CardioNet: A human metabolic network suited for the study of cardiomyocyte metabolism

BackgroundAvailability of oxygen and nutrients in the coronary circulation is a crucial determinant of cardiac performance. Nutrient composition of coronary blood may significantly vary in specific physiological and pathological conditions, for example, administration of special diets, long-term starvation, physical exercise or diabetes. Quantitative analysis of cardiac metabolism from a systems biology perspective may help to a better understanding of the relationship between nutrient supply and efficiency of metabolic processes required for an adequate cardiac output.ResultsHere we present CardioNet, the first large-scale reconstruction of the metabolic network of the human cardiomyocyte comprising 1793 metabolic reactions, including 560 transport processes in six compartments. We use flux-balance analysis to demonstrate the capability of the network to accomplish a set of 368 metabolic functions required for maintaining the structural and functional integrity of the cell. Taking the maintenance of ATP, biosynthesis of ceramide, cardiolipin and further important phospholipids as examples, we analyse how a changed supply of glucose, lactate, fatty acids and ketone bodies may influence the efficiency of these essential processes.ConclusionsCardioNet is a functionally validated metabolic network of the human cardiomyocyte that enables theorectical studies of cellular metabolic processes crucial for the accomplishment of an adequate cardiac output.

[1]  Fabio Di Lisa,et al.  Increased inducible nitric oxide synthase and arginase II expression in heart failure: no net nitrite/nitrate production and protein S-nitrosylation. , 2010, American journal of physiology. Heart and circulatory physiology.

[2]  B. McManus,et al.  Biological response to Bard Clamshell Septal Occluders in the canine heart. , 1996, Circulation.

[3]  E. Saggerson,et al.  Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation. , 1993, The Biochemical journal.

[4]  Jerry Vockley,et al.  Human Acyl-CoA Dehydrogenase-9 Plays a Novel Role in the Mitochondrial β-Oxidation of Unsaturated Fatty Acids* , 2005, Journal of Biological Chemistry.

[5]  O. Demin,et al.  The Edinburgh human metabolic network reconstruction and its functional analysis , 2007, Molecular systems biology.

[6]  M. Miyazaki,et al.  Loss of stearoyl-CoA desaturase 1 rescues cardiac function in obese leptin-deficient mice , 2010, Journal of Lipid Research.

[7]  P. Achterberg,et al.  Myocardial adenosine cycling rates during normoxia and under conditions of stimulated purine release. , 1986, The Biochemical journal.

[8]  A. Orth,et al.  Large-scale analysis of the human and mouse transcriptomes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. B. Davidson,et al.  Intermediary metabolism of phospholipids. The biosynthesis of phosphatidylglycerophosphate and phosphatidylglycerol in heart mitochondria. , 1969, Biochimica et biophysica acta.

[10]  N. G. Stepanova,et al.  Interrelationship between glycolysis and the anaerobic part of the pentose phosphate pathway of carbohydrate metabolism in the myocardium. , 1980, Advances in enzyme regulation.

[11]  H. Stam,et al.  Characterization of mono-, di- and triacylglycerol lipase activities in the isolated rat heart. , 1986, Biochimica et biophysica acta.

[12]  William C Stanley,et al.  Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-&agr; in Pacing-Induced Heart Failure , 2002, Circulation.

[13]  H. Holzhütter.  The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks. , 2004, European journal of biochemistry.

[14]  Andreas Hoppe,et al.  FASIMU: flexible software for flux-balance computation series in large metabolic networks , 2011, BMC Bioinformatics.

[15]  M. Rider,et al.  Mechanisms of control of heart glycolysis. , 1998, European journal of biochemistry.

[16]  Jing Liu,et al.  Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy. , 2003, The Journal of clinical investigation.

[17]  Monica L. Mo,et al.  Global reconstruction of the human metabolic network based on genomic and bibliomic data , 2007, Proceedings of the National Academy of Sciences.

[18]  H. Taegtmeyer,et al.  [5-3H]glucose overestimates glycolytic flux in isolated working rat heart: role of the pentose phosphate pathway. , 2001, American journal of physiology. Endocrinology and metabolism.

[19]  Y. Ho,et al.  Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1. , 2003, Journal of molecular and cellular cardiology.

