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(Circulation. 1996;94:2837-2842.)
© 1996 American Heart Association, Inc.
Articles |
Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart
the Departments of Medicine (M.N.S., T.A.R., D.P.K.) and Molecular Biology and Pharmacology (D.P.K.), Washington University School of Medicine, St Louis, Mo; the Department of Food Science and Technology, Ohio State University, Columbus (S.P., S.A.M.); and the Universite Paris, INSERM, Paris, France (J.B.).
Correspondence to Daniel P. Kelly, MD, Cardiovascular Division, Box 8086, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail kelly@visar.wustl.edu.
Background During the development of heart failure (HF), the chief myocardial energy substrate switches from fatty acids to glucose. This metabolic switch, which recapitulates fetal cardiac energy substrate preferences, is thought to maintain aerobic energetic balance. The regulatory mechanisms involved in this metabolic response are unknown.
Methods and Results To characterize the expression of genes involved in mitochondrial fatty acid ß-oxidation (FAO) in the failing heart, levels of mRNA encoding enzymes that catalyze the first and third steps of the FAO cycle were delineated in the left ventricles (LVs) of human cardiac transplant recipients. FAO enzyme and mRNA levels were coordinately downregulated (>40%) in failing human LVs compared with controls. The temporal pattern of this alteration in FAO enzyme gene expression was characterized in a rat model of progressive LV hypertrophy (LVH) and HF [SHHF/Mcc-facp (SHHF) rat]. FAO enzyme mRNA levels were coordinately downregulated (>70%) during both the LVH and HF stages in the SHHF rats compared with controls. In contrast, the activity and steady-state levels of medium-chain acyl-CoA dehydrogenase, which catalyzes a rate-limiting step in FAO, were not significantly reduced until the HF stage, indicating additional control at the translational or posttranslational levels in the hypertrophied but nonfailing ventricle.
Conclusions These findings identify a gene regulatory pathway involved in the control of cardiac energy production during the development of HF.
Key Words: heart failure • hypertrophy • fatty acids • metabolism
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 A. Hansson, N. Hance, E. Dufour, A. Rantanen, K. Hultenby, D. A. Clayton, R. Wibom, and N.-G. Larsson A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts PNAS, March 2, 2004; 101(9): 3136 - 3141. [Abstract] [Full Text] [PDF]
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S. Sharma, H. Taegtmeyer, J. Adrogue, P. Razeghi, S. Sen, K. Ngumbela, and M. F. Essop Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1185 - H1192. [Abstract] [Full Text] [PDF]
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 R. Ventura-Clapier, A. Garnier, and V. Veksler Energy metabolism in heart failure J. Physiol., February 15, 2004; 555(1): 1 - 13. [Abstract] [Full Text] [PDF]
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M. van Bilsen, P. J.H Smeets, A. J Gilde, and G. J van der Vusse Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res, February 1, 2004; 61(2): 218 - 226. [Abstract] [Full Text] [PDF]
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 M. P. Czubryt and E. N. Olson Balancing Contractility and Energy Production: The Role of Myocyte Enhancer Factor 2 (MEF2) in Cardiac Hypertrophy Recent Prog. Horm. Res., January 1, 2004; 59(1): 105 - 124. [Abstract] [Full Text]
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K. T. Morgan, M. Pino, L. M. Crosby, Min Wang, T. C. Elston, Z. Jayyosi, M. Bonnefoi, and G. Boorman Complementary Roles for Toxicologic Pathology and Mathematics in Toxicogenomics, With Special Reference to Data Interpretation and Oscillatory Dynamics Toxicol Pathol, January 1, 2004; 32(1_suppl): 13 - 25. [Abstract] [PDF]
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A Garnier, D Fortin, C Delomenie, I Momken, V Veksler, and R Ventura-Clapier Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles J. Physiol., September 1, 2003; 551(2): 491 - 501. [Abstract] [Full Text] [PDF]
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G. A. Francis, J.-S. Annicotte, and J. Auwerx PPAR-{alpha} effects on the heart and other vascular tissues Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H1 - H9. [Abstract] [Full Text] [PDF]
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C. A Lygate, K. Hulbert, M. Monfared, M. A Cole, K. Clarke, and S. Neubauer The PPAR{gamma}-activator rosiglitazone does not alter remodeling but increases mortality in rats post-myocardial infarction Cardiovasc Res, June 1, 2003; 58(3): 632 - 637. [Abstract] [Full Text] [PDF]
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H. Irie, I. B. Krukenkamp, J. F. F. Brinkmann, G. R. Gaudette, A. E. Saltman, W. Jou, J. F. C. Glatz, N. A. Abumrad, and A. Ibrahimi Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids PNAS, May 27, 2003; 100(11): 6819 - 6824. [Abstract] [Full Text] [PDF]
