The Effect of Short-Term Intermittent Hypoxia Exposure on Mouse Myocardial Oxidative Stress and Cardiac Function
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摘要:目的 探讨短期间歇性低氧暴露(intermittent hypoxia, IH)对小鼠心肌结构和功能的影响。方法 采用随机分组对照研究的方法,将30只雄性C57BL6/J小鼠随机分为常氧组和低氧(IH)组。IH组采用常压低氧方式,将小鼠暴露于10%浓度氧气中,每天8 h,连续14 d。常氧组小鼠暴露于常压常氧环境,其余操作同IH组。观察暴露期间小鼠生长情况,暴露结束后检测小鼠运动耐量、离体心脏功能、心脏组织学、心肌酶学,以及蛋白脂质过氧化等氧化应激相关指标。结果 两组小鼠运动耐量无明显差异,IH小鼠离体心肌做功能力增加(P<0.05)。与常氧组比较,IH组小鼠心肌电镜表现明显异常,血浆肌酸肌酶同工酶含量升高(P<0.05);组织活性氧簇水平、蛋白质羰基化水平及丙二醛含量均升高(P<0.05)。结论 IH暴露诱导小鼠心肌氧化应激损伤,心肌肌纤维结构改变,但不足以损害小鼠的运动耐力和离体心脏的收缩功能。Abstract:Objective To investigate the effect of short-term intermittent hypoxia (IH) on the structure and function of mouse myocardium.Methods Thirty male C57BL6/J mice were randomly assigned to two groups, a control (Con) group and an IH group exposed to hypoxic treatment at atmospheric pressure. The IH group received 10% oxygen pretreatment for 8 hours per day on 14 consecutive days, while the Con group was exposed to normoxia environment and all the other treatment the group received were identical to those given to the IH group, The body mass of the mice was monitored daily during the treatment. The exercise tolerance and the cardiac function of isolated heart were assessed at the end of IH exposure. Additionally, analysis was conducted regarding myocardial enzymology, histology, and other indicators relevant to oxidative stress, including protein carbonylation and lipid peroxidation.Results There was no significant difference in the exercise tolerance between the two groups. Nevertheless, IH mice showed enhanced cardiac function during isolated heart perfusion (P<0.05). As compared to the control group, prominent alterations of myocardial structure were detected by transmission electron microscopy of the IH heart, accompanied by elevated creatine kinase-MB levels (P<0.05). The levels of myocardial reactive oxygen species, protein carbonylation and lipid peroxidation were all significantly upregulated in the IH group as compared to the control group (P<0.05).Conclusion IH exposure induced myocardial oxidative stress damage and myofibrillar structural alteration in mice, but did not impair the exercise tolerance of the mice or the contractile function of the isolated heart.
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Keywords:
- Intermittent hypoxia /
- Myocardium /
- Cardiac function /
- Oxidative stress
