Low-Level Vagus Nerve Stimulation Attenuates Myocardial Ischemic Reperfusion Injury by Antioxidative Stress and Antiapoptosis Reactions in Canines
低水平迷走神经刺激减轻犬抗氧化应激和抗凋亡反应引起的心肌缺血再灌注损伤
首次发布:2015年10月7日https://doi.org/10.1111/jce.12850Citations: 50
Mingxian Chen and Xiaoya Zhou contributed equally to this work.
陈明贤和周晓亚对这项工作也有同样的贡献。
This work was supported by the grants from National Natural Science Foundation of China No. 81270257, No. 81270339, and No. 81300182, grant from the Science and Technology Research Project of Wuhan No. 201306060201010271, grant from the Natural Science Foundation of Hubei Province No. 2013CFB302, grant from the Natural Science Foundation of Zhejiang Province No. LY13H020003, and grants from the Fundamental Research Funds for the Central Universities No. 2042014kf0110.
基金资助:国家自然科学基金项目No. 81270257、No. 81270339、No. 81300182，武汉市科技攻关项目No. 201306060201010271，湖北省自然科学基金No. 2013CFB302，浙江省自然科学基金No. 81300182。中央高校基本科研业务费专项资金(2042014kf0110)资助。
Disclosures: None. 披露:没有。
Address for correspondence: Shenghua Zhou, M.D., Department of Cardiology, The Second Xiangya Hospital of Central South University, No. 139 middle Renmin Road, Furong District, Changsha City, Hunan Province 410011, China, Fax: + 86 731 85533525; E-mail: xyzhoushenghua@126.com. Co-correspondence: Hong Jiang, M.D., Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, China; E-mail: whujianghong@163.com
通讯地址:湖南省长沙市芙蓉区人民中路139号中南大学湘雅第二医院心内科周盛华医学博士，传真:+ 86 731 85533525;电子邮件:xyzhoushenghua@126.com。通讯作者:洪江，武汉大学人民医院心内科博士，武汉市武昌解放路238号，430060;电子邮件:whujianghong@163.com
Vagus Nerve Stimulation and Myocardial Ischemia-Reperfusion Injury
迷走神经刺激与心肌缺血再灌注损伤
Background 背景
Low-level vagus nerve stimulation (LL-VNS) has been demonstrated to protect myocardium against acute ischemia/reperfusion (I/R) injury. However, the underlying mechanism of this protective effect remains unknown.
低水平迷走神经刺激(LL-VNS)已被证明可以保护心肌免受急性缺血/再灌注(I/R)损伤。然而，这种保护作用的潜在机制尚不清楚。
Objective 客观的
This study aimed to test the hypothesis that LL-VNS exerts cardioprotective effect on acute I/R injury in canines via antioxidative stress and antiapoptosis reactions.
本研究旨在验证LL-VNS通过抗氧化应激和抗凋亡反应对犬急性I/R损伤的心脏保护作用。
Method 方法
Thirty anesthetized mongrel dogs were randomly divided into three groups: I/R group (N = 12, the left anterior descending coronary artery was occluded for 1 hour following by 1 hour reperfusion), LL-VNS group (N = 9, I/R plus LL-VNS), and sham group (N = 9, sham surgery without LL-VNS). The voltage threshold was set at 80% of the voltage required to slow the sinus rate. Infarct size was assessed with Evans Blue and triphenyltetrazolium chloride. Activity assays, TUNEL staining, and western blotting were performed to determine markers of oxidative stress and apoptosis.
30只麻醉后的杂种狗随机分为3组:I/R组(N = 12，阻断左冠状动脉前降支1 h，再灌注1 h)、LL-VNS组(N = 9, I/R加LL-VNS)和假手术组(N = 9，假手术不加LL-VNS)。电压阈值设置为减慢窦性心率所需电压的80%。用Evans Blue和三苯四唑氯评估梗死面积。通过活性测定、TUNEL染色和western blotting检测氧化应激和凋亡标志物。
Results 结果
LL-VNS significantly decreased the incidence of ventricular arrhythmias, increased vagal tone, as confirmed by heart rate viability, and reduced infarct size compared with the I/R group. This improvement was associated with a reduction in myocardial neutrophil infiltration, the inhibition of oxidative stress, and the suppression in cardiomyocyte apoptosis. In contrast, the lack of LL-VNS in the I/R group induced the opposite effect compared with the sham group.
与I/R组相比，LL-VNS显著降低了室性心律失常的发生率，增加了迷走神经张力，并减少了梗死面积。这种改善与心肌中性粒细胞浸润减少、氧化应激抑制和心肌细胞凋亡抑制有关。相比之下，与假手术组相比，I/R组缺乏LL-VNS诱导的效果相反。
Conclusion 结论
LL-VNS exerts protective effects on myocardial I/R injury. Its potential mechanisms involve the suppression of oxidative stress and cellular apoptosis.
l - vns对心肌I/R损伤有保护作用。其潜在机制包括抑制氧化应激和细胞凋亡。
Introduction 介绍
Acute myocardial infarction (AMI) is a major cardiac disease with high morbidity rate and mortality rates. Rapid reperfusion during the early period is still the most effective strategy because it rescues ischemic myocardium, limits infarct size, and improves clinical long-term outcomes.1-3 However, reperfusion after ischemia itself simultaneously causes irreversible myocardial cell loss in a process called myocardial ischemia reperfusion (I/R) injury. Myocardial I/R induces a devastating cascade of biological changes including the excessive production of oxidative stress and the activation of apoptotic pathways, both of which contribute to the exacerbation of myocardial damage and cardiomyocyte death.4, 5 I/R injury leading to arrhythmias, acute myocardial remodeling, and ventricular systolic dysfunction6 is the main cause for the poor prognosis of AMI. Currently, there is a lack of effective therapies to increase myocardial resistance to reperfusion injury. Therefore, an effective strategy that can at least minimize the extent of myocardial damage induced by reperfusion injury is greatly needed.
