活性氧在慢性间歇性低压低氧适应性心脏保护形成中的作用和机制
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摘要
近年来，慢性间歇性低压低氧（chronic intermittent hypobaric hypoxia,CIHH）对心脏的保护作用及其机制的研究越来越引起人们的关注，已成为临床医学、航天医学和高原医学等领域的研究热点之一。CIHH的心脏保护作用主要包括抗缺血性损伤，抗心律失常和改善心肌退行性变三个方面。其作用机制可能与促进心肌毛细血管增生、增加冠脉血流量、激活ATP敏感性钾通道、抑制线粒体通透转换孔以及抑制心肌细胞膜肾上腺素能受体活性等因素有关。然而，这些研究均是针对CIHH处理后结果，即CIHH处理的最终效应所进行的。然而，有关CIHH适应性心脏保护作用的形成过程及机制尚未见报道。目前一致的观点认为，活性氧（reactiveoxygen species，ROS）具有保护性或损伤性双重作用，取决于ROS的数量。大量证据表明，ROS在低浓度时表现心脏保护作用，而高浓度时可导致心肌损伤作用。在培养的细胞或者整体动物水平，间歇性低氧均可刺激ROS产生，ROS可以通过介导信号转导机制而参与细胞和机体对间歇性低氧的适应性反应。已有研究证实核转录因子2－硫氧还蛋白1－低氧诱导因子1（Nrf2-Trx1-HIF-1α）信号途径介导由ROS诱导的间歇性低氧反应。但迄今为止，尚不清楚ROS是否参与CIHH适应性心脏保护的形成。
本研究旨在利用功能学、药物学、形态学和分子生物学等方法，在清醒动物整体、离体心脏和细胞分子水平动态观测CIHH适应性心脏保护的产生过程，并探讨ROS在其中的作用及其信号转导机制。研究分为以下三个部分：（1）利用生理信号遥测系统在清醒大鼠，动态观测CIHH适应形成过程中心血管活动的变化，并明确ROS在其中的作用。（2）证实Nrf2-Trx1-HIF1α分子途径及其主要的下游信号分子参与CIHH适应性心脏保护的形成，以及ROS在其中的作用。（3）明确CIHH对劲动脉体化学感受器敏感性的影响及ROS在其中的作用。Ⅰ活性氧参与清醒大鼠慢性间歇性低压低氧适应过程中心血管活动的动态变化
目的：CIHH具有心脏保护作用。大量证据表明低氧刺激产生的ROS可作为第二信使激发机体产生各种适应性反应。本研究旨在探讨CIHH适应过程中心血管活动的动态变化，以及ROS所起的作用。
方法：雄性SD大鼠随机分为四组：对照组（Control）、间歇性低压低氧处理组（CIHH）、抗氧化剂N－乙酰半胱氨酸处理组（Control+NAC）和应用N－乙酰半胱氨酸同时间歇性低压低氧处理组（CIHH+NAC）。CIHH组大鼠置于低压氧舱，给予42天模拟海拔5000米的低压低氧处理，每天6小时，其余时间处于常氧环境。Control+NAC组大鼠每天同一时间皮下注射NAC（80mg/kg）。CIHH+NAC组大鼠每天上仓前皮下注射NAC。Control组动物除不接受CIHH及NAC处理外，其余处理与CIHH大鼠相同。利用清醒动物生理信号遥测系统监测和分析大鼠在相应处理过程中平均动脉压（MAP）和心率（HR）的变化。应用ELISA方法测定左心室心肌组织中总超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化酶(GPX)、丙二醛(MDA)、类脂褐素(LFP)、蛋白羰基（PCL）和谷胱甘肽/二硫化谷胱甘肽的比值（GSH/GSSG）以监测心肌的氧化应激水平。
结果：
（1）CIHH大鼠心肌组织GSH-PX, MDA和LFP增加， GSH/GSSG降低（P<0.05），说明CIHH可提高心肌氧化应激水平和ROS的产生。
（2）CIHH不影响常氧状态下各组动物的MAP。但可以取消HR随年龄的降低（P<0.05）, NAC处理可部分阻断CIHH（P<0.05）这一作用。
（3）在低压低氧仓内，CIHH大鼠的MAP和HR出现适应性变化。早期（上仓1小时内）MAP和HR迅速升高达到峰值（P<0.05），而后逐渐降至最低。后期（上仓2至6小时内），MAP和HR相对稳定，呈平台水平。随CIHH处理时间的延长，MAP和峰值和平台值逐渐升高，达峰值的时间缩短（P<0.05）。HR的峰值逐渐降低，达峰值时间延长，而其平台值逐渐升高（P<0.05）。NAC处理可部分取消MAP和HR的适应性变化。
（4）给予急性常压低氧刺激，CIHH大鼠的MAP和HR升高幅度明显低于Control和Control+NAC组动物（P<0.05）。CIHH的这种抗低氧损伤作用至少可持续两周。NAC处理可部分阻断CIHH的此种作用（P<0.05）。
结论：本研究首次在清醒大鼠证实，CIHH过程产生的适量ROS参与CIHH过程中MAP和HR的适应性变化，并参与形成对抗急性低氧损伤的适应性保护机制。这种ROS依赖的适应性保护作用产生至少需要28天的CIHH所激发；而且在CIHH处理结束后，这种保护作用可持续至少两周。Ⅱ活性氧激活的Nrf2-Trx1-HIF1信号途径参与大鼠慢性间歇性低压低氧适应性心脏保护的形成
目的：探讨CIHH适应形成过程中Nrf2-Trx1-HIF1信号途径及其主要下游分子的激活，以及ROS在其中的作用。
方法：实验分组和CIHH处理同本研究第一部分。利用Western印迹和免疫组织化学的方法观测左心室心肌组织中Nrf2, Trx1, HIF1α, iNOS,VEGF and EPO的表达。
结果：
（1）CIHH过程中Nrf2-Trx1-HIF1信号途径被激活。CIHH处理28天后，Nrf2, Trx1, HIF1α表达明显增强（P<0.05）。CIHH大鼠左心室心肌组织中，Nrf2的核转位及Nrf2阳性细胞核数均明显增加（P<0.05）。NAC处理可部分阻断这些效应（P<0.05）。
（2）ROS可诱导Nrf2的核转位，即Nrf2的激活。CIHH处理1天后，心肌细胞核中Nrf2的表达明显升高，阳性细胞核数增加（P<0.05）。应用NAC抑制了Nrf2的表达（P<0.05），Nrf2的激活推迟至CIHH处理2天以后。
（3）ROS介导CIHH过程中Nrf2-Trx1-HIF1信号途径的激活。在心肌的全细胞提取物中，Nrf2在CIHH处理的2天后被激活（P<0.05），Trx1和HIF1在CIHH处理3天后被激活（P<0.05）。应用NAC抑制这些信号分子的表达，并将Nrf2、Trx1和HIF1信号分子激活时间分别推迟至CIHH处理后3天或5天。
（4）接受CIHH处理7或14天后，Nrf2-Trx1-HIF1信号途径的下游信号分子iNOS, VEGF和EPO的表达明显提高（P<0.05）。NAC可部分取消CIHH的上述作用（P<0.05）。
结论：Nrf2-Trx1-HIF1信号途径及其主要下游分子iNOS, VEGF和EPO在CIHH适应形成过程中被激活。iNOS, VEGF和EPO参与ROS依赖的CIHH适应性心脏保护机制。Ⅲ慢性间歇性低压低氧通过适应过程中产生的ROS易化颈动脉体化学感受器活动
