时间限制性进食对HFpEF小鼠心肌损伤改善及血清和心肌组织FGF21水平调节作用  

Effect of time-restricted feeding on myocardial injury and its regulatory effect on FGF21 level in serum and myocardial tissues in mice with heart failure with preserved ejection fraction

作　　者：安慧仙 王瑞 孙梦娜 李炜 康晓军 曾广伟 AN Huixian;WANG Rui;SUN Mengna;LI Wei;KANG Xiaojun;ZENG Guangwei(Department of Cardiology,Xi'an International Medical Center Hospital,Xi'an 710100,China)

机构地区：[1]西安国际医学中心医院心内科,西安710100

出　　处：《山东医药》2024年第27期10-16,共7页Shandong Medical Journal

基　　金：陕西省重点研发项目(S2023-YF-YBSF-1488)。

摘　　要：目的观察时间限制性进食(TRF)对射血分数保留性心力衰竭(HFpEF)小鼠心功能障碍、心肌重构、心肌线粒体结构及功能、心肌氧化应激反应、心肌能量代谢的改善及对血清和心肌组织FGF21水平的调节作用,以探讨TRF对HFpEF心肌损伤的改善作用及机制。方法30只成纤维细胞生长因子21(FGF21)敲除(Fgf21^(-/-))小鼠均分为FGF21敲除自由进食(ALb)组和FGF21敲除TRF组,30只野生型(WT)小鼠均分为野生ALb组、野生TRF组。上述四组均给予60%高脂饲料,并且在每日饮水中加入Nω-硝基-L-精氨酸甲酯盐酸盐(L-NAME,0.5 g/L)建立HFpEF模型。野生TRF组和FGF21敲除TRF组小鼠接受TRF,每晚21:00至次日5:00进食,其余时间禁食;野生ALb组和FGF21敲除ALb组小鼠24 h均开放进食。四组均喂养8周,观察小鼠心肌损伤相关指标:心脏功能(LVEF、E/A、E/E'、BNP)、心肌重构情况(心肌肥厚程度相关指标心脏指数HW/TL、心肌细胞平均横截面积,心肌纤维化程度相关指标心肌胶原沉积程度及心肌纤维化相关基因Col1a1、Col3a1、Fn1和CTGF mRNA)、心肌线粒体结构及功能(损伤线粒体比、ATP生成量、心肌ATP含量、复合物Ⅰ活性、复合物Ⅴ活性)、心肌氧化应激水平(ROS、SOD活性,MDA含量)、心肌能量代谢情况(脂肪酸氧化关键分子CD36、CPT1b及13C Ac-CoA百分比,葡萄糖代谢相关基因Glut1、Glut4、PFK1 mRNA表达水平)以及血清、心肌组织FGF21表达水平。结果各组喂养8周时,与野生ALb组相比,野生TRF组小鼠E/A、E/E′值及血清BNP水平降低(P均<0.01);心脏质量、HW/TL值及心肌细胞平均横截面积降低(P均<0.01);心脏左室胶原占比及Col1a1、Col3a1、Fn1、CTGF mRNA表达降低(P均<0.01);心肌损伤线粒体占比减小,线粒体ATP生成量、线粒体复合物Ⅰ和Ⅴ活性升高(P均<0.01);心肌ROS生成及MDA含量减少,SOD活性升高(P均<0.01);心肌CD36和CPT1b表达升高,^(13)C Ac-CoA百分比上升(P均<0.01);心肌Glut 1、GObjective To observe the effects of time-restricted feeding(TRF)on cardiac dysfunction,myocardial remodeling,myocardial mitochondrial structure and function,myocardial oxidative stress response,and myocardial energy metabolism in mice with heart failure with preserved ejection fraction(HFpEF),and to investigate the regulatory role of TRF on the levels of fibroblast growth factor 21(FGF21)in serum and myocardial tissues,in order to explore the role and mechanism of TRF in ameliorating myocardial injury in HFpEF.Methods Thirty FGF21 knockout(Fgf21^(-/-))mice were divided into the Fgf21^(-/-)+ALb group and Fgf21^(-/-)+TRF group.Thirty wild-type(WT)mice were divided into the WT+ALb group and WT+TRF group.Mice in all the four groups were fed a 60%high-fat diet,and Nω-nitro-L-arginine methyl ester hydrochloride(L-NAME,0.5 g/L)was added to daily drinking water to establish the HFpEF models.Mice in the WT+TRF group and Fgf21^(-/-)+TRF group underwent TRF,with feeding allowed from 21:00 to 05:00 the next day and fasting during the rest of the time.Mice in the WT+ALb group and Fgf21^(-/-)+ALb group had access to food 24 h a day.After 8 weeks,the myocardial injury-related indicators were observed,including cardiac function(LVEF,E/A,E/E',BNP),myocardial remodeling(HW/TL,mean cross-sectional area of cardiomyocyte,myocardial collagen deposition,and the mRNA levels of fibrosis-related genes Col1a1,Col3a1,Fn1,and CTGF),myocardial mitochondrial structure and function(damaged mitochondria ratio,ATP production,myocardial ATP content,Complex I activity,Complex V activity),myo‐cardial oxidative stress levels(ROS production,SOD activity,MDA content),myocardial energy metabolism(protein ex‐pression levels of CD36,CPT1b,the percentage of ^(13)C Ac-CoA,and the mRNA levels of glucose metabolism-related genes Glut1,Glut4,PFK1),as well as FGF21 expression levels in serum and myocardial tissues.Results After 8 weeks of feeding,compared with the WT+ALb group,the E/A,E/E'values and serum BNP level decreased(all P<0.01),heart weight,HW/TL

关 键 词：时间限制性进食 心力衰竭 射血分数保留性心力衰竭 成纤维细胞生长因子21 线粒体功能 氧化应激 脂肪酸代谢 葡萄糖代谢 

分 类 号：R541.6[医药卫生—心血管疾病]