急性心肌梗死(AMI)是一种发病率和死亡率都很高的主要心脏疾病。早期快速再灌注仍然是最有效的策略，因为它可以挽救缺血心肌，限制梗死面积，改善临床长期预后。然而，缺血后再灌注本身同时引起不可逆的心肌细胞损失，这一过程称为心肌缺血再灌注(I/R)损伤。心肌I/R诱导了一系列毁灭性的生物变化，包括氧化应激的过度产生和凋亡途径的激活，这两者都有助于心肌损伤和心肌细胞死亡的加剧。4,5 I/R损伤导致心律失常、急性心肌重构、心室收缩功能障碍6是AMI预后不良的主要原因。目前，缺乏有效的方法来增加心肌对再灌注损伤的抵抗。因此，迫切需要一种有效的策略，使再灌注损伤对心肌的损害程度最小化。
It has been recognized that the pathogenesis of myocardial ischemia is accompanied by autonomic imbalance with over-activated sympathetic drive and withdrawal vagal tone.7, 8 Several relatively novel nonpharmacological interventions have been investigated to evaluate the effects of neuromodulation on cardiac diseases with autonomic disorder.9-12 Recently, low-level vagus nerve stimulation (LL-VNS) has been presented to reduce ventricular arrhythmic episodes and limit infarct size in an I/R injury swine model.13 However, the underlying mechanisms of the protective effects of LL-VNS remain unknown. Herein, we evaluate the vagal tone effect on myocardial I/R injury without change of heart rate and blood pressure. We also test the hypothesis that LL-VNS protects hearts from myocardial I/R injury by suppressing oxidative stress and cellular apoptosis.
目前认为，心肌缺血的发病机制是伴随交感神经驱动过度激活和迷走神经张力戒断的自主神经失衡。7,8研究人员研究了几种相对新颖的非药物干预措施，以评估神经调节对伴有自主神经障碍的心脏疾病的影响。最近，在I/R损伤猪模型中，低水平迷走神经刺激(LL-VNS)被证明可以减少室性心律失常发作和限制梗死面积。然而，LL-VNS保护作用的潜在机制尚不清楚。在不改变心率和血压的情况下，我们评估迷走神经张力对心肌I/R损伤的影响。我们还验证了LL-VNS通过抑制氧化应激和细胞凋亡来保护心脏免受心肌I/R损伤的假设。
Methods 方法
Animal Preparation 动物的准备
The study conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health. All animal studies were reviewed and approved by the animal experimental administration of Wuhan University. All of the surgeries were performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
该研究符合美国国立卫生研究院发布的《实验动物护理和使用指南》。所有动物实验均经武汉大学动物实验管理部门审核批准。所有手术均在戊巴比妥钠麻醉下进行，并尽一切努力将痛苦降到最低。
Dogs were anesthetized with sodium pentobarbital (30 mg/kg) and attached to a positive pressure respirator (MAO01746, Harvard Apparatus, Holliston, MA, USA) that was ventilated with room air. Intravenous injections of additional sodium pentobarbital (2 mg/kg) were administrated at the end of each hour during the procedure. Normal saline was infused at 50–100 mL/h to replace spontaneous fluid losses. A sensor-controlled heating pad was applied for all of the dogs to regulate their core body temperature at 36.5 ± 1.5 ℃. Standard electrocardiogram leads were continuously recorded.
犬用戊巴比妥钠(30mg /kg)麻醉，并连接正压呼吸器(MAO01746, Harvard Apparatus, Holliston, MA, USA)，用室内空气通风。在手术过程中每小时结束时静脉注射戊巴比妥钠(2mg /kg)。以50-100 mL/h的速度输注生理盐水，以补充自发失水。采用传感器控制的加热垫将犬体核心温度调节在36.5±1.5℃。连续记录标准心电图导联。
Low-Level Vagus Nerve Stimulation
低水平迷走神经刺激
The left cervical vagal trunk was dissected to expose and isolate it from the carotid sheath. A pair of Teflon-coated silver wires (0.1-mm diameter) was inserted into the cervical vagal trunk and was used to deliver high-frequency stimulation (HFS; 20 Hz, 0.1 millisecond duration, square waves) by a stimulator (Grass-S88, Astro-Med, West Warwick, RI, USA). The threshold was defined as the voltage necessary to slow the sinus rate or atrioventricular (AV) conduction. LL-VNS involved stimulation below the 80% voltage threshold. Prior to each hour of stimulation, the threshold of VNS was determined again to adjust the voltage for LL-VNS for the next hour. During the LL-VNS period, the sinus rate and AH interval were monitored to guarantee that the voltage for stimulation was below the threshold.14
解剖左颈迷走神经干，使其与颈动脉鞘分离。将一对直径为0.1 mm的teflon涂层银丝插入颈迷走干，用于提供高频刺激(HFS;20 Hz, 0.1毫秒持续时间，方波)通过刺激器(Grass-S88, Astro-Med, West Warwick, RI, USA)。阈值定义为减慢窦率或房室传导所需的电压。LL-VNS涉及低于80%电压阈值的刺激。在每小时刺激前，再次测定VNS阈值，调整下一小时的LL-VNS电压。在LL-VNS期间，监测窦率和AH间隔，以确保刺激电压低于阈值。14
Myocardial Ischemic Reperfusion Injury Protocol
心肌缺血再灌注损伤方案
A left thoracotomy was performed in the fourth intercostal space. The left anterior descending coronary (LAD) was isolated in all dogs, and the LAD positioned at approximately 1.0 cm distal from its origin was ligated to produce an I/R injury model. Occlusion was achieved via 3-0 silk and lasted for 60 minutes. After a 60-minute ischemic period, the LAD ligature was released to allow coronary artery circulation to be re-established for 60 minutes.
