自噬在严重烧伤早期心肌损害中的作用及其机制研究
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摘要
目的
严重烧伤早期，在毛细血管通透性增加造成血容量显著下降之前，就已出现了明显的心肌损害。这种即早出现的心肌损害，不仅诱发或加重休克，而且是其它脏器如肝、肾、肠等缺血缺氧性损害的重要因素之一。但严重烧伤早期心肌损害的机制尚不完全清楚。自噬是真核细胞高度保守的自我保护机制，它通过对细胞内长寿命蛋白质、细胞器等进行消化降解，以实现氨基酸、脂肪酸等原料的循环利用。自噬也会导致细胞死亡，自噬性细胞死亡被称第二型程序性细胞死亡，是区别于坏死和凋亡的第三种细胞死亡方式。本研究旨在观察自噬在严重烧伤后心肌损害中的作用，并探讨在缺氧和/或Ang II刺激条件下自噬发生的调控机制。
材料和方法
1．以30%III度烫伤S-D大鼠为烧伤模型，以颈总动脉插管的方式检测烧伤后1小时、3小时、6小时和12小时活体心功能；同样时相点剖取大鼠心脏，以Langendorff装置行游离心脏体外灌流，检测体外心功能的变化。
2．各时相点留取心肌标本，提取总蛋白，行免疫印迹实验（Western Blotting）观察自噬标志性蛋白质LC3和Beclin1表达，以反映烧伤后心肌细胞自噬活性的变化。
3．对各时相点心肌组织标本行免疫荧光染色，观察烧伤后心肌细胞自噬性死亡（Ubiquitin标记）、凋亡（TUNEL标记）和坏死（C5b9标记）的变化。
4．以加入自噬激活剂或抑制剂的K-H液对烧伤大鼠游离心脏进行灌流，观察心功能的变化、心肌细胞自噬活性和自噬性细胞死亡的变化；同样以ACEI、AT1受体阻滞剂和ROS抑制剂来灌流游离心脏，观察其对自噬和心功能的影响。
5．原代培养S-D大鼠乳鼠心肌细胞，以缺氧和/或Ang II刺激来模拟烧伤后心肌细胞的应激条件，首先以透射电镜确认此条件下心肌细胞自噬活性的变化。
6．再以DHE活细胞荧光染色来半定量缺氧和/或Ang II刺激条件下心肌细胞ROS含量；以MDC活细胞荧光染色以及Western Blotting方法来确定心肌细胞自噬活性的改变。抑制ROS后观察以上指标变化，明确ROS与自噬间的关系。
7．以ELISA的方法来定量缺氧和/或Ang II刺激条件下心肌细胞内PKCδ和PKCε表达量的变化，同时确认重组慢病毒siRNA调低PKCε表达的效果。
8．通过PKCδ特异性的抑制剂及PKCε慢病毒siRNA干扰，观察病缺氧和/或Ang II刺激条件下心肌细胞ROS含量和自噬活性的变化，明确PKCδ和PKCε在这些应激条件下的作用。
结果
1．严重烧伤后早期心肌细胞自噬活性即显著增强，伤后3小时，即可发现心肌细胞自噬性死亡的组织学变化，早于细胞凋亡和细胞坏死，并且其发生率高于凋亡，表明自噬性细胞死亡是烧伤后心肌细胞死亡的重要途径。
2．在游离心脏体外灌流模型上对自噬施加正负调控的结果表明，在烧伤后的特定时间段（伤后3小时以后），心肌细胞自噬可能发挥有害作用，抑制自噬能减少心肌细胞自噬性死亡数量，增强心功能。
3．30%III度烧伤后6小时大鼠游离心脏灌流实验提示，在烧伤这种应激条件下，AngII和ROS可能是诱发和激活心肌细胞自噬的重要信号转导分子。
4．体外培养的乳鼠心肌细胞，在缺氧和/或Ang II刺激条件下自噬活性增强，同时伴有细胞内ROS含量升高。
5．无论是在缺氧和/或Ang II刺激条件下，抑制ROS都能明显抑制原代培养心肌细胞自噬活性，提示ROS可能是诱导自噬的直接原因。
6．以特异性的抑制剂Rottlerin抑制PKCδ活性，在缺氧或混合Ang II刺激条件下细胞ROS含量和自噬活性明显降低，而在单独Ang II刺激条件下对ROS和自噬无影响。该结果提示，心肌细胞缺氧诱导自噬可能是经由PKCδ而发挥作用，但PKCδ不参与调控AngII诱导自噬的过程。
7．通过慢病毒载体对心肌细胞PKCε进行siRNA干扰，致使其PKCε蛋白表达水平降低，发现调低PKCε在Ang II刺激或合并缺氧的条件下能使心肌细胞ROS含量下降并调低自噬活性，而在单纯缺氧条件下对ROS和自噬活性无影响。这提示PKCε是Ang II诱导心肌细胞自噬的重要介导分子。
结论
严重烧伤后，缺氧和Ang II刺激都能使心肌细胞内ROS含量升高，ROS通过氧化损伤胞内大分子蛋白质以及破坏线粒体而诱发细胞自噬增强。然而，两者是通过不同信号通路来发挥作用的：单纯缺氧诱导自噬可能依赖PKCδ/NADPH oxidase/ROS途径，而Ang II则首先与AT1受体结合，然后激活下游的PKCε/NADPH oxidase/ROS而增强细胞自噬活性。烧伤初期，机体尚能通过代偿机制而保持内环境的相对稳定，在适度缺氧和/或适度Ang II刺激条件下，被激活的心肌细胞自噬发挥保护作用，同时自噬本身也是代偿机制的重要组成部分。但随着缺氧和Ang II刺激条件的持续，心肌细胞进入失代偿期，此时的自噬增强则有害，可导致自噬性细胞死亡数量增加，成为烧伤早期心肌损害/心功能降低的重要机制。