[20]  Y. Hatefi,et al.  Dehydrogenase and transhydrogenase properties of the soluble NADH dehydrogenase of bovine heart mitochondria. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Harvey J. Greenberg,et al.  Reconstruction and Functional Characterization of the Human Mitochondrial Metabolic Network Based on Proteomic and Biochemical Data* , 2004, Journal of Biological Chemistry.

[22]  Y. Hasin,et al.  Effect of cholesterol depletion on the electrical activity of rat heart myocytes in culture. , 1980, Journal of molecular and cellular cardiology.

[23]  Milton H. Saier,et al.  TCDB: the Transporter Classification Database for membrane transport protein analyses and information , 2005, Nucleic Acids Res..

[24]  R. Shohet,et al.  Specific antioxidant selenoproteins are induced in the heart during hypertrophy. , 2011, Archives of biochemistry and biophysics.

[25]  Carlo Guarnieri,et al.  Involvement of polyamines in apoptosis of cardiac myoblasts in a model of simulated ischemia. , 2006, Journal of molecular and cellular cardiology.

[26]  Gary Fiskum,et al.  Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition. , 2010, Biochimica et biophysica acta.

[27]  Matthew D. Jankowski,et al.  Group contribution method for thermodynamic analysis of complex metabolic networks. , 2008, Biophysical journal.

[28]  Steffen Scheer,et al.  Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure , 2011, European journal of heart failure.

[29]  Elmar Heinzle,et al.  Metabolic flux analysis in systems biology of mammalian cells. , 2012, Advances in biochemical engineering/biotechnology.

[30]  G. Lopaschuk,et al.  Contribution of glycogen to aerobic myocardial glucose utilization. , 1996, Circulation.

[31]  C M Caldarera,et al.  Polyamine and nucleic acid metabolism in myocardial hypertrophy of the overloaded heart. , 1974, Journal of molecular and cellular cardiology.

[32]  Andrew M. Jenkinson,et al.  Ensembl 2009 , 2008, Nucleic Acids Res..

[33]  Markus J. Herrgård,et al.  Network-based prediction of human tissue-specific metabolism , 2008, Nature Biotechnology.

[34]  Rakesh Nagarajan,et al.  Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment* , 2010, The Journal of Biological Chemistry.

[35]  David F. Horrobin,et al.  Metabolism of linoleic and α-linolenic acids in cultured cardiomyocytes: Effect of different N-6 and N-3 fatty acid Supplementation , 1996 .

[36]  Minghui Zhang,et al.  Cloning and functional characterization of ACAD-9, a novel member of human acyl-CoA dehydrogenase family. , 2002, Biochemical and biophysical research communications.

[37]  H A Krebs,et al.  Utilization of energy-providing substrates in the isolated working rat heart. , 1980, The Biochemical journal.

[38]  F. Galvano,et al.  Effects of omega-3 polyunsaturated fatty acids on cardiac myocyte protection. , 2011, Frontiers in bioscience.

[39]  M. Alterman,et al.  Direct identification of cytochrome P450 isozymes by matrix-assisted laser desorption/ionization time of flight-based proteomic approach. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[40]  C. Hoppel,et al.  Fatty acid import into mitochondria. , 2000, Biochimica et biophysica acta.

[41]  U. Sauer,et al.  Article number: 62 REVIEW Metabolic networks in motion: 13 C-based flux analysis , 2022 .

[42]  J. Górski,et al.  Effect of substrate supply and beta-adrenergic blockade on heart glycogen and triglyceride utilization during exercise in the rat , 1980, European Journal of Applied Physiology and Occupational Physiology.

[43]  David S. Wishart,et al.  HMDB: a knowledgebase for the human metabolome , 2008, Nucleic Acids Res..

[44]  Daniel A Beard,et al.  Phosphate metabolite concentrations and ATP hydrolysis potential in normal and ischaemic hearts , 2008, The Journal of physiology.

[45]  G. Shulman,et al.  Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. , 1999, The American journal of physiology.

[46]  Jingfei Huang,et al.  Reconstruction and analysis of human heart-specific metabolic network based on transcriptome and proteome data. , 2011, Biochemical and biophysical research communications.

[47]  A. Lochner,et al.  Sarcolemmal phospholipid fatty acid composition and permeability. , 1988, Biochimica et biophysica acta.

[48]  C Cobelli,et al.  Myocardial metabolism in insulin-deficient diabetic humans without coronary artery disease. , 1990, The American journal of physiology.