目的：探讨CIHH对颈动脉体化学感觉器敏感性及呼吸频率（respiration frequency，RF）的影响，明确ROS在其中的作用。
方法：实验分组和CIHH处理同本研究第一部分。利用生理信号遥测系统记录和分析不同处理过程中清醒动物的呼吸频率变化。采用全神经双根铂丝电极记录法记录颈动脉体窦神经放电活动（carotid sinus nerveactivity，CSNA）。
结果：
（1）Control组大鼠的RF无明显年龄依赖性变化。各组大鼠的基础RF无统计学差异。
（2）在低压低氧仓内，CIHH大鼠的RF出现适应性变化。早期（上仓1小时内）RF迅速升高达到峰值，而后逐渐降至最低（P<0.05）。后期（上仓2至6小时内），RF相对稳定，呈平台水平。随CIHH处理时间的延长，RF的峰值逐渐降低，达峰值时间延长（P<0.05），而其平台值逐渐升高（P<0.05）。NAC处理可部分取消RF的适应性变化（P<0.05）。
（3）给予急性常压低氧刺激，CIHH大鼠的RF升高幅度明显低于Control和Control+NAC组动物（P<0.05）。CIHH的这种抗低氧损伤作用至少可持续两周（P<0.05）。NAC处理可部分阻断CIHH的此种作用（P<0.05）。
（4）与Control组大鼠相比，CIHH大鼠的CSNA对急性常压低氧刺激的反应明显增强（P<0.05）。NAC处理可完全取消CIHH的这一作用（P<0.05）。
结论：CIHH可诱导ROS依赖性的RF适应性变化和抗急性低氧效应，这种抗急性低氧损伤作用可以维持至少两周。CIHH增强颈动脉体化学感觉器对低氧的敏感性，这种易化作用是由CIHH适应过程中产生的ROS所介导。
In recent years, the cardioprotective effect of chronic intermittenthypobaric hypoxia (CIHH) has been recognized and attracts the publicattention more and more. The study on the mechanism of CIHHcardioprotection is a hot research topic in clinical medicine, space medicineand high altitude medicine. The cardioprotective effects of CIHH can bemainly summarized as protecting the heart against ischemia injury,antagonizing arrhythmia, and improving the degeneration of myocardial cell.Multiple mechanisms or pathways have been suggested to contribute to thecardioprotection of CIHH, such as increase of myocardial capillaryangiogenesis and coronary flow, activation of ATP-sensitive K+channels,inhibition of mitochondrial permeability transition pores and suppression ofthe adrenergic receptor activity on cardiac membrane. However, these findingsare the end effects of CIHH treatment, that is to say, the observations of thefinal results of CIHH. What happened during CIHH exposure and how theseprotective effects of CIHH produced have not been reported. It is generallyaccepted that reactive oxygen species (ROS) exert both deleterious andbeneficial actions depending on the amount of ROS. A lot of evidence showsthat ROS are protective at low level but detrimental at high level on the heart.Intermittent hypoxia increases ROS generation both in cell culture and inintact animals and ROS-mediated signaling mechanisms contribute to cellularand systemic responses to intermittent hypoxia. The nuclear factor erythroid2-related factor2-thioredoxin1-hypoxia-inducible factor (Nrf2-Trx1-HIF-1α)signal transduction pathway was identified as ROS-induced mechanisms inresponse to intermittent hypoxia. However, it is still unknown whether ROSplay a role in the dynamic formation of CIHH cardiac protection.