在第四肋间隙行左开胸术。所有犬均分离左前降冠状动脉(LAD)，结扎位于其起源远端约1.0 cm处的LAD，制作I/R损伤模型。通过3-0丝闭塞，持续60分钟。缺血60分钟后，释放LAD结扎，使冠状动脉循环重新建立60分钟。
Experimental Design 实验设计
Thirty healthy adult male mongrel dogs (body weight, 13–15 kg) were supplied by the Center of Experimental Animals at the Medical College of Wuhan University. All of the dogs were randomly assigned to one of three groups: I/R group (I/R was induced by LAD ligature without LL-VNS, N = 12), LL-VNS group (I/R plus LL-VNS lasted for 120 minutes, N = 9), or sham group (sham surgery without LAD occlusion and LL-VNS, N = 9).
由武汉大学医学院实验动物中心提供健康成年雄性杂种犬30只(体重13-15 kg)。将所有的狗随机分为三组:I/R组(I/R为LAD结扎，无LL-VNS, N = 12)、LL-VNS组(I/R + LL-VNS，持续120分钟，N = 9)和假手术组(假手术，无LAD闭塞，无LL-VNS, N = 9)。
Measurement of Ventricular Arrhythmias Incidences
室性心律失常发生率的测量
After LAD ligation, electrocardiogram was continuously recorded to detect the incidence and duration of ventricular arrhythmias. According to the Lambeth diagnostic convention criteria with modifications,15 ventricular arrhythmias were classified as premature ventricular contraction (PVC), ventricular tachycardia (VT), and ventricular fibrillation (VF). Specifically, PVC was defined as ventricular contractions without atrial depolarization, whereas VT was characterized by more than six consecutive PVCs. VF was defined as a loss of synchronicity of the ECG accompanied by decreased amplitudes and a precipitous fall in blood pressure for 0.1 second.
LAD结扎后连续记录心电图，检测室性心律失常的发生率和持续时间。根据修改后的Lambeth诊断常规标准，将15例室性心律失常分为室性早搏(PVC)、室性心动过速(VT)和室性颤动(VF)。具体来说，PVC被定义为心室收缩而不伴有心房去极化，而VT的特征是连续6次以上的室性早搏。VF被定义为心电图同步性丧失，伴有振幅下降和血压急剧下降0.1秒。
Heart Rate Variability Power Spectral Analysis
心率变异性功率谱分析
Spectral power for HRV was analyzed on 5-minute segments at baseline and approximately 5 minutes after 2 hours I/R finish. The autoregressive algorithm was used to analyze digitized signals from BI9800 Holter monitor (Biomedical Instruments Co. Ltd., Shenzhen, Guangdong, China). Then, the power spectral variables, including a low-frequency component (LF, from 0.04 to 0.15 Hz), high-frequency component (HF, from 0.15 to 0.40 Hz), and a very low-frequency component (VLF, below 0.04 Hz), were determined. The ratio between the LF and HF powers was calculated. A data acquisition system (LabChart Pro, AD Instruments Ltd) was used to measure and analyze HRV.16
HRV的频谱功率在基线时的5分钟段和2小时I/R结束后的约5分钟段进行分析。采用自回归算法对BI9800动态心电图仪(深圳生物医学仪器有限公司)的数字化信号进行分析。然后，确定功率谱变量，包括低频分量(LF，从0.04到0.15 Hz)，高频分量(HF，从0.15到0.40 Hz)和极低频分量(VLF，低于0.04 Hz)。计算了低频功率与高频功率之比。使用数据采集系统(LabChart Pro, AD Instruments Ltd)测量和分析HRV。16
Ischemic-Infarction Size Determination
缺血-梗死大小测定
The myocardial infarct size was assessed with 0.5% Evans Blue and 1.0% triphenyltetrazolium chloride (TTC) staining (Sigma, St. Louis, MO, USA), as described previously.17 The left auricular appendage was cannulated. Evans blue solution was infused into this cannula, which resulted in a dark blue staining of the nonischemic area. Then, the heart was rapidly excised, removed, and irrigated with normal saline to wash out blood from chambers and vessels. Removed heart was cut into 4-mm coronal slices. Slices were placed in the vital dye TTC at 37 °C in the dark for 15 minutes. Nonischemic myocardium was stained blue with Evans blue and ischemic myocardium was stained red with TTC, whereas infarct myocardium was not stained blue or red but appeared white. The infarct size (white) and the area at risk (AAR) (red and white) from the section on the mitral side were determined by using Image Tool software version 3.0. The area ratio of infarct size to the AAR and of the AAR to the ventricular area was calculated and expressed as a percentage.
如前所述，采用0.5% Evans蓝和1.0%三苯基四唑氯(TTC)染色(Sigma, St. Louis, MO, USA)评估心肌梗死面积。17左耳附耳插管。静脉注射Evans蓝溶液，非缺血区呈深蓝色。然后，迅速切除心脏，用生理盐水冲洗心室和血管中的血液。将取出的心脏切成4毫米冠状切片。切片置于活性染料TTC中，37°C，黑暗中放置15分钟。非缺血心肌以Evans蓝染色为蓝色，缺血心肌以TTC染色为红色，而梗死心肌未染色为蓝色或红色，呈白色。使用Image Tool 3.0软件测定二尖瓣侧切片的梗死面积(白色)和危险面积(AAR)(红色和白色)。计算梗死面积与AAR的面积比以及AAR与心室面积的面积比，并以百分比表示。
Neutrophil Infiltration Degree Assessment
中性粒细胞浸润程度评价
Myeloperoxidase (MPO) activity was measured to evaluate the neutrophil infiltration as previously described.18 Aliquots of ischemic tissue (100 mg) in each dog were frozen and stored at –80 °C until MPO was assayed by a commercially available kit (Nanjing Jiancheng Bioengineering Institute, Nanjing City, China). The absorbance at 460 nm was measured via spectrophotometry. The activity of MPO was expressed as units (U) per gram of protein.
