Skip to main content

Carnitine Palmitoyltransferase-I, a New Target for the Treatment of Heart Failure

Perspectives on a Shift in Myocardial Metabolism as a Therapeutic Intervention

American Journal of Cardiovascular Drugs volume 4, pages 201–209 (2004)Cite this article

Abstract

Although the heart is capable of extracting energy from different types of substrates such as fatty acids and carbohydrates, fatty acids are the preferred fuel under physiological conditions. In view of the presence of diverse defects in myocardial metabolism in the failing heart, changes in metabolism of glucose and fatty acids are considered as viable targets for therapeutic modification in the treatment of heart failure. One of these changes involves the carnitine palmitoyltransferase (CPT) enzymes, which are required for the transfer of long chain fatty acids into the mitochondrial matrix for oxidation. Since CPT inhibitors have been shown to prevent the undesirable effects induced by mechanical overload, e. g. cardiac hypertrophy and heart failure, it was considered of interest to examine whether the inhibition of CPT enzymes represents a novel approach for the treatment of heart disease. A shift from fatty acid metabolism to glucose metabolism due to CPT-I inhibition has been reported to exert beneficial effects in both cardiac hypertrophy and heart failure. Since the inhibition of fatty acid oxidation is effective in controlling abnormalities in diabetes mellitus, CPT-I inhibitors may also prove useful in the treatment of diabetic cardiomyopathy. Accordingly, it is suggested that CPT-I may be a potential target for drug development for the therapy of heart disease in general and heart failure in particular.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Table I

References

  1. Katz AM. Evolving concepts of heart failure: cooling furnace, malfunctioning pump, enlarging muscle: part II. Hypertrophy and dilatation of the failing heart. J Card Fail 1998; 4: 67–81

    PubMed  CAS  Article  Google Scholar 

  2. Piano MR, Bondmass M, Schwertz DW. The molecular and cellular pathophysiology of heart failure. Heart Lung 1998; 27: 3–19

    PubMed  CAS  Article  Google Scholar 

  3. Calkins ME. Pathophysiology of congestive heart failure. ANNA J 1996; 23: 457–63

    PubMed  CAS  Google Scholar 

  4. Patterson JH, Adams KF. Pathophysiology of heart failure: changing perceptions. Pharmacotherapy 1996; 16: 27S–36S

    PubMed  CAS  Google Scholar 

  5. Dhalla NS, Afzal N, Beamish RE, et al. Pathophysiology of cardiac dysfunction in congestive heart failure. Can J Cardiol 1993; 9: 873–87

    PubMed  CAS  Google Scholar 

  6. Rich MW. Epidemiology, pathophysiology and etiology of congestive heart failure in older adults. J Am Geriat Soc 1997; 45: 968–74

    PubMed  CAS  Google Scholar 

  7. Dhalla NS, Sasaki S, Mochizuki S, et al. Catecholamine-induced cardiomyopathy. In: Acosta D, editor. Cardiovascular toxicology. New York: Taylor & Francis, 2001: 269–318

    Google Scholar 

  8. Faris R, Flather M, Purcell H, et al. Current evidence support the role of diuretics in heart failure: a meta analysis of randomised controlled trials. Int J Cardiol 2002; 82: 149–58

    PubMed  CAS  Article  Google Scholar 

  9. McMurray J, Cohen-Solai A, Dietz R, et al. Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: putting guidelines into practice. Eur J Heart Fail 2001; 3: 495–502

    PubMed  CAS  Article  Google Scholar 

  10. Goldstein S, Gottlieb SS. The impact of beta-blockade on mortality rates in patients with congestive heart failure. J Card Fail 2002; 6 Suppl. 1: 15–24

    Google Scholar 

  11. Cohn JN, Tognoni G. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667–76

    PubMed  CAS  Article  Google Scholar 

  12. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–17

    PubMed  CAS  Article  Google Scholar 

  13. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33

    Article  Google Scholar 

  14. McMurray JJV. Heart failure in 10 years time: focus on pharmacological treatment. Heart 2002; 88: ii40–6

    PubMed  Google Scholar 

  15. Lopaschuk GD. Metabolic abnormalities in the diabetic heart. Heart Fail Rev 2002; 7: 149–59

    PubMed  CAS  Article  Google Scholar 

  16. Sambandam N, Lopaschuk GD, Brownsey RW, et al. Energy metabolism in the hypertrophied heart. Heart Fail Rev 2002; 7: 161–73