This study aimed to investigate the role of ROS in adaptivecardioprotection of CIHH dynamically and the mechanism underlying thisprocess in conscious rats through physiological, pharmacological,morphological and molecular biology techniques. Our study consisted of threeparts:(1) To clarify the dynamic changes of the cardiovascular activity and therole of ROS during CIHH adaptation.(2) To investigate the Nrf2-Trx1-HIF1αsignaling pathway with its main cardioprotective molecules in adaptivecardioprotection.(3) To determine the effect of CIHH on the sensitization ofcarotid body chemoreceptor.Ⅰ Reactive oxygen species contribute to the dynamic changes ofcardiovascular responses during the process of chronic intermittenthypobaric hypoxia adaptation in conscious rats
Objective: CIHH has been reported to have cardioprotective effects.Cumulating evidences have indicated that ROS released during hypoxia assecond messengers may help to trigger various adaptive responses. The aim ofpresent study was to clarify the dynamic changes of the cardiovascular activityand the role of ROS during CIHH adaptation in conscious rats
Methods: Adult male Sprague-Dawley rats were randomly divided intothe four groups: control group (Control), CIHH treatment group (CIHH),antioxidant N-Acetylcysteine group (Control+NAC), CIHH plus NACtreatment group (CIHH+NAC). The rats in CIHH group were exposed tohypoxia simulating5000m high altitude (oxygen11.1%) in a hypobaricchamber for42days,6hours each day. Control+NAC rats accepted ROSscavenger NAC（80mg/kg）injection subcutaneously each day for42days.CIHH+NAC rats were given NAC before the hypobaric hypoxic exposure.Control rats were living in the same environment as CIHH rats with freeaccess to food and water, except no CIHH and NAC treatment. The meanarterial pressure (MAP) and heart rate (HR) were recorded and analyzedcontinuously in conscious rats by using the PhysioTelTMTelemetry system.The activity of total superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), malondialdehyde (MDA), lipofuscin-like pigments (LFP),protein carbonyl (PCL) and the ratio of glutathioneto glutathione disulfide(GSH/GSSG) in ventricular myocardium were measured with ELISA kit.
Results:
(1) CIHH enhanced oxidative stress and ROS generation in myocardialtissue with the increased GSH-PX, MDA and LFP (P<0.05), and decreasedGSH/GSSG (P<0.05).
(2) CIHH did not affect MAP, but abolished the age-dependent decreaseof HR under normobaric normoxia condition (P<0.05).
(3) During CIHH exposure in hypobaric chamber， MAP and HRdisplayed adaptive changes. The MAP and HR increased rapidly from thebaseline to the peak level, and gradually returned to the lowest level within theearly period (first hour)(P<0.05). In late period (from second to six hours),MAP and HR were keeping in plateau level. Along with hypobaric hypoxiaexposure, the peak and plateau level of MAP gradually increased and the timeto reach the peak gradually shortened (P<0.05), but the peak HR graduallydecreased and the time to reach the peak gradually prolonged (P<0.05) in earlyperiod, while plateau HR gradually increased in late period (P<0.05). Suchadaptive changes of MAP and HR in CIHH rats were partly abolished by theROS scavenger NAC (P<0.05).