Background: The prompt myocardial damage and cardiac dysfunction are key pointsto initiate the ischemic/hypoxic injuries to other organs at early stages in severe burns.However, the exact mechanisms of the prompt myocardial damage are still not totallyclarified. Autophagy acts as a highly conservative mechanism of self-protection bydigesting the long-life proteins and damaged organelles to recycle nutrients in eukaryocytes.And the autophagic cell death is described as a second type of programmed cell deathwhich differs from apoptosis and necrosis. The present study is designed to investigate theroles of autophagy in the myocardial damage after severe burns and further to explore theregulation mechanisms of autophagy under the conditions of hypoxia and Ang IIstimulation.
Methods: Firstly, based on the burn model of30%TBSA third degree scald rats, wedetected the cardiac function in vivo and in vitro on a Langendorff apparatus at1,3,6, and12h post-burn. Western blotting was used to determine the expressions of LC3and Beclin1proteins which indicated the autophagic activity in myocardium after burns.Immunofluorescence staining was performed to label myocardial cell death includingautophagic cell death (ubiquitin labeling), apoptosis (TUNEL labeling), and oncosis (C5b9labeling). For the perfusion hearts isolated at6h post-burn, the autophagy activator andinhibitor, ACEI, AT1blocker, and ROS inhibitor were added to the K-H perfusion bufferand the following changes in myocardial autophagy and cardiac function were thendetermined. Further, transmission electron microscope was used to confirm the changes ofautophagic status in the cultured neonatal cardiomyocytes of S-D rats under hypoxia and/orAng II stimulation. Based on the cultured cell model, in vivo fluorescence staining of DHE(ROS detection) and MDC (autophagosome vacuole labeling) were performed to explorethe relationship between ROS and autophagy in the setting of ROS inhibition. Expression of PKCδ and PKCε in the cultured cardiomyocytes under stress of hypoxia and Ang II werequantified by an ELISA method. Using the same method, we confirmed the downregulationeffect of the recombined lentivirus with siRNA on PKCε. In order to shed light on the rolesof PKCδ and PKCε under these stress conditions, we investigated the changes of cellularROS and autophagy in the setting of PKCδ specific inhibition and PKCε RNA interferingby the recombined lentivirus.
