压力超负荷和梗死小鼠心脏的代谢组学分析
Metabolomic analysis of pressure-overloaded and infarcted mouse hearts.
作者信息
Sansbury Brian E, DeMartino Angelica M, Xie Zhengzhi, Brooks Alan C, Brainard Robert E, Watson Lewis J, DeFilippis Andrew P, Cummins Timothy D, Harbeson Matthew A, Brittian Kenneth R, Prabhu Sumanth D, Bhatnagar Aruni, Jones Steven P, Hill Bradford G
机构信息
From the Department of Medicine, Institute of Molecular Cardiology, Division of Cardiology (B.E.S., A.M.D.M., Z.X., A.C.B., R.E.B., L.J.W., A.P.D., K.R.B., A.B., S.P.J., B.G.H.), Department of Medicine, Diabetes and Obesity Center (B.E.S., Z.X., A.C.B., T.D.C., M.A.H., K.R.B., A.B., S.P.J., B.G.H.), Department of Biochemistry and Molecular Biology (A.C.B., A.B., B.G.H.), and Department of Physiology and Biophysics (B.E.S., A.M.D., R.E.B., L.J.W., A.B., S.P.J., B.G.H.), University of Louisville, KY; Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, and Birmingham VAMC, AL (S.D.P.); and Department of Medicine, Johns Hopkins University, Baltimore, MD (A.P.D.).
出版信息
Circ Heart Fail. 2014 Jul;7(4):634-42. doi: 10.1161/CIRCHEARTFAILURE.114.001151. Epub 2014 Apr 24.
BACKGROUND
Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Hence, we investigated the impact of pressure overload and infarction on myocardial metabolism.
METHODS AND RESULTS
Male C57BL/6J mice were subjected to transverse aortic constriction or permanent coronary occlusion (myocardial infarction [MI]). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both transverse aortic constriction and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched-chain amino acids were observed after 1 week of transverse aortic constriction and 5 days after MI. Changes in branched-chain amino acids after MI were associated with myocardial insulin resistance. Longer duration of transverse aortic constriction and MI led to a decrease in purines, acylcarnitines, fatty acids, and several lysolipid and sphingolipid species but a marked increase in pyrimidines as well as ascorbate, heme, and other indices of oxidative stress. Cardiac remodeling and contractile dysfunction in hypertrophied hearts were associated with large increases in myocardial, but not plasma, levels of the polyamines putrescine and spermidine as well as the collagen breakdown product prolylhydroxyproline.
CONCLUSIONS
These findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extracellular matrix remodeling, insulin resistance and perturbations in amino acid, and lipid and nucleotide metabolism.
背景
心脏肥大和心力衰竭与代谢失调及慢性能量缺乏状态相关。尽管已描述了个体代谢途径中的几种不同变化，但尚未对体内肥厚和衰竭心脏的代谢组学变化进行全面评估。因此，我们研究了压力超负荷和梗死对心肌代谢的影响。
方法与结果
对雄性C57BL/6J小鼠进行主动脉缩窄或永久性冠状动脉闭塞（心肌梗死[MI]）。采用液相色谱/串联质谱（LC/MS/MS）和气相色谱/质谱（GC/MS）技术相结合的方法测量这些心脏中的288种代谢物。主动脉缩窄和心肌梗死均与心肌代谢的深刻变化相关，影响了所测所有代谢物的40%。主动脉缩窄1周后和心肌梗死后5天观察到支链氨基酸有显著变化。心肌梗死后支链氨基酸的变化与心肌胰岛素抵抗有关。主动脉缩窄和心肌梗死持续时间延长导致嘌呤、酰基肉碱、脂肪酸以及几种溶血磷脂和鞘脂类物质减少，但嘧啶以及抗坏血酸、血红素和其他氧化应激指标显著增加。肥厚心脏中的心脏重塑和收缩功能障碍与心肌中多胺腐胺和亚精胺以及胶原蛋白降解产物脯氨酰羟脯氨酸水平大幅升高有关，但血浆中这些物质水平未升高。
结论
这些发现揭示了肥厚和衰竭心脏共同存在的广泛代谢重塑，这表明细胞外基质重塑、胰岛素抵抗以及氨基酸、脂质和核苷酸代谢紊乱。
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