(4) During acute normoxia hypoxia, MAP and HR of rats were increasedsignificantly (P<0.05), but the increasing of MAP and HR was much smallerin CIHH rats than those in Control and NAC rats (P<0.05). This anti-acutehypoxia effect of CIHH lasted for two weeks and could be partly abolished byNAC (P<0.05).
Conclusion: The result of this study demonstrated for the first time thatappropriate ROS, produced during CIHH adaptation， contribute to theadaptive protection against acute hypoxia-induced changes of MAP and HR inconscious rats. Moreover, this ROS-dependent adaptive protection needs atleast28days CIHH to trigger, and can maintain effectively for two weeksafter CIHH schedule. Ⅱ The Nrf2-Trx1-HIF1pathway activated by reactive oxygen speciesparticipates the formation of chronic intermittent hypobaric hypoxiaadaptation in rats
Objective: The aim of this study was to investigate the activation ofNrf2-Trx1-HIF1α signaling pathway with its main cardioprotective moleculesand the role of ROS in the activation during the process of CIHH adaptation.
Methods: The experimental groups and CIHH exposure were the sameas those in Part. The expression of Nrf2, Trx1, HIF1α, inducible nitric oxidesynthase (iNOS), vascular endothelial growth factor (VEGF) anderythropoietin (EPO) in ventricular myocardium were detected by WesternBlot analysis and IHC staining.
Results:
(1) ROS-induced Nrf2-Trx1-HIF1α signaling pathway was activatedduring CIHH. The expression of Nrf2, Trx1and HIF1α were increased after28days of CIHH exposure (P<0.05). Consistently, CIHH significantlyenhanced nucleus Nrf2and increased the positive nuclei number in the LVmyocardial cells (P<0.05). NAC treatment abrogated these responses(P<0.05).
(2) ROS induced the translocation of Nrf2from the cytosolic fraction tothe nucleus, i.e. the activation of Nrf2. Nrf2expression was significantlyenhanced in the nucleus fraction and the positive nuclei number was increasedafter one day CIHH exposure (P<0.05). NAC treatment delayed thistranslocation to2days after CIHH as well as significantly abrogated theactivation of Nrf2(P<0.05).
(3) ROS mediated the activation of Nrf2-Trx1-HIF1α signaling pathwayduring CIHH. CIHH enhanced Nrf2protein in the whole-cell extraction after2days of CIHH exposure while increased Trx1and HIF1α after3days CIHHexposure (P<0.05). Chronic NAC injection attenuated the effects of CIHHmarkedly (P<0.05), and also prolonged the activation of Nrf2, Trx1and HIF1αto the3days and5days after CIHH exposure， respectively.
(4) CIHH significantly promoted the expression iNOS, VEGF and EPO, the downstream protective molecules of HIF (P<0.05). Among which theexpression of iNOS and VEGF were increased after7days of CIHH exposure(P<0.05) while the expression of EPO (P<0.05) was enhanced after14days ofCIHH exposure. NAC partially blocked these effects (P<0.05).
Conclusion: We found in this part of study that the Nrf2-Trx1-HIF1αpathway with its downstream genes iNOS, VEGF and EPO was activatedduring the formation of CIHH adaption. According to the fact thatenhancement of iNOS, VEGF and EPO attenuated by ROS scavenger NAC, itsuggests that activation of iNOS, VEGF and EPO genes induced byNrf2-Trx1-HIF1α pathway contribute to the ROS-depended adaptivecardiovascular protection.Ⅲ Chronic intermittent hypobaric hypoxia facilitates the chemoreceptoractivity in carotid body via reactive oxygen species during the process ofCIHH adaptation
Objective: To investigate the effect of CIHH on carotid body (CB)sensitization and the respiration frequency (RF). And to verify the role of ROSplay on the CB sensitization during CIHH adaptation.
Methods: The experimental groups and CIHH exposure were the sameas those in Part. The RF was recorded and analyzed continuously inconscious rats through the PhysioTelTMTelemetry system. The carotid sinusnerve activity (CSNA) was recorded by the conventional whole nerve bipolarplatinum electrodes recording techniques.
Results:
(1) The RF of control rats did not show age-dependent changes. Therewas no significant difference of RF among control, CIHH, Control+NAC andCIHH+NAC rats under normoxia conditions.
(2) During CIHH exposure in hypobaric chamber，RF shown adaptivechanges. The RF increased rapidly from the baseline to reach the peak level,and gradually returned to the lowest level within the early period (first hour)(P<0.05). In late period (from second to six hours), RF were keeping in plateau level (P<0.05). Along with hypobaric hypoxia exposure, the peak RFgradually decreased and the time to reach the peak gradually prolonged inearly period (P<0.05), while plateau HR gradually increased in late period(P<0.05). Such adaptive changes were partly abolished by the ROS scavengerNAC (P<0.05).
