间歇运动干预自发性高血压大鼠病理性心脏肥大:运动强度与健康效应的关系
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摘要
背景:体力活动的健康促进效应与运动强度呈现剂量-反应关系。中低强度持续有氧运动已成为诸多慢性非传染性疾病患者(包括但不限于心力衰竭、高血压、糖尿病、肥胖等)一级和二级预防的重要策略,然而间歇运动尤其是高强度间歇运动(HIIT)的疗效(特别对心血管疾病患者)仍存在争议。目的:对比长期不同强度间歇运动对自发性高血压大鼠(SHR)病理性心脏肥大的作用并在心脏形态、结构、功能和分子等层面分析其调控机制,探讨运动强度与健康效应的关系,为制定针对心血管疾病患者的最佳运动康复处方提供循证依据和有效方法。方法:45只雄性SHR随机分为安静对照组(SHR-SED)、中等强度间歇运动组(SHR-MIIT)和HIIT组(SHR-HIIT),同时将15只年龄、性别相匹配的WistarKyoto大鼠作为正常血压组(WKY)。WKY和SHR-SED组动物保持安静状态,SHR-MIIT、SHR-HIIT组分别进行18周MIIT或HIIT。末次实验后48h利用无创血压仪测定尾动脉血压,超声心动图检测心脏结构与功能,H&E和Masson染色进行组织病理学观察并分别获取心肌细胞横断面积(CSA)和间质胶原容积分数(CVF),RT-PCR法检测心肌胚胎基因[心房钠尿肽(ANP)、脑钠肽(BNP)和β-肌球蛋白重链(β-MHC)]mRNA表达量,Westernblot法检测病理性[钙调神经磷酸酶/活化T细胞核因子(Cn/NFAT)]和生理性[磷脂酰肌醇-3激酶/Akt(PI3-K/Akt)]心脏肥大信号途径各蛋白表达量。结果:1)心脏形态与结构:SHR-SED组左心室出现向心性肥大(心腔缩窄、室壁增厚、CSA升高),CVF增加(P<0.05);SHR-MIIT组左心室发生离心性肥大(心腔扩张、室壁厚度),CVF下降(P<0.05);SHR-HIIT组心脏同样发生离心性肥大,但心腔扩张同时室壁变薄,CVF进一步增加(P<0.05)。2)心功能:SHR-SED组左心室射血分数(LVEF)下降(P<0.05);与SHR-SED组比较,SHR-MIIT组LVEF升高(P<0.05),而SHR-HIIT组则进一步下降(P<0.05)。3)胚胎基因表达:SHR-SED组ANP、BNP和β-MHCm RNA表达量均上调(P<0.05);与SHR-SED组比较,SHR-MIIT组各胚胎基因表达量均下降(P<0.05),SHR-HIIT组BNP和β-MHC升高(P<0.05)。4)心脏肥大信号分子蛋白表达:SHRSED组Cn Aβ升高(P<0.05)、p-NFATc3/t-NFATc3比值降低(P<0.05),PI3-K(p110α)和p-Akt/t-Akt比值无显著性变化(P>0.05);与SHR-SED组比较,SHR-MIIT组CnAβ下降(P<0.05),p-NFATc3/t-NFATc3比值、PI3-K(p110α)和p-Akt/t-Akt比值升高(P<0.05),SHR-HIIT组CnAβ、PI3-K(p110α)和p-Akt/t-Akt比值升高(P<0.05),p-NFATc3/t-NFATc3比值下降(P<0.05)。结论:长期间歇运动对高血压的健康效应存在运动强度依赖性,MIIT诱导SHR心脏由病理性肥大向生理性肥大转变并改善心功能,而HIIT则加重心脏重塑并加速心力衰竭进展,其机制与不同强度间歇运动对心肌胶原代谢、胚胎基因表达以及Cn/NFAT和PI3-K/Akt信号通路的调控存在差异有关。因此,中等强度运动仍然是高血压患者临床康复的最佳方式,HIIT的安全性和有效性有待进一步证实。
Objective: To compare the effects of long-term interval training with different intensities on pathological cardiac hypertrophy in spontaneously hypertensive rats(SHR), and explore the relationship between exercise intensity and health effect.Methods: Forty-five male SHR were randomly divided into a sedentary group(SHR-SED), a moderate-intensity interval training group(SHR-MIIT), or a HIIT group(SHR-HIIT); another fifteen age-and sex-matched Wistar-Kyoto(WYK) rats were set as a normotensive group. Rats in SHR-MIIT and SHR-HIIT groups were performed 18 weeks of MIIT or HIIT training, respectively, and WYK and SHR-SED groups were keep sedentary during experiment. 48 hours after the last training, the caudal artery pressure was measured by using non-invasive blood pressure tester; the cardiac structure and function were detected by using echocardiogram; the myocardial cross sectional area(CSA) and interstitial collagen volumetric fraction(CVF) were obtained by H&E and Masson staining; RT-PCR was used to measure the mRNA levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP) and β-myosin heavy chain(β-MHC); Western blotting was used to measure the protein levels of calcineurin/nuclear factor of activation T cell(Cn/NFAT) and phosphoinositide 3-kinase/Akt(PI3-K/Akt). Results:(1) cardiac morphology and structure: the left ventricle was concentric hypertrophy(i.e., cardiac chamber was constricted, ventricular wall was thickened, CSA was increased) and the CVF was increased(P<0.05) in SHR-SED group; the left ventricle was eccentric hypertrophy(i.e., cardiac chamber was dilatated, ventricular wall was thickened) and the CVF was reduced(P<0.05) in SHR-MIIT group; the SHR-HIIT group was eccentric hypertrophy as well, but the cardiac chamber was dilated and ventricular wall was thinner, the CVF was further increased(P<0.05).(2) cardiac function: the left ventricular ejection fraction(LVEF) was decreased(P<0.05) in SHR-SED group; the LVEF was raised(P<0.05) in SHR-MIIT group but decreased(P<0.05) in SHR-HIIT group compared with SHR-SED group.(3) fetal genes expression: the m RNA levels of ANP, BNP and β-MHC was up-regulated(P<0.05) in SHR-SED group; compared with SHR-SED group, all genes were down-regulated(P<0.05) in SHR-MIIT group while BNP and β-MHC was up-regulated(P<0.05) in SHR-HIIT group.