Results: Myocardial autophagy was remarkably enhanced early after severe burns.Autophagic cardiomyocyte death was found3h post-burn, preceding apoptosis andnecrosis with a higher incidence rate, which indicated that autophagic cell death play animportant role in cardiomyocyte loss in severe burns. At the decompensation stage, e.g.after3h post-burn, autophagy was detrimental and its inhibition resulted in improvement ofheart function. ROS and Ang II participated in arousing myocardial autophagy. Resultsfrom cultured cardiomyocytes also indicated that autophagy was significantly enhancedunder the conditions of hypoxia and Ang II stimulation, accompanied with the increase ofcellular ROS. Inhibition of ROS caused to a sharp decrease of autophagic activity,suggesting that ROS may induce myocardial autophagy in a direct way. Under hypoxia orcombined with Ang II stimulation, PKCδ specific inhibition decreased cellular ROS contentand autophagic activity, while with Ang II stimulation alone, inhibition of PKCδ did not affectROS and autophagy. Interestingly, downregulation of PKCε by siRNA interfering decreased ROSamount and autophagic activity under Ang II stimulation or combined hypoxia, but it failed withhypoxia alone.
Conclusion: In severe burns, hypoxia and Ang II stimulation cause to an increase of ROSin cardiomyocytes, and ROS enhance autophagy by damage to cellular macromolecules andorganelles. However, hypoxia induces autophagy through a PKCδ/NADPH oxidase/ROSapproach, while Ang II inducing autophagy depends on an AT1/PKCε/NADPHoxidase/ROS way. Before decompensation, the internal environment can be maintained in arelatively stable level. Under moderate hypoxia and Ang II stimulation, autophagy isaroused to protect cardiomyocytes, which is also a part of cellular compensationmechanisms. However, with the hypoxia prolonged and Ang II accumulated, the internalenvironment homeostasis is broken, and autophagy turns to be detrimental, causingautophagic cell death and being an important mechanism of the prompt myocardial damage and cardiac dysfunction soon after a severe burn.
严重烧伤早期，在毛细血管通透性增加造成血容量显著下降之前，就已出现了明显的心肌损害。这种即早出现的心肌损害，不仅诱发或加重休克，而且是其它脏器如肝、肾、肠等缺血缺氧性损害的重要因素之一。但严重烧伤早期心肌损害的机制尚不完全清楚。自噬是真核细胞高度保守的自我保护机制，它通过对细胞内长寿命蛋白质、细胞器等进行消化降解，以实现氨基酸、脂肪酸等原料的循环利用。自噬也会导致细胞死亡，自噬性细胞死亡被称第二型程序性细胞死亡，是区别于坏死和凋亡的第三种细胞死亡方式。本研究旨在观察自噬在严重烧伤后心肌损害中的作用，并探讨在缺氧和/或Ang II刺激条件下自噬发生的调控机制。
材料和方法
1．以30%III度烫伤S-D大鼠为烧伤模型，以颈总动脉插管的方式检测烧伤后1小时、3小时、6小时和12小时活体心功能；同样时相点剖取大鼠心脏，以Langendorff装置行游离心脏体外灌流，检测体外心功能的变化。