髓过氧化物酶(MPO)活性测定评估中性粒细胞浸润如前所述。将每只狗的18等份缺血组织(100 mg)冷冻保存在-80°C，直到用市售试剂盒(南京建成生物工程研究所，中国南京市)检测MPO。用分光光度法测定460 nm处的吸光度。MPO的活性以每克蛋白质单位(U)表示。
Measurement of MDA and SOD Content in Serum and Ischemic Tissue
血清及缺血组织中丙二醛和超氧化物歧化酶含量测定
Blood samples (10 mL) were collected from the femoral vein at baseline and after 2 hours of reperfusion and were then infused into an ice-chilled coagulated tube. Serum was separated by centrifuging at 4,000 rpm for 15 minutes at 4 °C and was then stored at –80 °C until assayed. Aliquots of ischemic tissue (100 mg) were homogenized and centrifuged for 15 minutes at 10,000 rpm and 4 °C. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured using commercialized chemical assay kits (Nanjing Jiancheng Bioengineering Institute) to assess the levels of oxidant stress and antioxidant ability. SOD activity was measured by the xanthine oxidase method as previously described.19 The assay used the xanthine–xanthine oxidase system to yield superoxide ions and produce a red formazan dye with a maximum absorbance at 520 nm. SOD activity was expressed as units per milligram of protein. MDA concentrations were measured according to the thiobarbituric acid (TBA) method and spectrophotometric measurement. The color was generated as a result of a reaction of TBA with MDA. MDA concentrations were assessed via measuring the absorbance of TBA reactive substances at 528 nm.
在基线和再灌注2小时后从股静脉采血(10 mL)，然后输注到冰冻凝固管中。4℃下4000 rpm离心15分钟分离血清，-80℃保存待检测。等份缺血组织(100 mg)匀浆，4°C, 10000 rpm离心15分钟。采用商品化化学检测试剂盒(南京建成生物工程研究所)检测超氧化物歧化酶(SOD)和丙二醛(MDA)，评估氧化应激水平和抗氧化能力。如前所述，采用黄嘌呤氧化酶法测定SOD活性。19该试验使用黄嘌呤-黄嘌呤氧化酶体系产生超氧化物离子并产生最大吸光度为520 nm的红色甲醛染料。SOD活性以每毫克蛋白质的单位表示。采用硫代巴比妥酸(TBA)法和分光光度法测定MDA浓度。这种颜色是TBA与MDA反应的结果。通过测定TBA活性物质在528 nm处的吸光度来评估MDA浓度。
TUNEL Staining TUNEL染色
TUNEL staining was performed to detect apoptosis according to the manufacturer's instructions (Roche Bio-chemicals, Mannheim, Germany).20 Briefly after the sections were deparaffinized with xylene, they were rinsed in PBS and treated with protease K at room temperature. After washing twice, these sections were incubated with TUNEL reaction solution in a humidified environment at 37 °C. After washing in PBS three times, sections were treated with 50 mL of converter-POD in a humidified environment at 37 °C for 30 minutes. Fluorescence microscope (Nikon TE2000, Japan) at EX 450–500 nm/EM515–565 nm was used to analyze stained sections. The TUNEL-positive cells were defined as the cells that exhibited condensed nuclei with an irregular form or split into brown particles. Each slide was examined under a microscope. Three random fields were viewed to detect cell death and calculate the apoptotic index using IPP 6.0 software.
按照制造商的说明书(Roche biochemicals, Mannheim, Germany)进行TUNEL染色检测细胞凋亡。20切片用二甲苯脱蜡后，用PBS冲洗，室温下用蛋白酶K处理。清洗两次后，这些切片与TUNEL反应溶液在37°C的潮湿环境中孵育。PBS洗涤三次后，切片用50ml转化器- pod在37°C的潮湿环境中处理30分钟。使用荧光显微镜(Nikon TE2000，日本)，EX 450-500 nm/ EM515-565 nm对染色切片进行分析。tunel阳性细胞被定义为细胞核浓缩，形状不规则或分裂成棕色颗粒的细胞。每张载玻片都在显微镜下检查。采用IPP 6.0软件观察3个随机场检测细胞死亡，计算细胞凋亡指数。
Western Blotting of Bcl-2 and Bax
Bcl-2和Bax的Western Blotting
To clarify the influence of LL-VNS on apoptosis in this I/R model, the expression of Bcl-2 and Bax (Bcl-2 inhibits apoptosis and Bax induces apoptosis) in ischemic tissue was assessed. Briefly, aliquots of ischemic tissue (50 mg) were homogenized in liquid nitrogen and dissolved in lysis buffer. Extracted protein was denatured and subsequently transferred to polyvinylidene fluoride (PVDF) membranes. The membranes were blocked with nonfat dry milk and incubated overnight at 4 °C with the primary antibodies (monoclonal anti-B-cell Lymphoma Gene 2 [Bcl-2] and mouse anti-Bax Abcam, Inc., UK; used at 1:1000; mouse monoclonal anti-GAPDH, Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA; used at 1:1000). They were then washed in TBST, incubated with horseradish peroxidase (HRP)-conjugated second antibody, and revealed by Immun-Star HRP Substrate. The relative expression of protein was determined using image analyzer software (AlphaEase FC, USA).
为了明确LL-VNS对I/R模型中细胞凋亡的影响，我们检测了缺血组织中Bcl-2和Bax (Bcl-2抑制细胞凋亡，Bax诱导细胞凋亡)的表达。简单地说，将缺血组织等分液(50 mg)在液氮中均质，溶解在裂解缓冲液中。提取的蛋白质变性，随后转移到聚偏二氟乙烯(PVDF)膜。用脱脂牛奶阻断膜，用一抗(单克隆抗b细胞淋巴瘤基因2 [Bcl-2]和小鼠抗bax Abcam, Inc.， UK)在4°C下孵育过夜;1:1000使用;小鼠单克隆抗gapdh, Santa Cruz Biotechnology, Inc, Santa Cruz, CA, USA;1:1000)。然后用TBST洗涤，用辣根过氧化物酶(HRP)偶联的第二抗体孵育，用immune - star HRP底物显示。使用图像分析软件(AlphaEase FC, USA)测定蛋白的相对表达量。
Statistical Analysis 统计分析
Data were illustrated as the mean ± standard error. The independent-samples t-test was used to compare the mean of PVC and VT between two groups. Fisher's exact test was used to compare the incidence of VF. One-way ANOVA was used to demonstrate the difference among groups. In addition, SNK with contrast test was used to compare between two groups. P values <0.05 were considered statistically significant. The SPSS version 17.0 statistical program (SPSS, Inc., Chicago, IL, USA) was used for data analysis.