(3) During acute normoxia hypoxia, RF of rats was increasedsignificantly (P<0.05), but the increasing of RF was much smaller in CIHHrats than those in Control and NAC rats (P<0.05). This anti-acute hypoxiaeffect of CIHH lasted for two weeks and could be partly abolished by NAC(P<0.05).
(4) Compared with the control rats, CSNA response to hypoxia in CIHHrats significantly increased (P<0.05). Chronic NAC treatment completelyblocked augmentation effect of CIHH on CSNA (P<0.05).
Conclusion: CIHH can induce ROS-dependent adaptive respiratoryresponse and anti-acute hypoxia effect which can be preserved for two weeksat least. Also CIHH augments the carotid body chemoreceptor response tohypoxia and this CIHH-induced sensitization of CB activity is mediated byROS generated during CIHH exposure.
本研究旨在利用功能学、药物学、形态学和分子生物学等方法，在清醒动物整体、离体心脏和细胞分子水平动态观测CIHH适应性心脏保护的产生过程，并探讨ROS在其中的作用及其信号转导机制。研究分为以下三个部分：（1）利用生理信号遥测系统在清醒大鼠，动态观测CIHH适应形成过程中心血管活动的变化，并明确ROS在其中的作用。（2）证实Nrf2-Trx1-HIF1α分子途径及其主要的下游信号分子参与CIHH适应性心脏保护的形成，以及ROS在其中的作用。（3）明确CIHH对劲动脉体化学感受器敏感性的影响及ROS在其中的作用。Ⅰ活性氧参与清醒大鼠慢性间歇性低压低氧适应过程中心血管活动的动态变化
目的：CIHH具有心脏保护作用。大量证据表明低氧刺激产生的ROS可作为第二信使激发机体产生各种适应性反应。本研究旨在探讨CIHH适应过程中心血管活动的动态变化，以及ROS所起的作用。
方法：雄性SD大鼠随机分为四组：对照组（Control）、间歇性低压低氧处理组（CIHH）、抗氧化剂N－乙酰半胱氨酸处理组（Control+NAC）和应用N－乙酰半胱氨酸同时间歇性低压低氧处理组（CIHH+NAC）。CIHH组大鼠置于低压氧舱，给予42天模拟海拔5000米的低压低氧处理，每天6小时，其余时间处于常氧环境。Control+NAC组大鼠每天同一时间皮下注射NAC（80mg/kg）。CIHH+NAC组大鼠每天上仓前皮下注射NAC。Control组动物除不接受CIHH及NAC处理外，其余处理与CIHH大鼠相同。利用清醒动物生理信号遥测系统监测和分析大鼠在相应处理过程中平均动脉压（MAP）和心率（HR）的变化。应用ELISA方法测定左心室心肌组织中总超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化酶(GPX)、丙二醛(MDA)、类脂褐素(LFP)、蛋白羰基（PCL）和谷胱甘肽/二硫化谷胱甘肽的比值（GSH/GSSG）以监测心肌的氧化应激水平。
结果：
（1）CIHH大鼠心肌组织GSH-PX, MDA和LFP增加， GSH/GSSG降低（P<0.05），说明CIHH可提高心肌氧化应激水平和ROS的产生。
（2）CIHH不影响常氧状态下各组动物的MAP。但可以取消HR随年龄的降低（P<0.05）, NAC处理可部分阻断CIHH（P<0.05）这一作用。
（3）在低压低氧仓内，CIHH大鼠的MAP和HR出现适应性变化。早期（上仓1小时内）MAP和HR迅速升高达到峰值（P<0.05），而后逐渐降至最低。后期（上仓2至6小时内），MAP和HR相对稳定，呈平台水平。随CIHH处理时间的延长，MAP和峰值和平台值逐渐升高，达峰值的时间缩短（P<0.05）。HR的峰值逐渐降低，达峰值时间延长，而其平台值逐渐升高（P<0.05）。NAC处理可部分取消MAP和HR的适应性变化。
（4）给予急性常压低氧刺激，CIHH大鼠的MAP和HR升高幅度明显低于Control和Control+NAC组动物（P<0.05）。CIHH的这种抗低氧损伤作用至少可持续两周。NAC处理可部分阻断CIHH的此种作用（P<0.05）。
结论：本研究首次在清醒大鼠证实，CIHH过程产生的适量ROS参与CIHH过程中MAP和HR的适应性变化，并参与形成对抗急性低氧损伤的适应性保护机制。这种ROS依赖的适应性保护作用产生至少需要28天的CIHH所激发；而且在CIHH处理结束后，这种保护作用可持续至少两周。Ⅱ活性氧激活的Nrf2-Trx1-HIF1信号途径参与大鼠慢性间歇性低压低氧适应性心脏保护的形成
目的：探讨CIHH适应形成过程中Nrf2-Trx1-HIF1信号途径及其主要下游分子的激活，以及ROS在其中的作用。
方法：实验分组和CIHH处理同本研究第一部分。利用Western印迹和免疫组织化学的方法观测左心室心肌组织中Nrf2, Trx1, HIF1α, iNOS,VEGF and EPO的表达。
结果：
（1）CIHH过程中Nrf2-Trx1-HIF1信号途径被激活。CIHH处理28天后，Nrf2, Trx1, HIF1α表达明显增强（P<0.05）。CIHH大鼠左心室心肌组织中，Nrf2的核转位及Nrf2阳性细胞核数均明显增加（P<0.05）。NAC处理可部分阻断这些效应（P<0.05）。
（2）ROS可诱导Nrf2的核转位，即Nrf2的激活。CIHH处理1天后，心肌细胞核中Nrf2的表达明显升高，阳性细胞核数增加（P<0.05）。应用NAC抑制了Nrf2的表达（P<0.05），Nrf2的激活推迟至CIHH处理2天以后。
（3）ROS介导CIHH过程中Nrf2-Trx1-HIF1信号途径的激活。在心肌的全细胞提取物中，Nrf2在CIHH处理的2天后被激活（P<0.05），Trx1和HIF1在CIHH处理3天后被激活（P<0.05）。应用NAC抑制这些信号分子的表达，并将Nrf2、Trx1和HIF1信号分子激活时间分别推迟至CIHH处理后3天或5天。