2．各时相点留取心肌标本，提取总蛋白，行免疫印迹实验（Western Blotting）观察自噬标志性蛋白质LC3和Beclin1表达，以反映烧伤后心肌细胞自噬活性的变化。
3．对各时相点心肌组织标本行免疫荧光染色，观察烧伤后心肌细胞自噬性死亡（Ubiquitin标记）、凋亡（TUNEL标记）和坏死（C5b9标记）的变化。
4．以加入自噬激活剂或抑制剂的K-H液对烧伤大鼠游离心脏进行灌流，观察心功能的变化、心肌细胞自噬活性和自噬性细胞死亡的变化；同样以ACEI、AT1受体阻滞剂和ROS抑制剂来灌流游离心脏，观察其对自噬和心功能的影响。
5．原代培养S-D大鼠乳鼠心肌细胞，以缺氧和/或Ang II刺激来模拟烧伤后心肌细胞的应激条件，首先以透射电镜确认此条件下心肌细胞自噬活性的变化。
6．再以DHE活细胞荧光染色来半定量缺氧和/或Ang II刺激条件下心肌细胞ROS含量；以MDC活细胞荧光染色以及Western Blotting方法来确定心肌细胞自噬活性的改变。抑制ROS后观察以上指标变化，明确ROS与自噬间的关系。
7．以ELISA的方法来定量缺氧和/或Ang II刺激条件下心肌细胞内PKCδ和PKCε表达量的变化，同时确认重组慢病毒siRNA调低PKCε表达的效果。
8．通过PKCδ特异性的抑制剂及PKCε慢病毒siRNA干扰，观察病缺氧和/或Ang II刺激条件下心肌细胞ROS含量和自噬活性的变化，明确PKCδ和PKCε在这些应激条件下的作用。
结果
1．严重烧伤后早期心肌细胞自噬活性即显著增强，伤后3小时，即可发现心肌细胞自噬性死亡的组织学变化，早于细胞凋亡和细胞坏死，并且其发生率高于凋亡，表明自噬性细胞死亡是烧伤后心肌细胞死亡的重要途径。
2．在游离心脏体外灌流模型上对自噬施加正负调控的结果表明，在烧伤后的特定时间段（伤后3小时以后），心肌细胞自噬可能发挥有害作用，抑制自噬能减少心肌细胞自噬性死亡数量，增强心功能。
3．30%III度烧伤后6小时大鼠游离心脏灌流实验提示，在烧伤这种应激条件下，AngII和ROS可能是诱发和激活心肌细胞自噬的重要信号转导分子。
4．体外培养的乳鼠心肌细胞，在缺氧和/或Ang II刺激条件下自噬活性增强，同时伴有细胞内ROS含量升高。
5．无论是在缺氧和/或Ang II刺激条件下，抑制ROS都能明显抑制原代培养心肌细胞自噬活性，提示ROS可能是诱导自噬的直接原因。
6．以特异性的抑制剂Rottlerin抑制PKCδ活性，在缺氧或混合Ang II刺激条件下细胞ROS含量和自噬活性明显降低，而在单独Ang II刺激条件下对ROS和自噬无影响。该结果提示，心肌细胞缺氧诱导自噬可能是经由PKCδ而发挥作用，但PKCδ不参与调控AngII诱导自噬的过程。
7．通过慢病毒载体对心肌细胞PKCε进行siRNA干扰，致使其PKCε蛋白表达水平降低，发现调低PKCε在Ang II刺激或合并缺氧的条件下能使心肌细胞ROS含量下降并调低自噬活性，而在单纯缺氧条件下对ROS和自噬活性无影响。这提示PKCε是Ang II诱导心肌细胞自噬的重要介导分子。
结论
严重烧伤后，缺氧和Ang II刺激都能使心肌细胞内ROS含量升高，ROS通过氧化损伤胞内大分子蛋白质以及破坏线粒体而诱发细胞自噬增强。然而，两者是通过不同信号通路来发挥作用的：单纯缺氧诱导自噬可能依赖PKCδ/NADPH oxidase/ROS途径，而Ang II则首先与AT1受体结合，然后激活下游的PKCε/NADPH oxidase/ROS而增强细胞自噬活性。烧伤初期，机体尚能通过代偿机制而保持内环境的相对稳定，在适度缺氧和/或适度Ang II刺激条件下，被激活的心肌细胞自噬发挥保护作用，同时自噬本身也是代偿机制的重要组成部分。但随着缺氧和Ang II刺激条件的持续，心肌细胞进入失代偿期，此时的自噬增强则有害，可导致自噬性细胞死亡数量增加，成为烧伤早期心肌损害/心功能降低的重要机制。
Background: The prompt myocardial damage and cardiac dysfunction are key pointsto initiate the ischemic/hypoxic injuries to other organs at early stages in severe burns.However, the exact mechanisms of the prompt myocardial damage are still not totallyclarified. Autophagy acts as a highly conservative mechanism of self-protection bydigesting the long-life proteins and damaged organelles to recycle nutrients in eukaryocytes.And the autophagic cell death is described as a second type of programmed cell deathwhich differs from apoptosis and necrosis. The present study is designed to investigate theroles of autophagy in the myocardial damage after severe burns and further to explore theregulation mechanisms of autophagy under the conditions of hypoxia and Ang IIstimulation.