数据以平均值±标准误差表示。采用独立样本t检验比较两组患者PVC和VT的平均值。采用Fisher精确检验来比较VF的发生率。采用单因素方差分析显示组间差异。另外，采用SNK加对比检验对两组进行比较。P值<0.05认为有统计学意义。使用SPSS 17.0版统计程序(SPSS, Inc.， Chicago, IL, USA)进行数据分析。
Results 结果
There were no significant changes in the threshold of LL-VNS, which indicated that the left vagus nerve was not damaged during this experiment.
左- vns阈值未见明显变化，说明左侧迷走神经在实验过程中未受到损伤。
Effects of LL-VNS on VA Incidence in I/R Heart
l - vns对I/R心脏VA发生率的影响
After the occlusion of the left anterior descending coronary artery to induce I/R, 120 minutes of continuous electrocardiogram recordings indicated that the episodes of ventricular arrhythmias in the I/R group were significantly higher than those in the LL-VNS group. There was a noticeably increased occurrence of VPCs in the first 10–30 minutes after the occlusion of LAD and in the 5–25 minutes after the release of the LAD ligature (Fig. 1B). We observed that the episodes of VPCs and VT were significantly reduced in the LL-VNS group during ischemic and reperfusion periods when compared with the I/R group (Fig. 1C,D). In addition, the mean duration of VT in the ischemic period (I/R group: 11.5 ± 4.3 seconds; LL-VNS group: 3.5 ± 2.6 seconds) and in the reperfusion period (I/R group: 6.9 ± 3.2 seconds; LL-VNS group: 2.7 ± 2.1 seconds) was lower in LL-VNS as well (Fig. 1E, P < 0.05 for all). No interventions were conducted to convert ventricular arrhythmias when VF occurred and no VF episode spontaneously stopped. The dogs died when VF occurred. The number of VF episodes was significantly decreased in the LL-VNS group compared with the I/R group (Fig. 1F).
阻断左冠状动脉前降支诱导I/R后，120分钟连续心电图记录显示，I/R组室性心律失常发作次数明显高于LL-VNS组。在LAD闭塞后的前10-30分钟和LAD结扎解除后的5-25分钟内，VPCs的发生率明显增加(图1B)。我们观察到，与I/R组相比，LL-VNS组在缺血和再灌注期间的VPCs和VT发作明显减少(图1C,D)。缺血期VT平均持续时间(I/R组:11.5±4.3 s;l - vns组:3.5±2.6 s)和再灌注期(I/R组:6.9±3.2 s;LL-VNS组(2.7±2.1秒)的LL-VNS也较低(图1E, P < 0.05)。当室性心动过速发生时，未采取任何干预措施来转换室性心律失常，也没有室性心动过速自行停止。发生VF时，狗死亡。与I/R组相比，LL-VNS组的VF发作次数明显减少(图1F)。
l - vns对缺血再灌注损伤期室性心律失常发生的影响。A:记录左前降支闭塞前后有代表性的心电图。B:缺血期与再灌注期VPB发生的分布。C、D、F:分别表示PVCs、VTs、VFs个数。E: VT持续时间。*P < 0.05。ECG =心电图;低水平迷走神经刺激;PVC =室性早缩;VAs =室性心律失常;VF =心室颤动;室性心动过速。
Effects of LL-VNS on HRV
l - vns对HRV的影响
As shown in Figure 2 (A-C), 2 hours of myocardial I/R injury increased the LF power from 1.38 ± 0.3 to 2.05 ± 0.45 milliseconds2 and the LF/HF ratio from 0.75 ± 0.09 to 1.52 ± 0.16 (both P < 0.05), whereas the HF power was significantly decreased from 1.80 ± 0.40 milliseconds2 to 1.25 ± 0.26 milliseconds2. In contrast, 120 minutes of LL-VNS increased the HF power from 1.79 ± 0.33 to 2.68 ± 0.61 milliseconds2, reduced the LF power from 1.49 ± 0.29 to 0.83 ± 0.18 milliseconds2 and decreased the LF/HF ratio from 0.83 ± 0.12 to 0.32 ± 0.06 (all P < 0.05).
如图2 (A-C)所示，心肌I/R损伤2小时使LF功率从1.38±0.3毫秒增加到2.05±0.45毫秒 2 ，使LF/HF比值从0.75±0.09增加到1.52±0.16 (P均< 0.05)，而HF功率从1.80±0.40毫秒 2 显著降低到1.25±0.26毫秒 2 。相比之下，120分钟的LL-VNS使HF功率从1.79±0.33毫秒增加到2.68±0.61毫秒 2 ，使LF功率从1.49±0.29毫秒降低到0.83±0.18毫秒 2 ，使LF/HF比从0.83±0.12降低到0.32±0.06(均P < 0.05)。
HRV的变化。2 h心肌I/R显著升高LF和LF/HF，但降低HF。经LL-VNS治疗后，HRV的变化完全逆转。HF显著高于基线，LF和LF/HF显著低于基线。* p < 0.05。HF =高频;HRV =心率活力;LF =低频;LF/HF =低频/高频。
Effects of LL-VNS on Myocardial Infarct Size
l - vns对心肌梗死面积的影响
As shown in Figure 3, myocardial infarct size was expressed as the percentage of AAR. The AAR, expressed as the percentage of the total ventricular mass, was slightly higher in the I/R group than the LL-VNS group (43.3% ± 10.8% vs. 40.1% ± 11.3%, P = 0.83). LL-VNS for 120 minutes significantly reduced the myocardial infarction from 47.1% ± 15.1% to 24.9% ± 7.8% when compared to the I/R group (P < 0.05).