    PubMed  CAS  Article  Google Scholar 

  17. Dhalla NS, Shao Q, Panagia V. Remodeling of cardiac membranes during the development of congestive heart failure. Heart Fail Rev 1998; 2: 261–72

    CAS  Article  Google Scholar 

  18. Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev 2002; 7: 115–30

    PubMed  CAS  Article  Google Scholar 

  19. Wolff AA, Rotmensch HH, Stanley WC, et al. Metabolic approaches to the treatment of ischemic heart disease: the clinicians’ perspective. Heart Fail Rev 2002; 7: 187–203

    PubMed  CAS  Article  Google Scholar 

  20. Schofield RS, Hill JA. Role of metabolically active drugs in the management of ischemic heart disease. Am J Cardiovasc Drugs 2001; 1: 23–35

    PubMed  CAS  Article  Google Scholar 

  21. Zarain-Herzberg A, Rupp H. Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target. Expert Opin Investig Drugs 2002; 11: 345–56

    PubMed  CAS  Article  Google Scholar 

  22. Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci 2000; 99: 27–35

    PubMed  CAS  Article  Google Scholar 

  23. Ganguly PK, Lee SL, Beamish RE, et al. Altered sympathetic system and adrenoreceptors during the development of cardiac hypertrophy. Am Heart J 1989; 118: 520–5

    PubMed  CAS  Article  Google Scholar 

  24. Baker KM, Chernin MI, Wixson SK, et al. Renin-angiotensin system involvement in pressure-overloaded cardiac hypertrophy in rats. Am J Physiol 1990; 259: H324–32

    PubMed  CAS  Google Scholar 

  25. Middlekauff HR. Mechanisms and implications of autonomie nervous system dysfunction in heart failure. Curr Opin Cardiol 1997; 12: 265–75

    PubMed  CAS  Article  Google Scholar 

  26. Esler M, Kaye D, Lambert G, et al. Adrenergic nervous system in heart failure. Am J Cardiol 1997; 80: 7L–14

    PubMed  CAS  Article  Google Scholar 

  27. Sigurdusson A, Swedberg K. The role of neurohumoral activation in chronic heart failure and post myocardial infarction. Am Heart J 1996; 132: 29–34

    Google Scholar 

  28. Sakai S, Miyauchi T, Kobayashi M, et al. Inhibition of myocardial endothelin pathway improves long term survival in heart failure. Nature 1996; 384: 353–5

    PubMed  CAS  Article  Google Scholar 

  29. Spinale FG, Walker JD, Mukherjee R, et al. Concomitant endothelin receptor subtype-A blockade during the progression of pacing induced congestive heart failure in rabbits: beneficial effects on left ventricular function and myocyte function. Circulation 1997; 95: 1918–25

    PubMed  CAS  Article  Google Scholar 

  30. Moser DK. Pathophysiology of heart failure update: the role of neurohumoral activation in the progression of heart failure. AACN Clin Issues 1998; 9: 157–71

    PubMed  CAS  Article  Google Scholar 

  31. Hamrell BB, Alpert NR. The mechanical characteristics of hypertrophicd rabbit cardiac muscle in absence of congestive heart failure. Circ Res 1997; 40: 20–5

    Article  Google Scholar 

  32. Wikman-Coffelt J, Parmley WW, Mason DT. The cardiac hypertrophy process: analysis of factors determining pathological vs physiological development. Circ Res 1979; 49: 697–707

    Article  Google Scholar 

  33. Julian FJ, Morgan DL, Moss RL, et al. Myocyte growth without physiological impairment in gradually induced cardiac hypertrophy. Circ Res 1981; 49: 1300–10

    PubMed  CAS  Article  Google Scholar 

  34. Scheuer J, Malhotra A, Hirsch C, et al. Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy. J Clin Invest 1982; 70: 1300–5

    PubMed  CAS  Article  Google Scholar 

  35. Dhalla NS, Heyliger CE, Beamish RE, et al. Pathophysiologic aspects of myocardial hypertrophy. Can J Cardiol 1987; 3: 183–96

