早期和晚期有氧运动对野百合碱诱导肺动脉高压大鼠右心衰竭的影响

Effects of early and late aerobic exercise on right heart failure induced by monocrotaline in rats with pulmonary hypertension

背景:临床研究表明,有氧运动是肺动脉高压患者临床治疗的重要补充,能够缓解病情、增加运动耐量并改善生活质量。然而,尚不清楚处于肺动脉高压不同阶段的患者是否可以从运动训练中同等受益。目的:对比早期或晚期有氧运动训练对肺动脉高压大鼠右心衰竭的干预效果,并探讨其可能机制。方法:将60只雄性Wistar大鼠按照随机数字表法分为对照组、模型安静组、模型早期运动组和模型晚期运动组,每组15只。除对照组外,其余3组通过腹腔注射野百合碱(60 mg/kg)制作肺动脉高压模型。模型早期运动组造模后进行8周的跑台有氧运动(60%最大跑速,60 min/d、5 d/周),模型晚期运动组造模后2周进行6周的跑台有氧运动,对照组和模型安静组在鼠笼内安静饲养8周。训练结束后,进行运动能力、右心室血液动力学、心肺功能、心肺病理组织学、心肌线粒体活性氧水平、心肌线粒体呼吸链复合体活性及心肌组织蛋白表达检测。结果与结论:①与模型安静组比较,模型早期、晚期运动组大鼠的运动能力和右心室功能改善(P<0.05),心肌胶原含量及内皮素1、肿瘤坏死因子α/白细胞介素10比值、β-肌球蛋白重链/α-肌球蛋白重链比值下降(P<0.05),血管内皮生长因子和肌浆网钙-三磷酸腺苷酶的蛋白表达量升高(P<0.05),线粒体活性氧免疫荧光强度和3-硝基酪氨酸的蛋白表达量下降(P<0.05),复合体Ⅰ、Ⅱ、Ⅳ和Ⅴ活性升高(P<0.05),然而右心室最大压力、肺动脉加速时间和肺动脉管壁面积/血管总面积比值无明显变化(P>0.05);②与模型晚期运动组比较,模型早期运动组进一步改善了大鼠的运动能力和右心室功能,并下调心肌胶原含量、脑钠肽蛋白表达量及肿瘤坏死因子α/白细胞介素10比值、β-肌球蛋白重链/α-肌球蛋白重链的比值(P<0.05);③结果显示,尽管肺动脉高压大鼠肺血管重构和右心超负荷持续存在,但在疾病不同阶段进行有氧运动训练均具有心脏保护作用,其机制与改善心脏重构、神经激素系统失调、炎症反应以及线粒体氧化应激有关,在疾病早期阶段开始运动获益更大。

BACKGROUND:Clinical studies have shown that aerobic exercise is an important supplement to the clinical treatment of patients with pulmonary hypertension,which can alleviate the disease condition,increase exercise tolerance and improve the quality of life.However,it is not clear whether patients at different stages of pulmonary hypertension can benefit equally from exercise training.OBJECTIVE:To compare the intervention effects of early or late aerobic training on right heart failure in rats with pulmonary hypertension and explore its possible mechanism.METHODS:Sixty male Wistar rats were randomly divided into control group,model sedentary group,model early exercise group and model late exercise group,with 15 rats in each group.The model of pulmonary hypertension was established by intraperitoneal injection of monocrotaline(60 mg/kg)in the latter three groups.The model early exercise group was given 8 weeks of treadmill aerobic exercise(60%maximum running speed,60 minutes per day,5 days a week)after modeling,while the model late exercise group was trained for 6 weeks after 2 weeks of modeling.The control and model sedentary groups were fed quietly in the rat cage for 8 weeks.After training,the exercise performance,right ventricular hemodynamics,cardiopulmonary function,cardiopulmonary histopathology,reactive oxygen species level in mitochondria,activity of mitochondrial respiratory chain complex and expressions of myocardial tissue proteins were detected.RESULTS AND CONCLUSION:Compared with the model sedentary group,exercise performance and right ventricular function improved(P<0.05),myocardial collagen content,endothelin-1,tumor necrosis factor-α/interleukin-10 ratio andβ-myosin heavy chain/α-myosin heavy chain ratio decreased(P<0.05),vascular endothelial growth factor and sarcoplasmic reticulum calcium-adenosine triphosphate enzyme expression increased(P<0.05),immunofluorescence intensity of mitochondrial reactive oxygen species and the protein expression of 3-nitrotyrosine decreased(P<0.05),the activities of complex I,II,IV and V increased in the model early exercise and model late exercise groups(P<0.05),but there were no significant changes in right ventricular maximum pressure,pulmonary acceleration time and pulmonary artery wall area/total vascular area ratio(P>0.05).Compared with the model late exercise group,the model early exercise group further improved exercise performance and right ventricular function,and downregulated collagen content,brain natriuretic peptide protein expression,tumor necrosis factor-α/interleukin-10 ratio andβ-myosin heavy chain/α-myosin heavy chain ratio(P<0.05).To conclude,although pulmonary vascular remodeling and right ventricular overload persist in rats with pulmonary hypertension,exercise training at different stages of the disease has a cardioprotective effect.The mechanism is related to the improvement of cardiac remodeling,neurohormone system imbalance,inflammatory response and mitochondrial oxidative stress.Greater benefit is gained from initiating exercise in the early stage of the disease.