有氧运动激活PVN区FGF21/FGFR1-AMPK-Sirt1/PGC-1α通路并部分通过“脑-心轴”改善心肌梗死小鼠心功能  

Activation of the FGF21/FGFR1-AMPK-Sirt1/PGC-1αPathway in the PVN by Aerobic Exercise and Partial Improvement of Cardiac Function in Myocardial Infarction Mice via the“Brain-Heart Axis”

作　　者：冯丽丽 张泽洲 李博文 Yong Su Sean 田振军[1] FENG Lili;ZHANG Zezhou;LI Bowen;YONG Su Sean;TIAN Zhenjun(Institute of Sports Biology,College of Physical Education,Shaanxi Nomal University,Xi'an 710119,Shaanxi China;Department of Sport and Exercise Science,College of Education,Zhejiang University,Hangzhou 310058,Zhejiang China;Shaanxi Petroleum and Chemical Engineering School,Xi'an 710061,Shaanxi China)

机构地区：[1]陕西师范大学体育学院暨运动生物学研究所,陕西西安710119 [2]浙江大学教育学院体育学系,浙江杭州310058 [3]陕西省石油化工学校,陕西西安710061

出　　处：《北京体育大学学报》2024年第11期89-101,共13页Journal of Beijing Sport University

基　　金：国家自然科学基金面上项目“有氧运动通过GDF5介导发挥心梗心脏保护作用及其机制研究”(项目编号:32171128)。

摘　　要：目的:探讨有氧运动减轻心肌梗死小鼠下丘脑室旁核(paraventricular nucleus,PVN)氧化应激并通过“脑-心轴”改善心肌梗死小鼠心功能的作用机制。为“心-脑综合征”的运动康复方法与靶标筛选提供实验依据。材料与方法:10月龄雄性C57BL/6J野生型和Fgf21敲除小鼠,随机分为假手术组(S)、心肌梗死安静对照组(MI)、心肌梗死+有氧运动组(ME)、Fgf21敲除后心肌梗死+有氧运动组(KME)。采用左冠状动脉前降支永久性结扎制备MI模型,小动物跑台进行有氧运动干预,5 d/周×4周。神经示踪实验检测PVN区神经元与心脏的投射关系;心动超声检测心功能;心脏Masson染色评估心肌纤维化程度;试剂盒检测T-SOD和MDA;Western blotting检测PVN区组织FGF21、FGFR1、p-AMPK、AMPK、Sirt1、PGC-1α、SOD1、SOD2、ALCAT1、Bax和Bcl-2表达水平,检测心脏组织M2AChR、Collagen-1、Collagen-3、BNP基因和蛋白表达水平。结果:1)神经示踪结果显示,PVN区神经元与心脏存在直接投射关系;2)与S组比较,MI组PVN区Sirt1、ALCAT1、Bax/Bcl-2、ROS和MDA水平显著升高(P<0.01),TUNEL阳性颗粒增加(P<0.01),FGFR1、PGC-1α、SOD2蛋白表达和T-SOD水平显著降低(P<0.01),心肌纤维化面积增加,心功能受损;3)与MI组比较,ME组PVN区FGF21、FGFR1、p-AMPK/AMPK、Sirt1、PGC-1α、SOD1、SOD2蛋白表达与T-SOD水平显著升高(P<0.01,P<0.05),TUNEL阳性颗粒显著减少(P<0.01),ALCAT1、Bax/Bcl-2、ROS与MDA水平显著降低(P<0.01),心肌纤维化与心功能显著改善;4)与ME组比较,KME组PVN区Bax/Bcl-2比值显著升高(P<0.05),FGF21、FGFR1、p-AMPK/AMPK、Sirt1、PGC-1α、SOD1、SOD2蛋白表达水平显著降低(P<0.01,P<0.05),心肌纤维化面积增加,心功能改善作用被削弱。结论:有氧运动可激活PVN区的FGF21/FGFR1-AMPK-Sirt1/PGC-1α通路,降低氧化应激,抑制神经元凋亡,减轻心肌梗死小鼠PVN区神经元损伤,并部分通过“脑-心轴”发挥心肌梗死后心功能的改善作用。Objective:The aims of this study are to explore the mechanism by which aerobic exercise alleviates oxidative stress in the paraventricular nucleus(PVN)and improves cardiac function in mice with myocardial infarction via the brain-heart axis,and provide experimental basis for exercise rehabilitation method and target selection of“heart-brain syndrome”.Materials and Methods:Ten-month-old male C57BL/6J wild mice and Fgf21 knockout mice were randomly divided into sham-operated group(S),myocardial infarction group(MI),MI with aerobic exercise group(ME),and Fgf21 knockout MI with aerobic exercise group(KME).The MI model was established by permanent ligation of the left anterior descending coronary artery(LAD),and aerobic exercise intervention was performed by using a treadmill,5d/wk×4wk.Neural tracing experiment was conducted to detect the projection relationship between neurons in the PVN area and the heart in mice.The cardiac function was measured by echocardiography.Masson staining was used to evaluate myocardial fibrosis.Levels of T-SOD and MDA were detected by respective kits.Western Blotting was uses to detect the protein expression levels of FGF21,FGFR1,p-AMPK,AMPK,Sirt1,PGC-1α,SOD1,SOD2,ALCAT1,Bax and Bcl-2 in PVN tissues.The mRNA and protein expression levels of M2AChR,Collagen-1,Collagen-3,and BNP in cardiac tissues were analyzed.Results:(1)The results of neural tracer showed that there is a direct projection relationship between neurons in the PVN area and the heart;(2)Compared with the S group,the levels of Sirt1,ALCAT1,Bax/Bcl-2,ROS,MDA,and TUNEL positive particles were significantly increased in the PVN of MI mice,while the levels of FGFR1,PGC-1α,SOD2 and T-SOD were significantly decreased.There was also a significant impairment in cardiac function and an increase in myocardial fibrosis in the PVN of the MI group;(3)FGF21,FGFR1,p-AMPK/AMPK,Sirt1,PGC-1α,SOD1,SOD2 protein expression levels and T-SOD levels were significantly increased in the ME group,while the number of TUNEL positive particles,and

关 键 词：FGF21 有氧运动 心肌梗死 PVN 器官交互 心功能 

分 类 号：R54[医药卫生—心血管疾病]