    PubMed  CAS  Google Scholar 

  36. Rupp H, Elimban V, Dhalla NS. Modification of subcellular organelles in pressure overloaded hearts by etomoxir, a carnitine palmitoyltransferase I inhibitor. FASEB J 1992; 6: 2349–53

    PubMed  CAS  Google Scholar 

  37. Zarain-Herzberg A, Rupp H, Elimban V, et al. Modification of sarcoplasmic reticulum gene expression in pressure overload cardiac hypertrophy by etomoxir. FASEB J 1996; 10: 1303–9

    PubMed  CAS  Google Scholar 

  38. Dhalla NS, Heyliger C, Shah KR, et al. Remodeling of membrane systems during the development of cardiac hypertrophy due to pressure overload. In: Nagano M, Takeda N, Dhalla NS, editors. The adapted heart. New York: Raven Press, 1994: 27–49

    Google Scholar 

  39. Whitmer JT, Kumar P, Solaro RJ. Calcium transport properties of cardiac sarcoplasmic reticulum from cardiomyopathic Syrian hamsters: evidence for a quantitative defect in dilated myopathic hearts not evident in hypertrophic hearts. Circ Res 1988; 62: 81–5

    PubMed  CAS  Article  Google Scholar 

  40. Gwathney JK, Compelas L, MacKinnon R, et al. Abnormal intracellular calcium handling in myocardium from patients with endstage heart failure. Circ Res 1987; 61: 70–6

    Article  Google Scholar 

  41. Movsesian MA, Coyler J, Wang JH, et al. Phospholamban-mediated stimulation of Ca2+ uptake in sarcoplasmic reticulum from normal and failing hearts. J Clin Invest 1990; 85: 1698–702

    PubMed  CAS  Article  Google Scholar 

  42. Kusamochi T, Honda M, Tanaka K, et al. Contrasting effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on calcium transients in isolated rat cardiac myocytes. Cardiovasc Res 1994; 28: 1407–13

    Article  Google Scholar 

  43. Rupp H, Elimban V, Dhalla NS. Diabetes like action of intermittent fasting on sarcoplasmic reticulum Ca2+-pump ATPase and myosin isoenzymes can be prevented by sucrose. Biochem Biophys Res Commun 1989; 164: 319–25

    PubMed  CAS  Article  Google Scholar 

  44. Mercadier JJ, Lompre AM, Wisnewsky C, et al. Myosin isoenzyme changes in several models of rat cardiac hypertrophy. Circ Res 1981; 49: 525–32

    PubMed  CAS  Article  Google Scholar 

  45. Chevalier B, Callene F, Charlemagne D, et al. Signal and adaptational changes in gene expression during cardiac overload. J Mol Cell Cardiol 1989; 21: 71–7

    PubMed  Article  Google Scholar 

  46. Nandin V, Oliviero P, Rannou F, et al. The density of ryanodine receptors decreases with pressure overload-induced rat cardiac hypertrophy. FEBS Lett 1991; 285: 135–8

    Article  Google Scholar 

  47. Dhalla NS, Wang X, Sethi R, et al. β-Adrenergic linked signal transduction mechanisms in failing hearts. Heart Fail Rev 1997; 2: 55–65

    CAS  Article  Google Scholar 

  48. Schillinger W, Meyer M, Kuwajima G, et al. Unaltered ryanodine receptor protein levels in ischemic cardiomyopathy. Mol Cell Biochem 1996; 160/161: 297–302

    CAS  Article  Google Scholar 

  49. McNult N, Fawcett D. Myocardial ultrastructure. In: Lauger G, Brady A, editors. The mammalian myocardium. New York: John Wiley & Sons, 1984: 3–21

    Google Scholar 

  50. Taegtmeyer H, Roberts AFC, Rayne AEG. Energy metabolism in reperfused rat heart: return of function before normalization of ATP content. J Am Coll Cardiol 1985; 6: 864–70

    PubMed  CAS  Article  Google Scholar 

  51. Taegtmeyer H, King LM, Jones BE. Energy substrate metabolism, myocardial ischemia and targets for pharmacotherapy. Am J Cardiol 1998; 82: 54K–60

