Study on Regulation of Trimetlylamin Oxide by Four Gentlemen Decoction for Improving Myocardial Energy Metabolic Remodeling in Rats with Chronic Heart Failure
Study on Regulation of Trimetlylamin Oxide by Four Gentlemen Decoction for Improving Myocardial Energy Metabolic Remodeling in Rats with Chronic Heart Failure
李烨 1徐强 1袁宏伟1
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作者信息
1. 天津中医药大学第二附属医院,天津 300150
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摘要
目的:探讨四君子汤通过调节氧化三甲胺(trimetlylamine oxide,TMAO)对心力衰竭大鼠心肌能量代谢的影响.方法:70只清洁级健康雄性SD大鼠,适应性饲养3d后,随机选取8 只作为正常组,其余大鼠采用左冠状动脉前降支结扎术制备急性心肌梗死动物模型.采用随机数字表法将造模成功的24 只大鼠分为模型组、四君子汤低剂量组(2.97 g·kg-1)、四君子汤高剂量组(11.88 g·kg-1),每组各8 只,连续灌胃给药4 周,给药体积为10 mL·kg-1,正常组和模型组大鼠给予等体积的生理盐水.采用超声心动图测定各组大鼠左心室射血分数(left ventricular ejection fraction,LVEF)、左心室短轴缩短率(left ventricu-lar fractional shortening,LVFS)、左心室舒张末期内径(left ventricular end diastolic diameter,LVDd)、左心室收缩末期内径(left ventricular end systolic diamete,LVDs)、左心室后壁舒张末期厚度(left ventricular posterior wall at end-diastole,LVPWd)、左心室后壁收缩末期厚度(left ventricular posterior wall at end-systolic,LVPWs);ELISA法检测血清N末端B型利钠肽前体(N-ter-minal pro-B type natriuretic peptide,NT-proBNP)的水平;使用比色法检测血清丙酮酸(pyruvic acid,PA)、游离脂肪酸(free fat-ty acid,FFA)水平;RT-PCR检测心肌组织CPT-1 mRNA、PDH mRNA的表达情况;采用稳定同位素稀释液相色谱-串联质谱法检测大鼠血清中TMAO的含量及心肌组织中ATP的水平;HE染色和透射电镜观察各组大鼠心肌组织结构变化.结果:与正常组比较,模型组大鼠LVDs、LVDd显著升高(P<0.01),LVEF和LVFS明显降低(P<0.01);血清PA、FFA、NT-proBNP及TMAO含量明显升高(P<0.01);大鼠心肌组织CPT-1 mRNA、PDH mRNA水平明显降低(P<0.05),ATP水平明显降低(P<0.05).与模型组比较,四君子汤各剂量组大鼠LVEF、LVFS明显升高(P<0.01);血清FFA及TMAO含量均明显降低(P<0.01);心肌组织大鼠PDH mRNA水平明显升高(P<0.05),ATP水平明显升高(P<0.01).HE染色和透射电镜发现,四君子汤可明显改善心力衰竭大鼠心肌组织结构紊乱.结论:四君子汤可调节肠道菌群代谢产物TMAO的水平,从而改善心肌线粒体能量代谢,抑制心室重塑及心力衰竭的进展.
Abstract
Objective:To investigate the effect of Four Gentlemen Decoction on myocardial energy metabolism substrate utilization by reg-ulating trimethylamine-N-oxide(TMAO),thereby improving mitochondrial energy metabolism in the myocardium,inhibiting myocardial remodeling,and preventing the progression of heart failure.Methods:A total of 70 healthy male SD rats were used,with 8 randomly se-lected as the normal group after 3 days of adaptive feeding.The remaining rats underwent left anterior descending coronary artery liga-tion to establish an acute myocardial infarction model.Successfully modeled rats were randomly divided into the model group,the low-dose Four Gentlemen Decoction group(2.97 g·kg-1),and the high-dose Four Gentlemen Decoction group(11.88 g·kg-1),with8 rats in each group.They were administered the corresponding doses by gavage for 4 weeks,with a dose volume of 10 mL·kg-1.The normal and model groups received an equivalent volume of normal saline.Echocardiography was used to measure left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),left ventricular end-diastolic diameter(LVDd),left ventricular end-systolic diameter(LVDs),left ventricular posterior wall thickness at end-diastole(LVPWd),and left ventricular posterior wall thick-ness at end-systole(LVPWs)in each group.Serum levels of N-terminal pro-B type natriuretic peptide(NT-proBNP)were detected u-sing ELISA,while pyruvic acid(PA)and free fatty acids(FFA)levels were measured by colorimetry.RT-PCR was used to detect the expression of CPT-1 mRNA and PDH mRNA in myocardial tissue.Liquid chromatography-tandem mass spectrometry with stable isotope dilution was employed to measure TMAO levels in serum and ATP levels in myocardial tissue.HE staining and transmission electron mi-croscopy were used to observe structural changes in myocardial tissue across groups.Results:Compared with the normal group,the mod-el group showed significantly increased LVDs and LVDd(P<0.01)and significantly decreased LVEF and LVFS(P<0.01).Serum PA,FFA,NT-proBNP and TMAO levels were significantly elevated(P<0.01).CPT-1 mRNA and PDH mRNA expression in myocardi-al tissue,as well as ATP levels,were significantly decreased(P<0.05).Compared with the model group,each Four Gentlemen group had significantly higher LVEF and LVFS(P<0.01),with significantly reduced serum FFA and TMAO levels(P<0.01).PDH mRNA expression and ATP levels in myocardial tissue were significantly elevated(P<0.05).HE staining and transmission electron microsco-py revealed that Four Gentlemen Decoction significantly improved the disordered myocardial structure in rats with heart failure.Conclu-sion:Four Gentlemen Decoction can regulate the TMAO level of the gut microbiota metabolite,thereby improving myocardial mitochon-drial energy metabolism,inhibiting ventricular remodeling,and preventing the progression of heart failure.
关键词
氧化三甲胺/代谢重构/线粒体能量代谢/四君子汤/慢性心力衰竭/大鼠
Key words
trimetlylamine oxide(TMAO)/metabolic remodeling/mitochondrial energy metabolism/Four Gentlemen Decoction/chronic heart failure/rat
维普
万方数据