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间歇性低氧(intermittent hypoxia, IH)是一个相当广泛的概念,涵盖了高海拔地区活动到阻塞性睡眠呼吸暂停(obstructive sleep apnea, OSA)等各种情形。由于低氧周期、低氧程度、低氧频率以及低氧暴露总持续时间各异,IH对机体产生的效应也完全不同[1]。当前IH研究主要集中于OSA对心脏的影响,以OSA为基础的IH模型,通常导致心功能障碍、心肌重塑、缺血再灌注损伤敏感性增加等不良事件;另一方面,由于高原居民心肌梗死发生率明显较低[2],提示低氧适应提高心肌缺血缺氧耐受性。因此人们通过低压氧舱模拟高原低氧状态,或者使用常压低氧手段降低氧浓度以模拟高原的氧分压对实验动物进行IH预处理。大量文献报道,周期相对较长的低氧间歇,可以提高心肌收缩力、改善心肌缺血再灌注损伤[3-5]。目前认为缺氧反应性基因的激活,冠状动脉循环的改善,蛋白激酶C的激活,Ca2+稳态的维持以及线粒体通透性转换孔(mPTP)的开放抑制[4, 6-8],均与IH诱导的保护作用有关。尽管大量证据表明特定条件的IH具有心肌保护作用,但由于IH心血管效应的异质性,以及相关研究中环境及人种因素的影响,相关机制仍有待进一步明确,用以诱导心肌保护作用的IH条件也需不断优化。
随着我国西部建设深化,基础设施越来越完备,往返于高原与低海拔地区的务工人员越来越频繁,利用IH训练增强竞技能力的运动员也越来越多。这些没有心脏疾患的人员在经历类似的IH暴露后,心脏结构和功能会发生何种变化,还并不明确。本研究以小鼠为研究对象,旨在探究短期中等程度IH对小鼠心脏及运动功能的影响。
1. 对象与方法
1.1 实验动物
本研究符合《美国NIH实验室动物使用指南》的规定,并通过四川大学动物伦理委员会的审查。实验动物选用8~10周龄雄性C57BL6/J小鼠(22~24 g),购自北京华阜康生物科技股份有限公司,饲养于标准清洁级环境,昼夜对半,标准饮食,自由进食/饮水。
1.2 实验分组和模型制备
30只8~10周龄雄性C57BL6小鼠随机分为两组:①常氧组(Con组,n=15),按上述条件,于常压常氧环境饲养;②间歇性低氧组(IH组,n=15),小鼠放置于常压低氧舱中,通过灌入90% N2及10% O2混合气达到10% O2的低氧条件,每天9:00~17:00为低氧暴露时间段,当天余下时段恢复常氧状态,连续暴露14 d,维持光照、温湿度与常氧组一致。每天造模前对小鼠体质量进行测量并记录,持续至造模结束后第2天(即共测量15次)。低氧干预结束后,检测小鼠心脏中低氧诱导因子-1α(hypoxia inducible factor 1-α, HIF-1α)表达上调,即认为该模型造模成功。
1.3 运动耐量测试
暴露结束后次日,将常氧组和IH组小鼠置于坡度为6%的小动物跑步机(UgoBasile#74300),对小鼠进行环境适应和跑步训练:皮带速度设置为4 m/min,开始后第5 min加速至9 m/min,第7 min时升至10 m/min,第10 min时停止训练;次日,先按昨日流程缓慢加速至10 m/min,重新计时,在第5 min时加速至11 m/min,在第10 min时升至12 m/min,第15 min时停止训练;第三日进行正式测试,起始速度设置为12 m/min,开始后5 min内将速度提高至18 m/min,记录小鼠在18 m/min的速度下所能行进的最长距离。疲劳小鼠将从跑步机上取出。
1.4 心脏取材及心脏质量指数测量
腹腔注射三溴乙醇330 mg/kg麻醉小鼠,仰卧位固定,暴露其胸腔,迅速摘取心脏,放入冰磷酸盐缓冲液(PBS)中涮洗数次,轻柔挤出心腔内残存的血液,滤纸蘸干水分后于精细天秤上测量心脏质量(heart mass, HM);取该小鼠双侧胫骨,测量其长度(tibia length, TL)并取平均值;计算心脏质量/胫骨长度比(HM/TL),即心脏质量指数。心脏取材后或立即进行离体心功能检测,或固定用于石蜡切片,或用于冰冻切片、电镜标本、分子实验标本的制备。
1.5 离体心功能检测
每组各取3只小鼠进行离体心功能检测。腹腔注射肝素200 U,5 min后按1.4步骤摘取心脏,在PBS中暴露并游离主动脉;将20G灌注针插入主动脉,4-0丝线固定;在左心耳剪一小口,将测压球囊由此放入左心室,扩张球囊使初始压力处于5~12 mmHg(1 mmHg=0.133 kPa);使用恒压模式进行Krebs-Henseleit液(Krebs-Henseleitbuffer, KHB,含0.5 mmol/L EDTA、5.3 mmol/L氯化钾、1.2 mmol/L硫酸镁、118 mmol/L氯化钠、25 mmol/L碳酸氢钠、2 mmol/L氯化钙,10 mmol/L葡萄糖和0.5 mmol/L丙酮酸,pH7.4)灌流,灌注压力设定为80 mmHg,KHB温度维持在37 ℃。KHB灌流15 min后,使用含4 mmol/L氯化钙的KHB进行高负荷模式灌流。使用Powerlab联合Labchart7(ADinstrument)信息采集系统记录心功能指标:心率(heart rate, HR),左室发展压(left ventricular develop pressure, LVDevP),左室舒张末压(left ventricular end-diastolic pressure, LVEDP)以及心率压力乘积(rate pressure product, RPP)。
1.6 心肌酶学检测
