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微血管状态调节中HIF-1信号通路的参与研究

更新时间:2020-07-03 08:25点击:

 摘    要: 低氧诱导因子1(HIF-1)与微循环功能中的血管新生以及炎性反应密切相关。研究表明,HIF-1通过调控下游血红素加氧酶及血管内皮生长因子影响血管生成。另外一方面,HIF-1通过调控白细胞介素8等细胞趋化因子影响血管炎症状态。目前急性心肌梗死及糖尿病中的微循环障碍越来越受到关注。深入了解微循环障碍的分子靶点,对微循环障碍的治疗尤为重要。HIF-1作为低氧状态下的适应性调节因子,通过影响血管新生、细胞凋亡、炎症及氧化应激等多种环节参与微循环功能调节。鉴于HIF-1在微循环障碍中的地位,以HIF-1为靶点的微循环障碍治疗越来越得到关注。
 
  关键词: 微循环障碍; 低氧诱导因子; 血管新生;
 
  Abstract: Hypoxia inducible factor-1( HIF-1) is closely related to angiogenesis and inflammation response in the pathological process. Previous studies showed that HIF-1 affects angiogenesis by regulating the expression of heme oxygenase and vascular endothelial growth factor. Additionally,HIF-1 affects vascular inflammation by regulating chemokines such as interleukin-8. With the increasing evidences of microvascular dysfunction induced by acute myocardial infarction and diabetes,the microvascluar dysfunction treatment is getting important.A deep insight of HIF-1 is crucial in therapy of microvascular dysfunction.
 
  Keyword: Microvascular dysfunction; Hypoxia inducible factor; Angiogenesis ;
 
  低氧通常通过多种机制促进血管稳态失衡,包括血栓形成、动脉粥样硬化、缺血再灌注损伤。缺血再灌注损伤、急性心肌梗死以及糖尿病缺血过程中的微循环障碍,与低氧诱导的炎性反应、氧化应激、血管新生和细胞生存密切相关。短期及中等程度的缺氧激活促生长及促增殖转导途径,而长期、持续的缺氧导致内皮细胞死亡[1,2,3]。在适度低氧状态下,转录因子低氧诱导因子1(HIF-1)作为适应性反应调节因子[4]。在缺氧及复氧状态下,HIF-1的转录活性及HIF-1α蛋白表达水平显着增加。在心肌缺血及心肌梗死状态下,HIF-1表达显着增加。HIF-1通过调节血管新生以及血管功能,并通过将氧化应激转化为糖酵解,改善局部微循环功能[5,6]。在长期及持续的缺氧状态下,HIF-1信号转导通路的过度激活可能参与内皮细胞死亡[7]。因此,HIF-1信号通路参与微血管状态的调节,并可以作为微循环功能改善的重要作用靶点。
 
  1、 HIF-1
 
  HIF-1是一种异二聚体,由HIF-1α及HIF-1β两种亚型组成[8,9]。其活性由HIF-1α的稳定性表达决定。脯氨酸羟化酶抑制剂和缺氧稳定HIF-1α,导致细胞核HIF-1α/β活性异二聚体增加[10]。活化的HIF-1通过多种靶基因参与细胞自噬、能量代谢、离子平衡、血管重塑、细胞增殖以及血管新生[11,12,13]。HIF-1α的减少降低了细胞能量,低氧诱导的糖酵解,以及血管新生。在低氧诱导的代偿反应中,HIF-1表达上调促进细胞生存,增加糖酵解酶基因的表达以及促血管生成因子的合成。而另外一方面,过度活化的HIF-1参与持续低氧诱导的内皮细胞死亡。
 2、 HIF-1与血管新生
 
  研究表明,低氧促进人微血管内皮细胞HIF-1α的核聚集,通过增加血管内皮生长因子(VEGF)的合成[14]及糖酵解代谢促进血管新生[15]。Tal等[16]研究发现,C端转录激活结构域的持续激活及HIF-1α分子的稳定性对于其介导的最佳转录活性和血管新生十分重要。Befani和Liakos[17]也证实,低氧可以促进微血管内皮整合蛋白基因的表达,从而增加微血管内皮细胞的迁移和毛细血管结构的形成。Kütscher等[18]研究发现,HIF-1α的过表达提高内皮前体干细胞的血管生成能力。低密度脂蛋白通过阻断HIF-1α/VEGF信号通路从而抑制低氧诱导的血管新生[19]。
 