如图3所示，心肌梗死面积用AAR百分比表示。以总心室质量百分比表示的AAR在I/R组略高于LL-VNS组(43.3%±10.8% vs. 40.1%±11.3%，P = 0.83)。与I/R组相比，LL-VNS组120 min心肌梗死由47.1%±15.1%显著降低至24.9%±7.8% (P < 0.05)。
心肌梗死面积的测定。A: Evans蓝和TTC双染后的代表性图片。蓝色表示未受威胁心肌;红色表示非梗死面积;白色为心肌梗死区。B:心肌梗死面积以AAR百分比表示。* p < 0.05。MI =心肌梗死;TTC =三苯基四唑氯。
Effects of LL-VNS on Oxidative Stress Activity
l - vns对氧化应激活性的影响
MPO activity in myocardial tissues was used as a measure of neutrophil activity. Myocardial ischemia and reperfusion injury significantly increased MPO activity when compared with the sham group (1.98 ± 0.26 vs. 0.51 ± 0.09 U/g tissue, P < 0.05). LL-VNS significantly reversed this increase in MPO activity after reperfusion injury (0.84 ± 0.17 vs. 1.98 ± 0.26 U/g tissue, P < 0.05) (Fig. 4A).
心肌组织MPO活性作为中性粒细胞活性的量度。心肌缺血再灌注损伤与假手术组比较，MPO活性显著升高(1.98±0.26∶0.51±0.09 U/g, P < 0.05)。LL-VNS显著逆转了再灌注损伤后MPO活性的增加(0.84±0.17比1.98±0.26 U/g, P < 0.05)(图4A)。
心肌和血清氧化应激生物标志物的变化。LL-VNS对心肌MPO、MDA、SOD的影响见A、D、e。LL-VNS对血清MDA、SOD的影响见B、c。*P < 0.05。MDA =髓过氧化物酶;MPO =丙二醛;超氧化物歧化酶。
Figure 5 B,C shows the changes in the MDA and SOD concentrations in the serum. MDA, as a biomarker to detect the activity of pro-oxidative stress, was significantly increased in blood samples during I/R injury period (P < 0.05). In contrast, SOD, as an antioxidant biomarker, was significantly decreased in serum during the I/R injury period (P < 0.05). However, 120 minutes of LL-VNS significantly reduced the MDA concentration and increased the SOD concentration when compared with the I/R group (P < 0.05). Figure 4C,D shows the changes of MDA and SOD concentration in myocardium. Myocardial I/R injury significantly increased the MDA level and reduced the SOD level in cardiac tissue when compared with the sham group (P < 0.05). However, there was no statistical significance observed in the LL-VNS group when compared with the sham group.
图5 B、C显示了血清中MDA和SOD浓度的变化。作为检测促氧化应激活性的生物标志物，MDA在I/R损伤期间显著升高(P < 0.05)。相比之下，抗氧化生物标志物SOD在I/R损伤期间显著降低(P < 0.05)。但与I/R组相比，120分钟的LL-VNS显著降低MDA浓度，升高SOD浓度(P < 0.05)。图4C、D为心肌组织MDA、SOD浓度变化。心肌I/R损伤与假手术组比较，心肌组织MDA水平升高，SOD水平降低(P < 0.05)。然而，与假手术组相比，LL-VNS组无统计学意义。
TUNEL染色检测LL-VNS对心肌梗死细胞凋亡的影响。A:假手术组切片。B: I/R组的一个组。C: LL-VNS组切片(原放大倍数:× 200，棕色表示tunel阳性细胞核，蓝色表示非凋亡细胞)。D:三组细胞凋亡指标。* p < 0.05。末端脱氧核苷酸转移酶介导的dutp -生物素缺口末端标记试验。
Detection of Apoptotic Cells
凋亡细胞的检测
TUNEL staining was performed to detect cardiomyocyte apoptosis among the three groups. TUNEL-positive cells, reported as the percentage of total nuclei, were significantly increased in the I/R injury group compared with the sham group. However, LL-VNS could significantly reduce the percentage of TUNEL-positive cells compared with the I/R group (P < 0.05) (Fig. 5).
TUNEL染色检测各组心肌细胞凋亡情况。与假手术组相比，I/R损伤组tunel阳性细胞占总细胞核的百分比显著增加。但与I/R组相比，LL-VNS可显著降低tunel阳性细胞百分比(P < 0.05)(图5)。
Expression of Bcl-2 and Bax Protein
Bcl-2和Bax蛋白的表达
Western blot analyses of Bcl-2 and Bax protein extracts are shown in Figure 6. Bcl-2 and Bax were present in the ischemic zone in the I/R and LL-VNS groups and in the nonischemic zone in the sham group. Myocardial reperfusion injury was significantly associated with a lower expression of Bcl-2 (0.24 ± 0.06 vs. 0.75 ± 0.13, P < 0.05) and a higher expression of Bax (1.08 ± 0.14 vs. 0.78 ± 0.16, P < 0.05) compared with the sham group. However, LL-VNS significantly increased Bcl-2 protein expression (0.64 ± 0.14 vs. 0.24 ± 0.06, P < 0.05) and reduced Bax protein expression (0.85 ± 0.14 vs. 1.08 ± 0.14, P < 0.05) compared with the I/R group.