（4）接受CIHH处理7或14天后，Nrf2-Trx1-HIF1信号途径的下游信号分子iNOS, VEGF和EPO的表达明显提高（P<0.05）。NAC可部分取消CIHH的上述作用（P<0.05）。
结论：Nrf2-Trx1-HIF1信号途径及其主要下游分子iNOS, VEGF和EPO在CIHH适应形成过程中被激活。iNOS, VEGF和EPO参与ROS依赖的CIHH适应性心脏保护机制。Ⅲ慢性间歇性低压低氧通过适应过程中产生的ROS易化颈动脉体化学感受器活动
目的：探讨CIHH对颈动脉体化学感觉器敏感性及呼吸频率（respiration frequency，RF）的影响，明确ROS在其中的作用。
方法：实验分组和CIHH处理同本研究第一部分。利用生理信号遥测系统记录和分析不同处理过程中清醒动物的呼吸频率变化。采用全神经双根铂丝电极记录法记录颈动脉体窦神经放电活动（carotid sinus nerveactivity，CSNA）。
结果：
（1）Control组大鼠的RF无明显年龄依赖性变化。各组大鼠的基础RF无统计学差异。
（2）在低压低氧仓内，CIHH大鼠的RF出现适应性变化。早期（上仓1小时内）RF迅速升高达到峰值，而后逐渐降至最低（P<0.05）。后期（上仓2至6小时内），RF相对稳定，呈平台水平。随CIHH处理时间的延长，RF的峰值逐渐降低，达峰值时间延长（P<0.05），而其平台值逐渐升高（P<0.05）。NAC处理可部分取消RF的适应性变化（P<0.05）。
（3）给予急性常压低氧刺激，CIHH大鼠的RF升高幅度明显低于Control和Control+NAC组动物（P<0.05）。CIHH的这种抗低氧损伤作用至少可持续两周（P<0.05）。NAC处理可部分阻断CIHH的此种作用（P<0.05）。
（4）与Control组大鼠相比，CIHH大鼠的CSNA对急性常压低氧刺激的反应明显增强（P<0.05）。NAC处理可完全取消CIHH的这一作用（P<0.05）。
结论：CIHH可诱导ROS依赖性的RF适应性变化和抗急性低氧效应，这种抗急性低氧损伤作用可以维持至少两周。CIHH增强颈动脉体化学感觉器对低氧的敏感性，这种易化作用是由CIHH适应过程中产生的ROS所介导。
In recent years, the cardioprotective effect of chronic intermittenthypobaric hypoxia (CIHH) has been recognized and attracts the publicattention more and more. The study on the mechanism of CIHHcardioprotection is a hot research topic in clinical medicine, space medicineand high altitude medicine. The cardioprotective effects of CIHH can bemainly summarized as protecting the heart against ischemia injury,antagonizing arrhythmia, and improving the degeneration of myocardial cell.Multiple mechanisms or pathways have been suggested to contribute to thecardioprotection of CIHH, such as increase of myocardial capillaryangiogenesis and coronary flow, activation of ATP-sensitive K+channels,inhibition of mitochondrial permeability transition pores and suppression ofthe adrenergic receptor activity on cardiac membrane. However, these findingsare the end effects of CIHH treatment, that is to say, the observations of thefinal results of CIHH. What happened during CIHH exposure and how theseprotective effects of CIHH produced have not been reported. It is generallyaccepted that reactive oxygen species (ROS) exert both deleterious andbeneficial actions depending on the amount of ROS. A lot of evidence showsthat ROS are protective at low level but detrimental at high level on the heart.Intermittent hypoxia increases ROS generation both in cell culture and inintact animals and ROS-mediated signaling mechanisms contribute to cellularand systemic responses to intermittent hypoxia. The nuclear factor erythroid2-related factor2-thioredoxin1-hypoxia-inducible factor (Nrf2-Trx1-HIF-1α)signal transduction pathway was identified as ROS-induced mechanisms inresponse to intermittent hypoxia. However, it is still unknown whether ROSplay a role in the dynamic formation of CIHH cardiac protection.