[49]  C. Gille,et al.  HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology , 2010, Molecular systems biology.

[50]  María Martín,et al.  Ongoing and future developments at the Universal Protein Resource , 2010, Nucleic Acids Res..

[51]  Dan Shao,et al.  Nicotinamide Phosphoribosyltransferase Regulates Cell Survival Through NAD+ Synthesis in Cardiac Myocytes , 2009, Circulation research.

[52]  J. C. Gomez,et al.  Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-alpha in Pacing-Induced Heart Failure , 2002 .

[53]  M. Rovetto,et al.  Myocardial adenosine salvage rates and restoration of ATP content following ischemia. , 1979, The American journal of physiology.

[54]  Knut Mai,et al.  Sex differences in physiological cardiac hypertrophy are associated with exercise-mediated changes in energy substrate availability. , 2011, American journal of physiology. Heart and circulatory physiology.

[55]  L. Dinkelborg,et al.  Transport and metabolism of L-glutamate during oxygenation, anoxia, and reoxygenation of rat cardiac myocytes. , 1996, The American journal of physiology.

[56]  L. Guenot,et al.  Phospholipid content and fatty acid composition of human heart , 1989, Lipids.

[57]  G. Paradies,et al.  Decrease in Mitochondrial Complex I Activity in Ischemic/Reperfused Rat Heart: Involvement of Reactive Oxygen Species and Cardiolipin , 2004, Circulation research.

[58]  Christopher J Lynch,et al.  Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. , 2010, Cell metabolism.

[59]  Antje Chang,et al.  BRENDA, the enzyme information system in 2011 , 2010, Nucleic Acids Res..

[60]  J W Dow,et al.  Metabolism and salvage of adenine and hypoxanthine by myocytes isolated from mature rat heart. , 1985, Biochimica et biophysica acta.

[61]  J R Neely,et al.  Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. , 1974, Annual review of physiology.

[62]  X Chen,et al.  Changes in myofilament proteins, but not Ca²⁺ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure. , 2011, American journal of physiology. Heart and circulatory physiology.

[63]  E. Ruppin,et al.  Computational reconstruction of tissue-specific metabolic models: application to human liver metabolism , 2010, Molecular systems biology.

[64]  B. Lorell,et al.  Mechanisms for Increased Glycolysis in the Hypertrophied Rat Heart , 2004, Hypertension.

[65]  E. Justrabo,et al.  Fatty acid composition of human heart phospholipids: data from 53 biopsy specimens. , 1985, Journal of molecular and cellular cardiology.

[66]  N. Galeva,et al.  Comparison of one‐dimensional and two‐dimensional gel electrophoresis as a separation tool for proteomic analysis of rat liver microsomes: Cytochromes P450 and other membrane proteins , 2002, Proteomics.

[67]  Niels-Henrik Holstein-Rathlou,et al.  Phosphatidylinositol-bisphosphate regulates intercellular coupling in cardiac myocytes , 2008, Pflügers Archiv - European Journal of Physiology.

[68]  J. Bremer.  Carnitine--metabolism and functions. , 1983, Physiological reviews.

[69]  P Louisot,et al.  Mitochondrial contact sites. Lipid composition and dynamics. , 1990, The Journal of biological chemistry.

[70]  H. Taegtmeyer,et al.  Load-induced changes in vivo alter substrate fluxes and insulin responsiveness of rat heart in vitro. , 2001, Metabolism: clinical and experimental.

[71]  Xiaoming Sheng,et al.  Mitochondrial Energetics in the Heart in Obesity-Related Diabetes , 2007, Diabetes.

[72]  I S Harper,et al.  Myocardial membrane cholesterol: effects of ischaemia. , 1991, Journal of molecular and cellular cardiology.

[73]  Lars Stegger,et al.  Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number , 2008, Circulation.

[74]  Fausto G. Hegardt,et al.  Differential HMG-CoA lyase expression in human tissues provides clues about 3-hydroxy-3-methylglutaric aciduria , 2010, Journal of Inherited Metabolic Disease.

[75]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[76]  J. Vockley,et al.  Cloning and characterization of the human type II arginase gene. , 1996, Genomics.

[77]  A. Alwan.  Global status report on noncommunicable diseases 2010. , 2011 .