Bcl-2和Bax蛋白提取物的Western blot分析如图6所示。Bcl-2和Bax存在于I/R组和LL-VNS组的缺血区，假手术组的非缺血区。心肌再灌注损伤与假手术组相比，Bcl-2表达降低(0.24±0.06比0.75±0.13,P < 0.05)， Bax表达升高(1.08±0.14比0.78±0.16,P < 0.05)。而与I/R组相比，LL-VNS显著提高Bcl-2蛋白表达(0.64±0.14比0.24±0.06,P < 0.05)，降低Bax蛋白表达(0.85±0.14比1.08±0.14,P < 0.05)。
Western blotting检测Bcl-2、Bax蛋白表达。A:三组心肌梗死区均检测到Bcl-2 26 kDa和Bax 21 kDa的特异条带。以31 kDa特异带的GAPDH抗体为参考。B:相对表达为蛋白与GAPDH的比值。* p < 0.05。
Discussion 讨论
In the present study, we observed that LL-VNS exerted protective effects on the myocardium against cardiac damage produced by I/R injury. We also provided evidence for the first time that LL-VNS attenuated myocardial damage and prevented ventricular arrhythmias by inhibiting oxidative stress and reducing cellular apoptosis.
在本研究中，我们观察到LL-VNS对I/R损伤引起的心肌损伤具有保护作用。我们还首次提供了证据表明，LL-VNS通过抑制氧化应激和减少细胞凋亡来减轻心肌损伤和预防室性心律失常。
In the present study, our data show that LL-VNS significantly decreased the occurrence of ventricular arrhythmias including PVCs and spontaneous VT/VF episodes, and that it was equally effective as found in previous studies that showed that VNS protects I/R-injured heart tissue against VAs. Zuanetti et al.21 provided evidence that VNS could reduce the occurrence of ventricular arrhythmias induced by reperfusion injury. Furthermore, Inagaki et al. showed that VNS provided significant protection by increasing the vagal tone against ventricular arrhythmias in a conscious canines model during myocardial ischemia.22 VNS also protects the heart against polymorphic ventricular tachycardia induced by overdriven sympathetic tone.23 Our data indicated that LL-VNS in the absence of any significant change in heart rate conferred similar benefits as VNS in the I/R injury model by modulating the autonomic nervous tone.
在本研究中，我们的数据显示，LL-VNS显著降低室性心律失常(包括室性早搏和自发性VT/VF发作)的发生，并且与之前的研究发现的VNS保护I/ r损伤的心脏组织免受VAs的影响同样有效。Zuanetti等21提供的证据表明，VNS可减少再灌注损伤引起的室性心律失常的发生。此外，Inagaki等人发现，在有意识的犬模型中，VNS通过增加迷走神经张力来对抗心肌缺血期间的室性心律失常，从而提供了显著的保护作用。VNS还可以保护心脏免受交感神经张力过度引起的多形性室性心动过速的影响。我们的数据表明，在心率没有任何显著变化的情况下，通过调节自主神经张力，LL-VNS与I/R损伤模型中的VNS具有相似的益处。
VNS not only reduces the occurrence of VAs22 but also attenuates cardiac remodeling, rescues ischemic myocardium and limits infarct size.24 A previous study demonstrated that VNS could prevent reperfusion injury and reduce infarct size, which suggests that VNS has an antiapoptotic effect on the myocardium both during and after the ischemia-reperfusion period in a rat model.25 More interestingly, Shinlapawittayatorn et al.13 showed that low-amplitude vagal nerve stimulation reduced the ratio of infarct size to the AAR by preventing cardiac mitochondrial dysfunction during the I/R injury period in swine. In the present study, our finding that VNS reduced infarct size and increased vagal tone is consistent with those of previous studies. However, the process of myocardial I/R injury is complex and includes oxidative stress, mitochondrial damage, inflammatory activation, and myocardial apoptosis.
VNS不仅可以减少VAs 22的发生，而且可以减轻心脏重构，挽救缺血心肌，限制梗死面积。24既往研究表明，VNS可预防再灌注损伤，减小梗死面积，提示VNS对大鼠模型缺血-再灌注期及缺血-再灌注后心肌均有抗凋亡作用。25更有趣的是，Shinlapawittayatorn等人13表明，低幅度迷走神经刺激通过防止猪I/R损伤期间心脏线粒体功能障碍，降低了梗死面积与AAR的比例。在本研究中，我们发现VNS减少梗死面积和增加迷走神经张力与先前的研究一致。然而，心肌I/R损伤的过程是复杂的，包括氧化应激、线粒体损伤、炎症激活和心肌凋亡。
Reperfusion triggers a vigorous inflammatory response and augments the generation and release of reactive oxygen species (ROS). ROS induces myocardial oxidative stress, which ultimately exacerbates myocardial cell apoptosis. The balance between antioxidant biomarkers (SOD) and pro-oxidant biomarkers (MDA) represents the activity of oxidant stress.1 A study has shown that VNS effectively reduced the ROS production induced in the ischemic heart rat model.26 Katare et al. demonstrated that VNS prevented the downregulation of the antiapoptotic protein and attenuated left ventricular dysfunction in an I/R rat model.27 All of these data showed that VNS exerted protective effects against the ischemic heart in a strong density with heart rate change. Our data showed that LL-VNS without heart rate reduction inhibited the activity of oxidative stress, as confirmed by the change in the SOD and MDA levels. Apoptosis is an important mechanism for cell death in I/R-injury myocardium and could be regulated by oxygen free radicals and neutrophil accumulation.28, 29 The Bcl-2 family consists of pro-apoptotic and antiapoptotic proteins. The balance between pro- and antiapoptotic proteins determines the occurrence of myocardial apoptosis during the I/R injury period. When myocardial tissues are exposed to oxidative stress, several signal pathways are activated, Bcl-2 family protein expression is changed, and myocardial apoptosis is ultimately induced.30-32 Our study showed that LL-VNS could regulate myocardial apoptosis, as verified by the change in the percentage of TUNEL-positive cells and the ratio of pro-apoptotic (Bax) and antiapoptotic (Bcl-2) proteins. Therefore, we suggested that one potential possible mechanism for the cardiac protective effect of LL-VNS against ischemic reperfusion damage might involve the suppression of oxidant stress and cellular apoptotic reactions.