Methods: Firstly, based on the burn model of30%TBSA third degree scald rats, wedetected the cardiac function in vivo and in vitro on a Langendorff apparatus at1,3,6, and12h post-burn. Western blotting was used to determine the expressions of LC3and Beclin1proteins which indicated the autophagic activity in myocardium after burns.Immunofluorescence staining was performed to label myocardial cell death includingautophagic cell death (ubiquitin labeling), apoptosis (TUNEL labeling), and oncosis (C5b9labeling). For the perfusion hearts isolated at6h post-burn, the autophagy activator andinhibitor, ACEI, AT1blocker, and ROS inhibitor were added to the K-H perfusion bufferand the following changes in myocardial autophagy and cardiac function were thendetermined. Further, transmission electron microscope was used to confirm the changes ofautophagic status in the cultured neonatal cardiomyocytes of S-D rats under hypoxia and/orAng II stimulation. Based on the cultured cell model, in vivo fluorescence staining of DHE(ROS detection) and MDC (autophagosome vacuole labeling) were performed to explorethe relationship between ROS and autophagy in the setting of ROS inhibition. Expression of PKCδ and PKCε in the cultured cardiomyocytes under stress of hypoxia and Ang II werequantified by an ELISA method. Using the same method, we confirmed the downregulationeffect of the recombined lentivirus with siRNA on PKCε. In order to shed light on the rolesof PKCδ and PKCε under these stress conditions, we investigated the changes of cellularROS and autophagy in the setting of PKCδ specific inhibition and PKCε RNA interferingby the recombined lentivirus.
Results: Myocardial autophagy was remarkably enhanced early after severe burns.Autophagic cardiomyocyte death was found3h post-burn, preceding apoptosis andnecrosis with a higher incidence rate, which indicated that autophagic cell death play animportant role in cardiomyocyte loss in severe burns. At the decompensation stage, e.g.after3h post-burn, autophagy was detrimental and its inhibition resulted in improvement ofheart function. ROS and Ang II participated in arousing myocardial autophagy. Resultsfrom cultured cardiomyocytes also indicated that autophagy was significantly enhancedunder the conditions of hypoxia and Ang II stimulation, accompanied with the increase ofcellular ROS. Inhibition of ROS caused to a sharp decrease of autophagic activity,suggesting that ROS may induce myocardial autophagy in a direct way. Under hypoxia orcombined with Ang II stimulation, PKCδ specific inhibition decreased cellular ROS contentand autophagic activity, while with Ang II stimulation alone, inhibition of PKCδ did not affectROS and autophagy. Interestingly, downregulation of PKCε by siRNA interfering decreased ROSamount and autophagic activity under Ang II stimulation or combined hypoxia, but it failed withhypoxia alone.
Conclusion: In severe burns, hypoxia and Ang II stimulation cause to an increase of ROSin cardiomyocytes, and ROS enhance autophagy by damage to cellular macromolecules andorganelles. However, hypoxia induces autophagy through a PKCδ/NADPH oxidase/ROSapproach, while Ang II inducing autophagy depends on an AT1/PKCε/NADPHoxidase/ROS way. Before decompensation, the internal environment can be maintained in arelatively stable level. Under moderate hypoxia and Ang II stimulation, autophagy isaroused to protect cardiomyocytes, which is also a part of cellular compensationmechanisms. However, with the hypoxia prolonged and Ang II accumulated, the internalenvironment homeostasis is broken, and autophagy turns to be detrimental, causingautophagic cell death and being an important mechanism of the prompt myocardial damage and cardiac dysfunction soon after a severe burn.
引文
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