Metabolomic analysis of pressure-overloaded and infarcted mouse hearts

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...

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Published in:Circulation. Heart failure Vol. 7; no. 4; p. 634
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 01.07.2014
Subjects:
Animals
Cardiomegaly - diagnosis
Cardiomegaly - metabolism
Cardiomegaly - physiopathology
Disease Models, Animal
Echocardiography
Energy Metabolism - physiology
Heart Failure - diagnosis
Heart Failure - metabolism
Heart Failure - physiopathology
Male
Mice
Mice, Inbred C57BL
Myocardial Infarction - diagnosis
Myocardial Infarction - metabolism
Myocardial Infarction - physiopathology
Myocardium - metabolism
Myocardium - pathology
Oxidative Stress
Stroke Volume
Tandem Mass Spectrometry
heart failure
hypertrophy
metabolomics
mitochondria
amino acids
glycolysis
oxidative stress
ISSN:1941-3297, 1941-3297
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Summary: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. 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. 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.
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ISSN:1941-3297
1941-3297
DOI:10.1161/CIRCHEARTFAILURE.114.001151