麻醉小鼠后,使用肝素化的注射器从心尖取血,随后3 000 r/min离心10 min,收集上清,使用自动生化仪(MindrayBS-120)对上清液中肌酸肌酶同工酶(creatine kinase-MB, CK-MB)、乳酸脱氢酶(lactate dehydrogenase, LDH)和α-羟丁酸脱氢酶(α-hydroxybutyrate dehydrogenase, α-HBDH)水平进行检测。
1.7 组织学检测
每组取3只小鼠心脏,用预冷的PBS灌注心脏,接着用体积分数为4%多聚甲醛灌注心脏后再将心脏取下置于体积分数为4%多聚甲醛中固定24 h,组织固定妥后使用30%和20%蔗糖梯度脱水并石蜡包埋,用于苏木精和伊红(HE)染色。标本制好后使用全玻片扫描系统(OlympusVS200)拍摄,观察心脏心肌细胞形态及走行排列是否存在异常,是否存在炎性细胞浸润等。
1.8 透射电镜检测
各组取3只小鼠新鲜心脏,在乳头肌平面切1~2 mm3室间隔组织,经3%戊二醛预固定,1%四氧化锇再固定,丙酮逐级脱水,环氧树脂包埋后,切成50 nm厚的切片;醋酸铀染色10~15 min,再用枸橼酸铅染色1~2 min,使用透射电镜(JEOL, JEM-1400PLUS)拍照,观察心肌纤维排列及线粒体数量等指标。
1.9 组织活性氧簇(reactive oxygen species, ROS)检测
取新鲜心脏在乳头肌平面切2 mm厚度切片,用冰冻切片包埋剂包埋,使用冰冻切片机切成10 μm厚度;将切片置于潮湿暗盒中与10 μmol/L二氢乙锭(dihydro-ethidium, DHE)(Sigma-Aldrich,货号D7008)孵育30 min,PBS洗涤后用荧光显微镜(Olympus IX83)观察并拍照(Ex/Em:488/610 nm)。使用Image J软件对两组心脏切片的荧光强度进行相对定量分析。
1.10 蛋白质免疫印迹
提取心肌总蛋白,BCA法定量后通过电泳并转膜,将PVDF膜用5%白蛋白在室温下封闭1 h。随后加入一抗溶液(HIF-1α抗体稀释度 1∶5000,GAPDH抗体稀释度 1∶20000,蛋白羰基化抗体稀释度 1∶150),在4 ℃下摇床孵育过夜。次日,TBST洗膜3次,加入二抗溶液室温摇床孵育1 h,TBST洗膜3次后使用ECL法显影。用Image J(NIH)测得各蛋白条带相对灰度值,取目的蛋白和内参蛋白3磷酸甘油醛脱氢酶(GAPDH)灰度值的比值作为目的蛋白的相对表达量。HIF-1α抗体(货号20960-1-AP)、GAPDH抗体(货号10494-1-AP)、化学二抗(货号SA00001-2)均购于Proteintech公司,蛋白羰基化检测试剂盒购于Sigma-Aldrich公司(货号S7150),ECL显影液购于苏州新赛美公司(货号P10100)。
1.11 脂质过氧化水平检测
丙二醛(MDA)使用碧云天生物技术公司商品化试剂盒(货号S0131S)进行检测,取10 mg新鲜心尖组织放入1.5 mL EP管中,加入PBS 200 μL及灭菌钢珠三粒,放入高通量匀浆仪进行组织匀浆;随后12 000×g离心10 min,吸取上清100 μL至1.5 mL EP管并加入MDA工作液200 μL(TBA 0.091%,抗氧化剂1.48%),混匀后封口100 ℃加热15 min,1 000×g离心10 min,取200 μL上清加入到96孔板中,用酶标仪在532 nm测定吸光度,按标准曲线得出样本MDA浓度,并根据样本蛋白浓度对结果进行标化。
1.12 统计学方法
所有数据均以
$ \bar x $ ±s表示。两组间比较采用非配对双尾Student t检验,多组间比较采用重复测量单因素方差分析结合Sidak检验,P<0.05为差异有统计学意义。2. 结果
2.1 基础状态
结果见图1。造模期间两组小鼠体质量差异无统计学意义。IH组第3天体质量有下降趋势,但相较第1天无明显差异(P>0.05)。IH暴露结束后,IH组低氧诱导因子HIF-1α蛋白表达增高(P<0.05),表明低氧造模成功。
2.2 IH对小鼠心功能的影响
结果见图2。运动耐量测试结果显示,IH小鼠与常氧组相比并无明显差异(P>0.05)。离体心功能检测结果显示,IH小鼠离体心脏在基线状态和高负荷状态下15 min时心率高于常氧组(P<0.05),全时段心率曲线下面积大于常氧组(P<0.05);常氧组与IH组的LVEDP和LVDevP表现并无差异(P>0.05)。因IH小鼠心率升高,故高负荷状态下不同时点心脏做功水平(RPP)高于常氧组(P<0.05)。
图 2 两组小鼠心功能比较Figure 2. Comparison of cardiac function between the two groupsA: Exercise tolerance of mice in each group (Con group: n=7, IH group: n=10); B-F: The cardiac performance of the isolated heart (n=3). LVEDP: Left ventricular end-diastolic pressure; LVDevP: Left ventricular developed pressure (systolic minus diastolic pressure); RPP: Rate pressure product. *P<0.05, **P<0.01, ***P<0.001, vs. Con group.2.3 IH对小鼠心肌结构和心肌酶学的影响
结果见图3。两组小鼠HW/TL无差异,且组织HE染色未见心肌细胞肥大、空泡化等病理改变。但是电镜结果显示,IH组心肌呈现明显的异质化,肌纤维明显水肿、排列紊乱,线粒体体积减小,数量增加(P<0.05)。此外,虽然IH组小鼠LDH、α-HBDH表达水平无明显变化,但是心肌损伤标记物CK-MB水平高于常氧组(P<0.05),提示存在潜在的心肌损伤。