    PubMed  CAS  Article  Google Scholar 

  52. Bing RJ. Cardiac metabolism. Physiol Rev 1965; 45: 171–213

    PubMed  CAS  Google Scholar 

  53. Neely JR, Rovetto MJ, Oram JF. Myocardial utilization of carbohydrate and lipids. Prog Cardiovasc Dis 1972; 15: 289–329

    PubMed  CAS  Article  Google Scholar 

  54. Masoro EJ. Lipids and lipid metabolism. Annu Rev Physiol 1977; 39: 301–21

    PubMed  CAS  Article  Google Scholar 

  55. Opie LH. Effects of regional ischemia on metabolism of glucose and fatty acids: relative rates of aerobic and anaerobic energy production during myocardial infarction and comparison with effects of anoxia. Circ Res 1976; 38 Suppl. 1: 152–86

    Google Scholar 

  56. Borst P, Loos J, Christ E, et al. Uncoupling activity of long chain fatty acids. Biochem Biophys Acta 1962; 62: 509–18

    PubMed  CAS  Article  Google Scholar 

  57. Neely JR, Morgan HE. Relationship between carbohydrate and lipid metabolism and the energy balance of the heart muscle. Annu Rev Physiol 1974; 36: 413–59

    PubMed  CAS  Article  Google Scholar 

  58. Yeaman SJ, Armstrong JL, Bonavaud SM, et al. Regulations of glycogen synthesis in human muscle cells. Biochem Soc Trans 2001; 29: 537–41

    PubMed  CAS  Article  Google Scholar 

  59. Depre C, Vanoverschelde J, Taegtmeyer H. Glucose for the heart. Circulation 1999; 99: 578–88

    PubMed  CAS  Article  Google Scholar 

  60. Tirosh R, Mishor T, Pinson A. Glucose is essential for the initiation of fatty acid oxidation in ATP-depleted cultured ventricular myocytes. Mol Cell Biochem 1996; 162: 159–63

    PubMed  CAS  Article  Google Scholar 

  61. Randle PJ, Tubbs PK. Carbohydrate and fatty acid metabolism. In: Berne RM, Sperelakis N, editors. The cardiovascular system: vol. 1. The heart. Bethesda (MD): American Physiological Society, 1992: 805–44

    Google Scholar 

  62. Vary TC, Reibel DK, Neely JR. Control of energy metabolism of heart muscle. Annu Rev Physiol 1981; 43: 419–30

    PubMed  CAS  Article  Google Scholar 

  63. Liedtke JA. Alterations of carbohydrate and lipid metabolism in the actively ischemic heart. Prog Cardiovasc Dis 1981; 23: 321–36

    PubMed  CAS  Article  Google Scholar 

  64. Van der Vusse GJ, Stam H. Lipid and carbohydrate metabolism in the ischemic heart. Basic Res Cardiol 1987; 82 Suppl. 1: 149–54

    PubMed  Google Scholar 

  65. Dhalla NS, Elimban V, Rupp H. Paradoxical role of lipid metabolism in heart function and dysfunction. Mol Cell Biochem 1992; 116: 3–9

    PubMed  CAS  Article  Google Scholar 

  66. Evans JR, Opie LH, Shipp JC. Metabolism of palmitic acid in perfused rat heart. Am J Physiol 1963; 205: 706–7

    Google Scholar 

  67. Saddik M, Lopaschuk GD. Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 1991; 266: 8162–70

    PubMed  CAS  Google Scholar 

  68. Tanphaichiti V, Leelahagul P. Carnitine metabolism and human carnitine deficiency. Nutrition 1993; 3: 246–54

    Google Scholar 

  69. Goa KL, Brogden R. L-carnitine, a preliminary review of its pharmacokinetics and its therapeutic use in ischaemic cardiac disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism. Drugs 1987; 34: 1–24

    PubMed  CAS  Article  Google Scholar 

  70. De Jong JW, Hulsmann WC. A comparative study of palmitoyl-CoA synthetase activity in rat-liver, heart and gut mitochondrial and microsomal preparations. Biochem Biophys Acta 1969; 197: 127–35