(4) protein expression of cardiac hypertrophy: the CnAβ was increased(P<0.05) and the p-NFATc3/t-NFATc3 ratio was decreased(P<0.05), but the PI3-K(p110α) and p-Akt/t-Akt ratio showed no significant difference(P>0.05) in SHR-SED group; compared with SHR-SED group, the CnAβ was reduced(P<0.05), and the p-NFATc3/t-NFATc3 ratio, PI3-K(p110α) and p-Akt/t-Akt ratio were raised(P<0.05) in SHR-MIIT group; in addition, the CnAβ, PI3-K(p110α) and p-Akt/t-Akt ratio were increased(P<0.05), the pNFATc3/t-NFATc3 ratio was decreased(P<0.05) in SHR-HIIT group. Conclusion: The health effect of long-term interval training on hypertension was dependent on exercise intensity, the MIIT can transform the pathological into physiological hypertrophy to improve the cardiac function, but the HIIT exacerbated cardiac remodeling and accelerate heart failure in SHR. The mechanism was considered to be related to the different regulation of interval training on myocardial collagen metabolism, fetal genes expression as well as the regulation of Cn/NFAT and PI3-K/Akt. Therefore, moderate intensity exercise is still an optimal mode for hypertension patients to rehabilitation in clinical, however, the security and efficiency of HIIT should be further verified.
Objective: To compare the effects of long-term interval training with different intensities on pathological cardiac hypertrophy in spontaneously hypertensive rats(SHR), and explore the relationship between exercise intensity and health effect.Methods: Forty-five male SHR were randomly divided into a sedentary group(SHR-SED), a moderate-intensity interval training group(SHR-MIIT), or a HIIT group(SHR-HIIT); another fifteen age-and sex-matched Wistar-Kyoto(WYK) rats were set as a normotensive group. Rats in SHR-MIIT and SHR-HIIT groups were performed 18 weeks of MIIT or HIIT training, respectively, and WYK and SHR-SED groups were keep sedentary during experiment. 48 hours after the last training, the caudal artery pressure was measured by using non-invasive blood pressure tester; the cardiac structure and function were detected by using echocardiogram; the myocardial cross sectional area(CSA) and interstitial collagen volumetric fraction(CVF) were obtained by H&E and Masson staining; RT-PCR was used to measure the mRNA levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP) and β-myosin heavy chain(β-MHC); Western blotting was used to measure the protein levels of calcineurin/nuclear factor of activation T cell(Cn/NFAT) and phosphoinositide 3-kinase/Akt(PI3-K/Akt). Results:(1) cardiac morphology and structure: the left ventricle was concentric hypertrophy(i.e., cardiac chamber was constricted, ventricular wall was thickened, CSA was increased) and the CVF was increased(P<0.05) in SHR-SED group; the left ventricle was eccentric hypertrophy(i.e., cardiac chamber was dilatated, ventricular wall was thickened) and the CVF was reduced(P<0.05) in SHR-MIIT group; the SHR-HIIT group was eccentric hypertrophy as well, but the cardiac chamber was dilated and ventricular wall was thinner, the CVF was further increased(P<0.05).(2) cardiac function: the left ventricular ejection fraction(LVEF) was decreased(P<0.05) in SHR-SED group; the LVEF was raised(P<0.05) in SHR-MIIT group but decreased(P<0.05) in SHR-HIIT group compared with SHR-SED group.(3) fetal genes expression: the m RNA levels of ANP, BNP and β-MHC was up-regulated(P<0.05) in SHR-SED group; compared with SHR-SED group, all genes were down-regulated(P<0.05) in SHR-MIIT group while BNP and β-MHC was up-regulated(P<0.05) in SHR-HIIT group.(4) protein expression of cardiac hypertrophy: the CnAβ was increased(P<0.05) and the p-NFATc3/t-NFATc3 ratio was decreased(P<0.05), but the PI3-K(p110α) and p-Akt/t-Akt ratio showed no significant difference(P>0.05) in SHR-SED group; compared with SHR-SED group, the CnAβ was reduced(P<0.05), and the p-NFATc3/t-NFATc3 ratio, PI3-K(p110α) and p-Akt/t-Akt ratio were raised(P<0.05) in SHR-MIIT group; in addition, the CnAβ, PI3-K(p110α) and p-Akt/t-Akt ratio were increased(P<0.05), the pNFATc3/t-NFATc3 ratio was decreased(P<0.05) in SHR-HIIT group. Conclusion: The health effect of long-term interval training on hypertension was dependent on exercise intensity, the MIIT can transform the pathological into physiological hypertrophy to improve the cardiac function, but the HIIT exacerbated cardiac remodeling and accelerate heart failure in SHR. The mechanism was considered to be related to the different regulation of interval training on myocardial collagen metabolism, fetal genes expression as well as the regulation of Cn/NFAT and PI3-K/Akt. Therefore, moderate intensity exercise is still an optimal mode for hypertension patients to rehabilitation in clinical, however, the security and efficiency of HIIT should be further verified.