图 3 IH诱导小鼠心肌线粒体异常与心肌损伤Figure 3. IH exposure induced cardiac mitochondrial abnormalities and myocardial damageA: The heart mass to tibia length (HM/TL) ratio of each group (Con group: n=3, IH group: n=4); B: Representative images of HE stained left ventricle (LV) tissue sections (n=3); C: Representative electron microscopy images of heart sections (n=3); D: Fold differences in mitochondrial number. Mitochondrial number was counted in a total of 3 images per heart (255 μm2 per image at 10 000 magnification) (n=3); E: The levels of creatine kinase-MB (CK-MB) in plasma (n=5); F: The levels of lactate dehydrogenase (LDH) in plasma (n=5); G: The levels of α-hydroxybutyrate dehydrogenase (α-HBDH) in plasma (n=5). * P<0.05,** P<0.01.2.4 IH对小鼠心肌氧化应激水平的影响
结果见图4。IH组心肌DHE染色荧光水平高于常氧组,反映心肌组织ROS生成增加。进一步研究发现,心肌组织蛋白羰基化水平与MDA含量均高于常氧组(P<0.05),提示IH促进心肌蛋白过氧化与脂质过氧化水平,心肌呈现氧化应激损伤。
图 4 IH诱发小鼠心肌氧化应激Figure 4. IH exposure induced myocardial oxidative stress in mice heartA: Representative images for dihydroethidium (DHE) staining; B: Relative fluorescence intensity of DHE (n=3); C: Representative immunoblots of 2,4-dinitrophenylhydrazone (DNP) which was derivatized from protein carbonyls; D: The DNP levels of derivatized proteins were normalized by GAPDH and data were expressed as fold change relative to Con group (n=5); E: Malondialdehyde (MDA) levels in cardiac tissues (n=4). * P<0.05.3. 讨论
本研究中,连续两周每天8 h的常压10% O2低氧条件,可诱导小鼠心肌组织HIF-1α上调,对小鼠的体质量和心肌结构未产生明显影响。然而,进一步通过电镜检测发现,IH暴露后,小鼠心肌肌丝明显稀疏,Z线、M线模糊,提示心肌肌纤维损伤;与之相一致的是,IH小鼠循环心肌损伤标志物CK-MB水平明显高于常氧组,进一步佐证了这一发现。
心脏是高耗能、高能量需求的器官,心肌丰富的线粒体为其正常运作提供了能量保障,心肌线粒体形态、功能的异常被证明与多种心脏疾病联系密切[9]。线粒体通过电子传递链上的氧化磷酸化生成三磷酸腺苷用于供能,而此过程也不可避免地伴随着副产物过氧化物簇(reactive oxygen species, ROS)的生成,事实上,线粒体是细胞产生ROS最主要的场所,尤其是电子传递链中的复合体Ⅰ、Ⅲ[10-11]。心肌缺血再灌注过程中,由于复合体Ⅱ反向传递大量电子给复合体Ⅰ,更是大量ROS形成的来源[12]。ROS激活有关的信号通路有助于对IH心脏的保护作用[13],然而,当过量ROS的产生超过了细胞抗氧化防御系统的代偿能力时,将导致心肌收缩功能的降低,并引发心脏重构,参与心脏若干病变发生发展[14-15];并且心肌纤维中结构蛋白可被ROS过氧化,影响其正常形态和功能[16]。本研究中IH组小鼠心肌ROS水平增高,蛋白质、脂质过氧化水平增加,表明IH导致了小鼠心肌氧化应激损伤,并且可能进一步导致其心肌纤维的损伤。而缺氧程度更为严重的IH如OSA,甚至可能导致心室重塑[17-18]。
在正常生理条件下,ROS产生与清除之间存在内稳态,以控制和维持信号通路严格调控的氧化还原平衡。研究显示,短期中度低氧(每天6 h,28~42 d)对豚鼠进行IH暴露,心肌中SOD活性上调[6],表明其抗氧化能力提高。值得注意的是ROS所具有的双重作用,高水平的ROS导致氧化应激损伤,而低中度水平的ROS又作为必要的信号分子参与慢性低氧适应保护机制。ESTRADA等[19]在IH期间同时应用抗氧化剂N-乙酰半胱氨酸,该举明显削弱了IH在狗心脏诱导的缺血再灌注损伤的保护作用。因此,通过ROS介导的心肌预适应是IH在心肌保护作用中不可或缺的重要环节。
