenic; Zn: zinc; U: uranium; PHD: prolyl hydroxylase domain; PI3K: phosphoinositide 3-kinase; mTOR: mammalian target of rapamycin; EGF: epidermal growth factor; V-SRC: virus-sarcoma;NF-κB: nuclear factor kappa-B; NOX4: nicotinamide adenine dinucleotide oxidase 4; Ref-1: redox factor-1;IGF-1R: insulin-like growth factor 1; IRS1: insulin receptor substrate 1; ING4: inhibitor of growth-4; HIF1A-AS2: HIF1A antisense RNA 2; PKA-AS1: PKA antisense RNA 1.

    图  3   HIF-1参与多种高原病的发生

    Figure  3.   HIF-1 is involved in the pathogenesis of many types of high-altitude diseases

    PDGF: platelet-derived growth factor; NOX4: nicotinamide adenine dinucleotide oxidase 4; PPAR-γ: peroxisome proliferator-activated receptor γ; Nur77: orphan nuclear receptor; VEGF: vascular endothelial growth factor; ET-1: endothelin 1; TRPC1: classical transient receptor potential channel 1; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase 1; IL-1: interleukin 1; IL-6: interleukin 6; LDH: lactate dehydrogenase; EGLN1: egl-9 family hypoxia inducible factor 1; ENaC: epithelial sodium channel; GSH: glutathione; SOD: superoxide dismutase; ERK: extracellular regulated protein kinases; TGF-β: transforming growth factor beta; MMPs: matrix metalloproteinases; CLDN: claudin; OCLN: occludin; EPO: erythropoietin; GATA1: GATA binding protein 1.

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  • 收稿日期:  2024-09-06
  • 修回日期:  2024-11-14
  • 发布日期:  2024-11-19
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