引文
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施曼莉,李晓霞,2015.有氧运动对慢性心力衰竭大鼠病理性心脏肥大的影响[J].体育学刊,22(3):127-134.
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贾祁,李丼,石丼君,等,2018.CaN/NFAT信号通路在有氧运动改善高血压心肌肥大中的作用[J].体育科学,38(12):45-52.
廖兴林,常芸,高晓嶙,等,2009.力竭运动后不同时相大鼠心肌CnAβ的变化[J].中国运动医学杂志,28(4):388-390.
施曼莉,李晓霞,2015.有氧运动对慢性心力衰竭大鼠病理性心脏肥大的影响[J].体育学刊,22(3):127-134.
王增喜,李洁,王悦,2018.高强度间歇训练对大鼠心肌线粒体呼吸链复合体活性的影响[J].中国运动医学杂志,37(4):315-322.
BARNA I,NYúL D,SZENTES T,et al.,2018.Review of the relation between gut microbiome,metabolic disease and hypertension[J].Orv Hetil,159(9):346-351.
BATACAN R B,DUNCAN M J,DALBO V J,et al.,2016.Lightintensity and high-intensity interval training improve cardiometabolic health in rats[J].Appl Physiol Nutr Metab,41(9):945-952.
BENITO B,GAY-JORDI G,SERRANO-MOLLAR A,et al.,2011.Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training[J].Circulat,123(1):13-22.
BESSEM B,DE BRUIJN M C,NIEUWLAND W,et al.,2018.The electrocardiographic manifestations of athlete's heart and their association with exercise exposure[J].Eur J Sport Sci,18(4):587-593.
BORGES J P,MASSON G S,TIBIRICA E,et al.,2014.Aerobic interval exercise training induces greater reduction in cardiac workload in the recovery period in rats[J].Arq Bras Cardiol,102(1):47-53.
BOUTCHER Y N,BOUTCHER S H,2017.Exercise intensity and hypertension:what's new?[J].J Hum Hypertens,31(3):157-164.
CHRISTENSEN P M,KRUSTRUP P,GUNNARSSON T P,et al.,2011.VO2 kinetics and performance in soccer players after intense training and inactivity[J].Med Sci Sports Exerc,43(9):1716-1724.
CONDORELLI G,DRUSCO A,STASSI G,et al.,2002.Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice[J].Proc Natl Acad Sci,99(19):12333-12338.
DIRKX E,DA C M P A,DE WINDT L J,2013.Regulation of fetal gene expression in heart failure[J].Biochim Biophys Acta,1832(12):2414-2424.
DZUDIE A,DZEKEM B S,KENGNE A P,2017.NT-pro BNP and plasma-soluble ST2 as promising biomarkers for hypertension,hypertensive heart disease and heart failure in sub-Saharan Africa[J].Cardiovasc J Afr,28(6):406-407.
GARCIARENA C D,PINILLA O A,NOLLY M B,et al.,2009.Endurance training in the spontaneously hypertensive rat:Conversion of pathological into physiological cardiac hypertrophy[J].Hypertension,53(4):708-714.
GILLEN J B,GIBALA M J,2014.Is high-intensity interval training a time-efficient exercise strategy to improve health and fitness?[J].Appl Physiol Nutr Metab,39(3):409-412.
HAFSTAD A D,LUND J,HADLER-OLSEN E,et al.,2013.Highand moderate-intensity training normalizes ventricular function and mechanoenergetics in mice with diet-induced obesity[J].Diabetes,62(7):2287-2294.
HOLLOWAY T M,BLOEMBERG D,SILVA M L D,et al.,2015.High intensity interval and endurance training have opposing effects on markers of heart failure and cardiac remodeling in hypertensive rats[J].PLoS One,10(3):e0121138.
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