    Google Scholar 

  71. Bremer J. Carnitine dependent pathways in heart muscle. In: De Jong JW, Ferrari R, editors. The carnitine system. Dordrecht: Kluwer Academic Publishers, 1995: 7–20

    Chapter  Google Scholar 

  72. Mascaro C, Acosta E, Ortiz JA, et al. Control of human muscle type carnitine palmitoyl transferase 1: gene transcription by peroxisome proliferator activated receptor. J Biol Chem 1998; 273: 8560–3

    PubMed  CAS  Article  Google Scholar 

  73. Ramsay RR. The role of the carnitine system in peroxisomal fatty acid oxidation. Am J Med Sci 1999; 318: 28–35

    PubMed  CAS  Article  Google Scholar 

  74. Swiegers JH, Dippenaar N, Pretorius IS, et al. Carnitine-dependent metabolic activities in Saccharomyces cerevisiae: three carnitine acetyltransferases are essential in a carnitine-dependent strain. Yeast 2001; 18: 585–95

    PubMed  CAS  Article  Google Scholar 

  75. Zammit VA, Price NT, Fraser F, et al. Structure-function relationships of the liver and muscle isoforms of carnitine palmitoyltransferase I. Biochem Soc Trans 2001; 29: 287–92

    PubMed  CAS  Article  Google Scholar 

  76. Vaz FM, Wanders RJ. Carnitine biosynthesis in animals. Biochem J 2002; 361: 417–29

    PubMed  CAS  Article  Google Scholar 

  77. McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system: from concept to molecular analysis. Eur J Biochem 1997; 244: 1–14

    PubMed  CAS  Article  Google Scholar 

  78. Morillas M, Gomez-Puertas P, Roca R, et al. Structural model of the catalytic core of carnitine palmitoyltransferase I and carnitine octanoyl transferase (COT): mutation of CPT I histidine 473 and alanine 381 and COT alanine 238 impairs the catalytic activity. J Biol Chem 2001; 276: 45001–8

    PubMed  CAS  Article  Google Scholar 

  79. Bieber LL. Carnitine. Annu Rev Biochem 1988; 57: 261–83

    PubMed  CAS  Article  Google Scholar 

  80. Bremer J. Carnitine: metabolism and functions. Physiol Rev 1983; 63: 1420–80

    PubMed  CAS  Google Scholar 

  81. Miyazawa S, Ozasa H, Furata S, et al. Purification and properties of carnitine acetyltransferase from rat liver. J Biochem 1983; 93: 439–51

    PubMed  CAS  Google Scholar 

  82. Farrell SO, Bieber LL. Carnitine octanoyltransferase of mouse liver peroxisomes: properties and effects of hypolipidaemic drugs. Arch Biochem Biophys 1983; 222: 123–32

    PubMed  CAS  Article  Google Scholar 

  83. Maxwell MAK, Tolbert NE, Bieber LL. Comparison of the carnitine acyltransferase activities from rat liver peroxisomes and microsomes. Arch Biochem Biophys 1976; 176: 479–88

    Article  Google Scholar 

  84. Murthy MSR, Pande SV. Malonyl-CoA binding site and overt carnitine palmitoyltransferase activity reside on the opposite sides of the outer mitochondrial membrane. Proc Natl Acad Sci U S A 1987; 84: 378–82

    PubMed  CAS  Article  Google Scholar 

  85. Norum KR, Bremer J. The localization of acyl coenzyme A: carnitine acyltransferase in rat liver cells. J Biol Chem 1967; 242: 407–11

    PubMed  CAS  Google Scholar 

  86. McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem 1980; 73: 77–84

    Google Scholar 

  87. Elgerssma Y, van Roermund CW, Wanders RJ, et al. Peroxisomal and mitochondrial carnitine acetyltransferases of Saccharomyces cerevisiae are encoded by a single gene. EMBO J 1995; 14: 3472–9

    Google Scholar 

  88. Van der Vusse GJ. Accumulation of fatty acids and their carnitine derivatives during myocardial ischemia. In: De Jong JW, Ferrari R, editors. The carnitine system. Dordrecht: Kluwer Academic Publishers, 1995: 53–68

