射血分数保留的心力衰竭小鼠端粒缩短的研究

Effect of telomere attrition in mice of heart failure with preserved ejection fraction

目的:探讨端粒缩短与射血分数保留的心力衰竭(HFpEF)间的关系。方法:野生型C57BL/6J小鼠、第二代端粒酶敲除(mTRG2)和第三代mTRKO(mTRG3)小鼠简单随机抽样法分为对照组和HFpEF组,每组各8只。对照组给予标准饲料和饮水,HFpEF组给予60%高脂饲料和含0.5 g/L N-硝基-L-精氨酸甲酯(L-NAME)的饮水,造模16周。造模开始后每2周检测小鼠左室射血分数(LVEF)、二尖瓣口舒张早期和晚期血流速度峰值的比值(E/A)、舒张早期二尖瓣口血流速度峰值和二尖瓣环运动速度峰值的比值(E/e')、左室整体纵向应变(GLS)、舒张末期左室前壁厚度(LVAWd)和舒张末期左室后壁厚度(LVPWd),评估左室收缩与舒张功能及心室重构情况。造模16周后,评估小鼠收缩期血压(SBP)、舒张期血压(DBP)和血脂水平。结果:高脂饮食和L-NAME饮水诱导造模的16周期间,各组LVEF差异无统计学意义,HFpEF组野生型小鼠在第8周出现了E/e'、E/A、LVAWd和LVPWd上升及GLS的下降(P<0.05),提示舒张功能降低和左室肥厚,即出现HFpEF表型。HFpEF组mTRG2小鼠、mTRG3小鼠分别在第6周和第4周出现了HFpEF表型。造模16周后,HFpEF组各基因型小鼠的血脂、收缩压、舒张压均较对照组同基因型小鼠明显升高(P<0.05)。结论:端粒缩短可以促进由高脂饮食和L-NAME饮水联合诱导的小鼠HFpEF早期发生和形成。

Objective:To explore the relationship between telomere attrition and heart failure with preserved ejection fraction(HFpEF).Methods:Wild-type C57BL/6J mice,second-generation mTRKO mice(mTRG2)and third-generation mTRKO mice(mTRG3)were divided into control and HFpEF groups by a random sampling method(n=8 in each group).The control group was given routine feed and normal drinking water,while the model group was given 60%high-fat diet and drinking water containing 0.5 g/L N-nitro-L-arginine methyl ester(L-NAME)for 16 weeks.Left ventricular ejection fraction(LVEF),peak early to late trans-mitral flow velocity ratio(E/A),peak early diastolic mitral valve flow to annular motion velocity ratio(E/e'),global longitudinal strain(GLS),left ventricular anterior(LVAWd)and posterior wall dimensions(LVPWd)were assessed every 2 weeks.Systolic(SBP)and diastolic blood pressure(DBP)and lipid profile were determined at 16 weeks.Results:After 16 weeks of treatment with high-fat diet and L-NAME drinking water,there were no significant differences in LVEF values between groups in each genotype.Wild-type mice showed a decrease in diastolic function indices including a increse in E/e',E/A,LVAWd and LVPWd and a decrease in GLS at 8 weeks.HFpEF phenotype was observed in mTRG2 at 6 weeks and in mTRG3 at 4 weeks,respectively.After 16 weeks of modeling,lipid levels,SBP and DBP were significantly higher in the HFpEF group compared to control group of same genotypes(P<0.05).Conclusion:Telomere attrition accelerates the development of HFpEF with the combination of high-fat diet and L-NAME drinking water.