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M. P. Czubryt, J. McAnally, G. I. Fishman, and E. N. Olson Regulation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha ) and mitochondrial function by MEF2 and HDAC5 PNAS, February 18, 2003; 100(4): 1711 - 1716. [Abstract] [Full Text] [PDF]
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 K. Q. Stolen, J. Kemppainen, H. Ukkonen, K. K. Kalliokoski, M. Luotolahti, P. Lehikoinen, H. Hamalainen, T. Salo, K. E. Juhani Airaksinen, P. Nuutila, et al. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., February 5, 2003; 41(3): 460 - 467. [Abstract] [Full Text] [PDF]
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H. Degens, A. J. Gilde, M. Lindhout, P. H. M. Willemsen, G. J. van der Vusse, and M. van Bilsen Functional and metabolic adaptation of the heart to prolonged thyroid hormone treatment Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H108 - H115. [Abstract] [Full Text] [PDF]
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T. Kuznetsova, J. A. Staessen, A. Olszanecka, A. Ryabikov, K. Stolarz, S. Malyutina, R. Fagard, K. Kawecka-Jaszcz, and Y. Nikitin Maternal and Paternal Influences on Left Ventricular Mass of Offspring Hypertension, January 1, 2003; 41(1): 69 - 74. [Abstract] [Full Text] [PDF]
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L. de las Fuentes, P. Herrero, L. R. Peterson, D. P. Kelly, R. J. Gropler, and V. G. Davila-Roman Myocardial Fatty Acid Metabolism: Independent Predictor of Left Ventricular Mass in Hypertensive Heart Disease Hypertension, January 1, 2003; 41(1): 83 - 87. [Abstract] [Full Text] [PDF]
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H. Taegtmeyer Switching Metabolic Genes to Build a Better Heart Circulation, October 15, 2002; 106(16): 2043 - 2045. [Full Text] [PDF]
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J. C. Osorio, W. C. Stanley, A. Linke, M. Castellari, Q. N. Diep, A. R. Panchal, T. H. Hintze, G. D. Lopaschuk, and F. A. Recchia Impaired Myocardial Fatty Acid Oxidation and Reduced Protein Expression of Retinoid X Receptor-{alpha} in Pacing-Induced Heart Failure Circulation, July 30, 2002; 106(5): 606 - 612. [Abstract] [Full Text] [PDF]
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V.i. G. Davila-Roman, G. Vedala, P. Herrero, L. de las Fuentes, J. G. Rogers, D. P. Kelly, and R. J. Gropler Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy J. Am. Coll. Cardiol., July 17, 2002; 40(2): 271 - 277. [Abstract] [Full Text] [PDF]
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J. Marin-Garcia and M. J. Goldenthal Fatty acid metabolism in cardiac failure: biochemical, genetic and cellular analysis Cardiovasc Res, June 1, 2002; 54(3): 516 - 527. [Full Text] [PDF]
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D. P. Kelly Peroxisome Proliferator-Activated Receptor {alpha} as a Genetic Determinant of Cardiac Hypertrophic Growth: Culprit or Innocent Bystander? Circulation, March 5, 2002; 105(9): 1025 - 1027. [Full Text] [PDF]
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H. Ashrafian, E. Johannsson, O. M. Sejersted, P. K. Lunde, I. Sjaastad, M. J. Thomas, L. Bergersen, T. W. Blackstad, O. P. Ottersen, C. Heddle, et al. Cardiac Energetics in Congestive Heart Failure Response Circulation, February 12, 2002; 105 (6): e44 - e45. [Full Text] [PDF]
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 B.N. FINCK, J.J. LEHMAN, P.M. BARGER, and D.P. KELLY Regulatory Networks Controlling Mitochondrial Energy Production in the Developing, Hypertrophied, and Diabetic Heart Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 371 - 382. [Abstract] [PDF]
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P. Razeghi, M. E. Young, J. L. Alcorn, C. S. Moravec, O.H. Frazier, and H. Taegtmeyer Metabolic Gene Expression in Fetal and Failing Human Heart Circulation, December 11, 2001; 104(24): 2923 - 2931. [Abstract] [Full Text] [PDF]
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L. A. Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P. Shannon Mechanisms whereby rapid RV pacing causes LV dysfunction: perfusion-contraction matching and NO Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2270 - H2281. [Abstract] [Full Text] [PDF]
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N. Rosenblatt-Velin, C. Montessuit, I. Papageorgiou, J. Terrand, and R. Lerch Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism Cardiovasc Res, December 1, 2001; 52(3): 407 - 416. [Abstract] [Full Text] [PDF]
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 F.M. Bengel, B. Permanetter, M. Ungerer, S.G. Nekolla, and M. Schwaiger Relationship between altered sympathetic innervation, oxidative metabolism and contractile function in the cardiomyopathic human heart; a non-invasive study using positron emission tomography Eur. Heart J., September 1, 2001; 22(17): 1594 - 1600. [Abstract] [PDF]
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