  以骨髓间充质干细胞(BMMSC)转染编码突变型HIF-1α的载体(BMMSC-HIF),干预缺血再灌注损伤的羊,与对照组相比,在BMMSC-HIF治疗7 d及60 d后,动物心肌中小血管及毛细血管密度显着增加,BMMSC-HIF干预显着降低缺血再灌注损伤后梗死面积,改善左心室功能[20]。Ríos-Navarro等[21]研究发现,与对照组相比,猪冠状动脉结扎后90 min微循环密度显着降低,表现为梗死区CD+31表达及微循环密度显着减少。此外,微循环栓塞在再灌注1 min后发生。微循环密度减低和微循环栓塞在再灌注1周后达到高峰,于再灌注1个月后恢复。缺血后动物血清HIF-1α显着增加,冠状动脉血清促进体外培养冠状动脉内皮细胞的血管新生,而HIF-1α的阻断降低血清诱导的血管新生。
 
  高糖状态促发的低氧与缺血及微循环障碍密切相关,目前高糖对HIF-1表达的影响仍不明确,有研究表明,高糖状态降低了HIF-1α的稳定性[22],此外在高糖状态下,活性氧自由基被激活,是造成HIF-1α表达及转录减少的重要因素,从而使得低氧状态下HIF-1、VEGF及血红素加氧酶(HO-1)的表达减少,血管化减少,低氧诱导的血管新生的代偿反应减低[23,24]。高糖抑制HIF-1的机制涉及多个方面。氧离子和一氧化氮的相互作用,导致稳态一氧化氮浓度降低,从而降低一氧化氮诱导的HIF-1α聚集和激活。活性氧自由基通过激活脯氨酸羟化酶,增加泛素蛋白酶体活性降解HIF-1α。此外,肿瘤坏死因子途径,血管紧张素及胰岛素途径参与高糖状态下活性氧自由基对HIF-1α的抑制。Rho家族中小鸟苷酸三磷酸酶Rac1是细胞内氧化还原状态的关键因素,在低氧诱导的HIF-1α表达及转录中起重要作用[25]。Rac1促进HIF-1α的表达和转录激活,活性氧自由基通过抑制Rac1的表达进而抑制HIF-1的表达[25]。Marfella等[26]研究表明,糖尿病大鼠HIF-1α及Rac1 mRNA表达降低与缺血后梗死面积增加密切相关,而这些效应可以被抗氧化剂谷胱甘肽拮抗。目前,高糖状态对于HIF-1α的表达影响仍有不同的研究结果,在另外一些研究中,高糖能够促进细胞中HIF-1α的表达以及稳定性[27,28]。总之,高糖对HIF-1α的影响取决于不同的细胞类型及不同的组织类型。
 
  低氧状态可以触发HIF-1α/VEGF在内的一系列代偿机制。去乙酰化酶(SIRT)是位于HIF-1α上游调控血管新生的因子。缺乏SIRT3表达的内皮细胞,其低氧诱导的血管新生能力显着降低[29]。高糖状态下,SIRT1、HIF-1α的表达降低,减低了低氧触发的代偿反应。Mi等[30]以低氧/高糖刺激大鼠脑微血管内皮细胞,模拟糖尿病状态下的脑微循环障碍,结果表明,低氧及高糖状态下,脑微血管内皮增殖和迁移显着减少,二肽基肽酶4抑制剂拮抗低氧/高糖状态下被抑制的SIRT1、HIF-1α,从而通过SIRT1/HIF-1α/VEGF通路发挥改善脑微循环的作用。
 