This study aimed to investigate the role of ROS in adaptivecardioprotection of CIHH dynamically and the mechanism underlying thisprocess in conscious rats through physiological, pharmacological,morphological and molecular biology techniques. Our study consisted of threeparts:(1) To clarify the dynamic changes of the cardiovascular activity and therole of ROS during CIHH adaptation.(2) To investigate the Nrf2-Trx1-HIF1αsignaling pathway with its main cardioprotective molecules in adaptivecardioprotection.(3) To determine the effect of CIHH on the sensitization ofcarotid body chemoreceptor.Ⅰ Reactive oxygen species contribute to the dynamic changes ofcardiovascular responses during the process of chronic intermittenthypobaric hypoxia adaptation in conscious rats
Objective: CIHH has been reported to have cardioprotective effects.Cumulating evidences have indicated that ROS released during hypoxia assecond messengers may help to trigger various adaptive responses. The aim ofpresent study was to clarify the dynamic changes of the cardiovascular activityand the role of ROS during CIHH adaptation in conscious rats
Methods: Adult male Sprague-Dawley rats were randomly divided intothe four groups: control group (Control), CIHH treatment group (CIHH),antioxidant N-Acetylcysteine group (Control+NAC), CIHH plus NACtreatment group (CIHH+NAC). The rats in CIHH group were exposed tohypoxia simulating5000m high altitude (oxygen11.1%) in a hypobaricchamber for42days,6hours each day. Control+NAC rats accepted ROSscavenger NAC（80mg/kg）injection subcutaneously each day for42days.CIHH+NAC rats were given NAC before the hypobaric hypoxic exposure.Control rats were living in the same environment as CIHH rats with freeaccess to food and water, except no CIHH and NAC treatment. The meanarterial pressure (MAP) and heart rate (HR) were recorded and analyzedcontinuously in conscious rats by using the PhysioTelTMTelemetry system.The activity of total superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), malondialdehyde (MDA), lipofuscin-like pigments (LFP),protein carbonyl (PCL) and the ratio of glutathioneto glutathione disulfide(GSH/GSSG) in ventricular myocardium were measured with ELISA kit.
Results:
(1) CIHH enhanced oxidative stress and ROS generation in myocardialtissue with the increased GSH-PX, MDA and LFP (P<0.05), and decreasedGSH/GSSG (P<0.05).
(2) CIHH did not affect MAP, but abolished the age-dependent decreaseof HR under normobaric normoxia condition (P<0.05).
(3) During CIHH exposure in hypobaric chamber， MAP and HRdisplayed adaptive changes. The MAP and HR increased rapidly from thebaseline to the peak level, and gradually returned to the lowest level within theearly period (first hour)(P<0.05). In late period (from second to six hours),MAP and HR were keeping in plateau level. Along with hypobaric hypoxiaexposure, the peak and plateau level of MAP gradually increased and the timeto reach the peak gradually shortened (P<0.05), but the peak HR graduallydecreased and the time to reach the peak gradually prolonged (P<0.05) in earlyperiod, while plateau HR gradually increased in late period (P<0.05). Suchadaptive changes of MAP and HR in CIHH rats were partly abolished by theROS scavenger NAC (P<0.05).
(4) During acute normoxia hypoxia, MAP and HR of rats were increasedsignificantly (P<0.05), but the increasing of MAP and HR was much smallerin CIHH rats than those in Control and NAC rats (P<0.05). This anti-acutehypoxia effect of CIHH lasted for two weeks and could be partly abolished byNAC (P<0.05).
Conclusion: The result of this study demonstrated for the first time thatappropriate ROS, produced during CIHH adaptation， contribute to theadaptive protection against acute hypoxia-induced changes of MAP and HR inconscious rats. Moreover, this ROS-dependent adaptive protection needs atleast28days CIHH to trigger, and can maintain effectively for two weeksafter CIHH schedule. Ⅱ The Nrf2-Trx1-HIF1pathway activated by reactive oxygen speciesparticipates the formation of chronic intermittent hypobaric hypoxiaadaptation in rats
Objective: The aim of this study was to investigate the activation ofNrf2-Trx1-HIF1α signaling pathway with its main cardioprotective moleculesand the role of ROS in the activation during the process of CIHH adaptation.