[78]  H. Schulz,et al.  On the rate-limiting step in the beta-oxidation of polyunsaturated fatty acids in the heart. , 1995, Biochimica et biophysica acta.

[79]  C A Beltrami,et al.  Apoptosis in the failing human heart. , 1997, The New England journal of medicine.

[80]  David F. Horrobin,et al.  Metabolism of linoleic and α-linolenic acids in cultured cardiomyocytes: Effect of different N-6 and N-3 fatty acid supplementation , 1996, Molecular and Cellular Biochemistry.

[81]  Ronan M. T. Fleming,et al.  Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0 , 2007, Nature Protocols.

[82]  Shota Suto,et al.  ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis , 2010, Proceedings of the National Academy of Sciences.

[83]  S. Steavenson,et al.  The pentose phosphate pathway in the endoplasmic reticulum. , 1988, The Journal of biological chemistry.

[84]  R. M. Mills,et al.  Alterations of myocardial amino acid metabolism in chronic ischemic heart disease. , 1976, The Journal of clinical investigation.

[85]  Abdullah Sener,et al.  Perturbation of phospholipid and triacylglycerol fatty acid positional location in the heart of rats depleted of n-3 long-chain polyunsaturates. , 2008, Nutrition research.

[86]  K Beyer,et al.  ADP/ATP carrier protein from beef heart mitochondria has high amounts of tightly bound cardiolipin, as revealed by 31P nuclear magnetic resonance. , 1985, Biochemistry.

[87]  G E Reed,et al.  Release of nucleosides from canine and human hearts as an index of prior ischemia. , 1979, The American journal of cardiology.

[88]  T. Raghunathan,et al.  Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. , 1995, JAMA.

[89]  Bernhard O. Palsson,et al.  Connecting Extracellular Metabolomic Measurements to Intracellular Flux States in Yeast , 2022 .

[90]  D. Fell,et al.  Is maximization of molar yield in metabolic networks favoured by evolution? , 2008, Journal of theoretical biology.

[91]  Ron Edgar,et al.  Gene Expression Omnibus ( GEO ) : Microarray data storage , submission , retrieval , and analysis , 2008 .

[92]  Jan Neckář,et al.  Chronic hypoxia alters fatty acid composition of phospholipids in right and left ventricular myocardium , 2002, Molecular and Cellular Biochemistry.

[93]  Ashim Malhotra,et al.  Cardiolipin affects the supramolecular organization of ATP synthase in mitochondria. , 2011, Biophysical journal.

[94]  Ronan M. T. Fleming,et al.  Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0 , 2007, Nature Protocols.

[95]  B. Morio,et al.  Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. , 2008, The Journal of clinical investigation.

[96]  Heinrich Taegtmeyer,et al.  Regulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation. , 1999, American journal of physiology. Endocrinology and metabolism.

[97]  Hermann-Georg Holzhütter,et al.  Uncovering Metabolic Objectives Pursued by Changes of Enzyme Levels , 2009, Annals of the New York Academy of Sciences.

[98]  Alan J. Robinson,et al.  A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle , 2011, BMC Systems Biology.

[99]  G. Hatch,et al.  Cardiolipin biosynthesis in the isolated heart. , 1994, The Biochemical journal.

[100]  H. Holzhütter,et al.  Pruning genome-scale metabolic models to consistent ad functionem networks. , 2007, Genome informatics. International Conference on Genome Informatics.

[101]  Peter L McLennan,et al.  Cardiac Membrane Fatty Acid Composition Modulates Myocardial Oxygen Consumption and Postischemic Recovery of Contractile Function , 2002, Circulation.

[102]  Hermann-Georg Holzhütter,et al.  METANNOGEN: compiling features of biochemical reactions needed for the reconstruction of metabolic networks , 2007, BMC Syst. Biol..

[103]  Hongzhu Li,et al.  Downregulation of the Ornithine Decarboxylase/polyamine System Inhibits Angiotensin-induced Hypertrophy of Cardiomyocytes Through the NO/cGMP-dependent Protein Kinase Type-I Pathway , 2010, Cellular Physiology and Biochemistry.

[104]  P. Binkley,et al.  Quantitative investigation of cardiomyocyte hypertrophy and myocardial fibrosis over 6 years after cardiac transplantation. , 1998, Journal of the American College of Cardiology.