  3 、HIF-1与炎症及氧化应激
 
  白细胞介素8(IL-8)介导血液中的中性粒细胞黏附、聚集、活化并迁移到炎症部位,参与心血管损伤过程[30,31]。血清IL-8升高可以预测冠状动脉介入手术后缺血复发,心肌梗死以及心源性死亡等不良心血管事件[31,32,33]。Ockaili等[34]研究表明,在体外,脯氨酸羟化酶抑制剂二甲基草酸甘氨酸上调人冠状动脉微血管内皮细胞HIF-1的表达,进而增加HO-1表达,降低细胞因子诱导的炎症细胞对人冠状动脉微循环内皮细胞的迁移。在体内,脯氨酸羟化酶抑制剂促进缺血心肌HO-1表达,降低血清IL-8水平,减轻缺血再灌注损伤兔模型心肌梗死面积。此外,HIF-1的活化降低缺血后心肌细胞黏附因子的表达,减轻缺血再灌注损伤及梗死面积[35]。在持续低氧状态下,HIF-1α的活化介导活性氧自由基对心脏微血管内皮的损伤。以siRNA抑制HIF-1α表达后,低氧诱导的活性氧自由基合成以及心脏微血管内皮凋亡显着降低[36]。
 
  4、 HIF-1与细胞自噬
 
  适度的细胞自噬促进细胞存活,过度的细胞自噬促进细胞凋亡。如前所述,持续低氧触发细胞死亡,而HIF-1参与细胞死亡信号转导途径。有研究表明,低氧通过诱导细胞过度自噬参与人脐静脉内皮细胞死亡,而低氧诱导的HIF-1的过表达参与低氧触发的细胞自噬小体形成。以siRNA敲除HIF-1的表达显着降低自噬小体的形成。此外,LC3在自噬小体的聚集和裂解由HIF-1的过表达而增加,但随着HIF-1的敲除降低。因此表明,在持续低氧状态下,HIF-1的过表达可以诱导过度的细胞自噬,从而降低细胞活性[7,13]。
 
  5、 HIF-1相关的微循环障碍治疗
 
  Xiao等[37]综述了在高糖状态下,以增加被抑制的HIF-1α为靶点的治疗方案。二甲基草酸甘氨酸可以增加糖尿病动物的血管新生。此外,去铁胺可以增加糖尿病缺血组织HIF-1α的转录活性以及VEGF表达。Feng等[38]发现金属硫蛋白可以降低高糖诱导的活性氧自由基的产生,减轻高糖对心肌HIF-1α蛋白表达的抑制。
 
  目前,中医药以及植物药在以HIF-1α为靶点的微循环治疗中得到关注。Chen等[39]研究发现,人参皂苷Rg1通过激活磷脂酰肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白信号转导通路,进而活化HIF-1α和下游的VEGF,促进血管新生。Wang等[40]研究表明,芪苈强心可以通过上调HIF-1α/VEGF信号转导途径,增加心脏微血管内皮细胞的增殖以及血管新生能力。Wang等[41]研究发现,浒苔多糖通过上调HIF-1α降低大鼠心肌梗死面积。Dai等[42]报道,芪参益气滴丸上调HIF-1α表达,进而提高大鼠微血管内皮血管新生能力。白藜芦醇增加HIF-1α表达,从而改善冠状动脉微循环功能[43]。
 
  除药物干预外,目前基础研究发现基因治疗在糖尿病动物中的治疗潜能,应用表达HIF-1α活性的复合物(Ad2/HIF-α/VP16)的腺病毒载体促进糖尿病大鼠侧支循环发育[24]。一种编码HIF-1α活性形式的腺病毒可以有效阻断高糖对VEGF蛋白表达的抑制[44]。Natarajan等[45]研究发现,以siRNA沉默小鼠脯氨酰-4-羟化酶-2表达,可以显着增加HIF-1的转录活性,改善小鼠微血管内皮功能,发挥心脏保护效应。
 
  6、 展望
 
  急性缺血与糖尿病状态均与低氧状态诱发的微循环障碍密切相关。HIF-1作为低氧状态下的适应性调节因子,通过影响血管新生、细胞凋亡、炎症及氧化应激等多种环节参与微循环功能调节。未来以HIF-1为靶点的治疗方式值得期待。
 
  利益冲突所有作者均声明不存在利益冲突
 
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