IH小鼠心肌中另一值得注意的表现是其线粒体体积减小,数量增加,线粒体周围空泡增多。线粒体的形态受其分裂和融合的调控,而融合/分裂会根据细胞代谢条件的变化而调节[20];低氧状态下,线粒体产能效率低下,线粒体一方面通过分裂保存mtDNA,维持电子传递链功能以保持正常的膜电势,从而保留其功能;另一方面,线粒体通过自噬清除受损的线粒体,避免线粒体内物质外泄[21]。因此我们推测IH暴露导致部分线粒体功能障碍,导致胞内ROS增加,同时线粒体质控机制激活,通过线粒体分裂提高氧化磷酸化和能量物质利用率,增强线粒体自噬清除受损线粒体以维持线粒体整体健康程度。
既然ROS是IH诱导心肌保护作用所必须,那么IH过程中诱导的氧化应激损伤是否会影响心脏功能?本研究中,小鼠在进行IH暴露后,运动耐量并无显著变化,其原因可能是本研究中运动耐力测试所采用的条件主要用于测试小鼠有氧运动的耐力,而IH暴露所增强的运动储备对于无氧运动能力的提升帮助可能更大。在离体心功能测试中,IH组心脏收缩舒张功能,与常氧组表现无明显差异,但IH组心率明显增高,这可能与IH上调心脏交感活性有关[22-23]。因此,在2周的IH暴露后,小鼠离体心脏的做功能力得到增强,但在涉及更多器官功能的运动耐力中,这一增强并没有得到体现。
综上所述,IH暴露诱导小鼠心肌氧化应激,引起蛋白质脂质过氧化,从而导致心肌肌纤维结构改变,但上述结果不足以损害离体心脏的收缩功能和小鼠的运动功能,是一种心脏IH适应过程中必要、可控的病理生理反应,但对于存在隐匿性心脏疾病的人群,该适应性反应是否会造成更为严重的心脏损害还有待进一步研究。
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利益冲突 所有作者均声明不存在利益冲突
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图 2 两组小鼠心功能比较
Figure 2. Comparison of cardiac function between the two groups
A: Exercise tolerance of mice in each group (Con group: n=7, IH group: n=10); B-F: The cardiac performance of the isolated heart (n=3). LVEDP: Left ventricular end-diastolic pressure; LVDevP: Left ventricular developed pressure (systolic minus diastolic pressure); RPP: Rate pressure product. *P<0.05, **P<0.01, ***P<0.001, vs. Con group.
图 3 IH诱导小鼠心肌线粒体异常与心肌损伤
Figure 3. IH exposure induced cardiac mitochondrial abnormalities and myocardial damage
A: The heart mass to tibia length (HM/TL) ratio of each group (Con group: n=3, IH group: n=4); B: Representative images of HE stained left ventricle (LV) tissue sections (n=3); C: Representative electron microscopy images of heart sections (n=3); D: Fold differences in mitochondrial number. Mitochondrial number was counted in a total of 3 images per heart (255 μm2 per image at 10 000 magnification) (n=3); E: The levels of creatine kinase-MB (CK-MB) in plasma (n=5); F: The levels of lactate dehydrogenase (LDH) in plasma (n=5); G: The levels of α-hydroxybutyrate dehydrogenase (α-HBDH) in plasma (n=5). * P<0.05,** P<0.01.
图 4 IH诱发小鼠心肌氧化应激
Figure 4. IH exposure induced myocardial oxidative stress in mice heart
A: Representative images for dihydroethidium (DHE) staining; B: Relative fluorescence intensity of DHE (n=3); C: Representative immunoblots of 2,4-dinitrophenylhydrazone (DNP) which was derivatized from protein carbonyls; D: The DNP levels of derivatized proteins were normalized by GAPDH and data were expressed as fold change relative to Con group (n=5); E: Malondialdehyde (MDA) levels in cardiac tissues (n=4). * P<0.05.
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