Methods: The experimental groups and CIHH exposure were the sameas those in Part. The expression of Nrf2, Trx1, HIF1α, inducible nitric oxidesynthase (iNOS), vascular endothelial growth factor (VEGF) anderythropoietin (EPO) in ventricular myocardium were detected by WesternBlot analysis and IHC staining.
Results:
(1) ROS-induced Nrf2-Trx1-HIF1α signaling pathway was activatedduring CIHH. The expression of Nrf2, Trx1and HIF1α were increased after28days of CIHH exposure (P<0.05). Consistently, CIHH significantlyenhanced nucleus Nrf2and increased the positive nuclei number in the LVmyocardial cells (P<0.05). NAC treatment abrogated these responses(P<0.05).
(2) ROS induced the translocation of Nrf2from the cytosolic fraction tothe nucleus, i.e. the activation of Nrf2. Nrf2expression was significantlyenhanced in the nucleus fraction and the positive nuclei number was increasedafter one day CIHH exposure (P<0.05). NAC treatment delayed thistranslocation to2days after CIHH as well as significantly abrogated theactivation of Nrf2(P<0.05).
(3) ROS mediated the activation of Nrf2-Trx1-HIF1α signaling pathwayduring CIHH. CIHH enhanced Nrf2protein in the whole-cell extraction after2days of CIHH exposure while increased Trx1and HIF1α after3days CIHHexposure (P<0.05). Chronic NAC injection attenuated the effects of CIHHmarkedly (P<0.05), and also prolonged the activation of Nrf2, Trx1and HIF1αto the3days and5days after CIHH exposure， respectively.
(4) CIHH significantly promoted the expression iNOS, VEGF and EPO, the downstream protective molecules of HIF (P<0.05). Among which theexpression of iNOS and VEGF were increased after7days of CIHH exposure(P<0.05) while the expression of EPO (P<0.05) was enhanced after14days ofCIHH exposure. NAC partially blocked these effects (P<0.05).
Conclusion: We found in this part of study that the Nrf2-Trx1-HIF1αpathway with its downstream genes iNOS, VEGF and EPO was activatedduring the formation of CIHH adaption. According to the fact thatenhancement of iNOS, VEGF and EPO attenuated by ROS scavenger NAC, itsuggests that activation of iNOS, VEGF and EPO genes induced byNrf2-Trx1-HIF1α pathway contribute to the ROS-depended adaptivecardiovascular protection.Ⅲ Chronic intermittent hypobaric hypoxia facilitates the chemoreceptoractivity in carotid body via reactive oxygen species during the process ofCIHH adaptation
Objective: To investigate the effect of CIHH on carotid body (CB)sensitization and the respiration frequency (RF). And to verify the role of ROSplay on the CB sensitization during CIHH adaptation.
Methods: The experimental groups and CIHH exposure were the sameas those in Part. The RF was recorded and analyzed continuously inconscious rats through the PhysioTelTMTelemetry system. The carotid sinusnerve activity (CSNA) was recorded by the conventional whole nerve bipolarplatinum electrodes recording techniques.
Results:
(1) The RF of control rats did not show age-dependent changes. Therewas no significant difference of RF among control, CIHH, Control+NAC andCIHH+NAC rats under normoxia conditions.
(2) During CIHH exposure in hypobaric chamber，RF shown adaptivechanges. The RF increased rapidly from the baseline to reach the peak level,and gradually returned to the lowest level within the early period (first hour)(P<0.05). In late period (from second to six hours), RF were keeping in plateau level (P<0.05). Along with hypobaric hypoxia exposure, the peak RFgradually decreased and the time to reach the peak gradually prolonged inearly period (P<0.05), while plateau HR gradually increased in late period(P<0.05). Such adaptive changes were partly abolished by the ROS scavengerNAC (P<0.05).
(3) During acute normoxia hypoxia, RF of rats was increasedsignificantly (P<0.05), but the increasing of RF was much smaller in CIHHrats than those in Control and NAC rats (P<0.05). This anti-acute hypoxiaeffect of CIHH lasted for two weeks and could be partly abolished by NAC(P<0.05).
(4) Compared with the control rats, CSNA response to hypoxia in CIHHrats significantly increased (P<0.05). Chronic NAC treatment completelyblocked augmentation effect of CIHH on CSNA (P<0.05).
Conclusion: CIHH can induce ROS-dependent adaptive respiratoryresponse and anti-acute hypoxia effect which can be preserved for two weeksat least. Also CIHH augments the carotid body chemoreceptor response tohypoxia and this CIHH-induced sensitization of CB activity is mediated byROS generated during CIHH exposure.
引文
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