再灌注触发强烈的炎症反应，增加活性氧(ROS)的生成和释放。ROS诱导心肌氧化应激，最终加重心肌细胞凋亡。抗氧化生物标志物(SOD)和促氧化生物标志物(MDA)之间的平衡代表了氧化应激的活性。1有研究表明，VNS可有效降低缺血心脏大鼠模型诱导的ROS生成。Katare等人在I/R大鼠模型中证实，VNS可阻止抗凋亡蛋白的下调并减轻左心室功能障碍。27这些数据表明，随着心率的变化，VNS对缺血性心脏具有较强的保护作用。我们的数据显示，未降低心率的LL-VNS可以抑制氧化应激活性，这可以通过SOD和MDA水平的变化得到证实。细胞凋亡是I/ r损伤心肌细胞死亡的重要机制，可受氧自由基和中性粒细胞积累的调控。28,29 Bcl-2家族由促凋亡蛋白和抗凋亡蛋白组成。促凋亡和抗凋亡蛋白之间的平衡决定了I/R损伤期心肌凋亡的发生。当心肌组织暴露于氧化应激时，多种信号通路被激活，Bcl-2家族蛋白表达发生改变，最终诱导心肌凋亡。30- 32我们的研究表明，通过tunel阳性细胞百分比的变化以及促凋亡(Bax)和抗凋亡(Bcl-2)蛋白比例的变化，LL-VNS可以调节心肌凋亡。 因此，我们认为LL-VNS对缺血再灌注损伤心脏保护作用的潜在机制可能与抑制氧化应激和细胞凋亡反应有关。
Several mechanisms might be responsible for the cardioprotective effects of VNS against oxidant stress and cellular apoptosis. First, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a major source of oxidant production in the I/R heart. VNS could attenuate NADPH oxidase (Nox) activity by reserving the antioxidant enzyme activity.33 Second, a possible factor might mediate the antioxidant effect of VNS via anti-inflammatory properties. The pro-inflammatory cytokine activated the formation of free radicals during ischemia-reperfusion.34 Thus, inhibition of the inflammatory response with VNS might contribute to the suppression of oxidative stress. Third, a high concentration of norepinephrine (NE) causes oxidative stress and induces cell apoptosis.35, 36 Vagal nerve tone activation suppresses NE release by sympathetic nerves via muscarinic receptors located at adrenergic nerve terminals.37
几种机制可能负责VNS抗氧化应激和细胞凋亡的心脏保护作用。首先，烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶是I/R心脏中氧化剂产生的主要来源。VNS可以通过保留抗氧化酶活性来减弱NADPH氧化酶(Nox)的活性。33其次，一个可能的因素可能通过抗炎特性介导VNS的抗氧化作用。促炎细胞因子激活缺血-再灌注过程中自由基的形成。因此，VNS对炎症反应的抑制可能有助于氧化应激的抑制。第三，高浓度的去甲肾上腺素(NE)引起氧化应激，诱导细胞凋亡。35,36迷走神经张力激活通过位于肾上腺素能神经末梢的毒蕈碱受体抑制交感神经释放NE。37
Clinical Implications 临床意义
Left cervical VNS is an approved treatment for refractory epilepsy and resistant depression.38 Right cervical VNS has been proven to be an effective option for treating heart failure in preclinical studies and a phase II clinical trial. In our present study, we suggested that LL-VNS might be an effective therapeutic strategy for attenuating cardiac remodeling, reducing infarct size, and preventing ventricular arrhythmias during ischemia reperfusion period in the absence of any significant change of heart rate.
左颈VNS是一种被批准的治疗顽固性癫痫和顽固性抑郁症的方法。38在临床前研究和II期临床试验中，右颈VNS已被证明是治疗心力衰竭的有效选择。在我们目前的研究中，我们认为在没有明显心率变化的情况下，低剂量vns可能是一种有效的治疗策略，可以减轻心脏重构，减少梗死面积，防止缺血再灌注期间室性心律失常。
Study Limitations 研究的局限性
There are several limitations in the present study. First, all animals were anesthetized by sodium pentobarbital, which may affect autonomic activity. However, all of the experiments were conducted under identical anesthetic condition. Second, although we found that LL-VNS effectively exerted cardiac protection against myocardial I/R injury via antioxidant stress and antiapoptotic reaction, the exact mechanism needed further study. Third, we identified the effect of LL-VNS on heart in a canine model of I/R damage and immediately performed electrical stimulation after myocardial ischemia occurrence. There is a difference in the amount of time between animal experiments and clinical practice.
目前的研究有几个局限性。首先，所有动物都被戊巴比妥钠麻醉，这可能会影响自主神经活动。然而，所有的实验都是在相同的麻醉条件下进行的。第二，虽然我们发现LL-VNS通过抗氧化应激和抗凋亡反应对心肌I/R损伤有保护作用，但其确切机制有待进一步研究。第三，我们在犬I/R损伤模型中确定了LL-VNS对心脏的影响，并在心肌缺血发生后立即进行电刺激。动物实验和临床实践所需的时间是不同的。
Conclusions 结论
We have provided evidence that LL-VNS exerted significant cardioprotection against ventricular arrhythmias and reduced infarct size by increasing vagal tone during the acute I/R period in canine models. A potential mechanism of such effects of LL-VNS is associated with antioxidative stress and antiapoptosis reactions. Therefore, our data suggested that LL-VNS is a promising neuromodulator for the treatment of ischemic-reperfusion damage when the ischemic myocardium re-oxygenated. More importantly, these beneficial effects of LL-VNS are independent of heart rate reduction.
我们提供的证据表明，在犬模型的急性I/R期，LL-VNS通过增加迷走神经张力，对室性心律失常和减少梗死面积具有显著的心脏保护作用。这种作用的潜在机制可能与抗氧化应激和抗细胞凋亡反应有关。因此，我们的数据表明，LL-VNS是一种很有前途的神经调节剂，用于治疗缺血心肌再氧合时的缺血再灌注损伤。更重要的是，LL-VNS的这些有益作用与心率降低无关。
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