    Chapter  Google Scholar 

  89. Mikulic E, Cohn JW, Franciosa JA. Comparative hemodynamic effects of inotropic drags in severe heart failure. Circulation 1977; 56: 528–33

    PubMed  CAS  Article  Google Scholar 

  90. Cohn JN. Vasodilator therapy of congestive heart failure. Adv Intern Med 1980; 26: 293–315

    PubMed  CAS  Google Scholar 

  91. Goldenberg IF, Cohn JN. New inotropic drugs for heart failure. JAMA 1987; 258: 493–6

    PubMed  CAS  Article  Google Scholar 

  92. Katz AM. Changing strategies in the management of heart failure. J Am Coll Cardiol 1989; 13: 513–23

    PubMed  CAS  Article  Google Scholar 

  93. Franciosa JA, Jordan RA, Wilen MM, et al. Minoxidil in patients with chronic left heart failure: contrasting hemodynamic and clinical effects in a controlled trial. Circulation 1984; 70: 63–8

    PubMed  CAS  Article  Google Scholar 

  94. Rupp H, Vetter R. Sarcoplasmic reticulum function and carnitine itoyltransferase-I inhibition during progression of heart failure. Br J Pharmacol 2000; 131: 1748–56

    PubMed  CAS  Article  Google Scholar 

  95. Anderson RC. Carnitine palmitoyltransferase: a viable target for the treatment of NIDDM. Curr Pharm Des 1998; 14: 1–15

    Google Scholar 

  96. Pearce FJ, Forster J, Deleeuw G, et al. Inhibition of fatty acid oxidation in normal and hypoxic perfused rat hearts by 2-tetradecylglycidic acid. J Mol Cell Cardiol 1979; 11: 893–916

    PubMed  CAS  Article  Google Scholar 

  97. Wolf HP. Possible new therapeutic approach in diabetes mellitus by inhibition of carnitine palmitoyltransferase 1 (CPT1). Horm Metab Res Suppl 1992; 26: 672–67

    Google Scholar 

  98. Kanamuru T, Shinagawa S, Asi M, et al. Emeriamine, an antidiabetic β-aminobetaine derived from a novel fungal metabolite. Life Sci 1985; 37: 217–33

    Article  Google Scholar 

  99. Higgins AJ, Morvile M, Burges RA, et al. Oxfenicine diverts rat muscle metabolism from fatty acid to carbohydrate oxidation and protects the ischemic heart. Life Sci 1980; 27: 963–70

    PubMed  CAS  Article  Google Scholar 

  100. Lopaschuck GD, Wall SR, Olley PM, et al. Etomoxir, a carnitine palmitoyltransferase-I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 1988; 3: 1036–43

    Article  Google Scholar 

  101. Corr PB, Creer MH, Yamada KA, et al. Prophylaxis of early ventricular fibrillation by inhibition of acylcarnitine accumulation. J Clin Invest 1989; 83: 927–36

    PubMed  CAS  Article  Google Scholar 

  102. Yamada KA, Michowat J, Yan GX, et al. Cellular uncoupling induced by accumulation of long chain acylcarnitine during ischemia. Circ Res 1994; 74: 83–95

    PubMed  CAS  Article  Google Scholar 

  103. Litwin SE, Raya TE, Anderson PG, et al. Induction of myocardial hypertrophy after coronary ligation in rats decreases ventricular dilatation and improves systolic function. Circulation 1991; 84: 1819–27

    PubMed  CAS  Article  Google Scholar 

  104. Rupp H, Jacob R. Metabolically modulated growth and phenotype of rat heart. Eur Heart J 1992; 13: 56–61

    PubMed  CAS  Google Scholar 

  105. Vetter R, Rupp H. CPT-I inhibition by etomoxir has a chamber related action on cardiac sarcoplasmic reticulum and isomyosins. Am J Physiol 1994; 267: H2091–9

    PubMed  CAS  Google Scholar 

  106. Turcani M, Rupp H. Etomoxir improves left ventricular performance of pressure overloaded rat heart. Circulation 1997; 26: 3681–6

    Article  Google Scholar 

  107. Brandt JM, Djonadi F, Kelly DP. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisomes proliferator activated receptor alpha. J Biol Chem 1998; 273: 23786–92

    PubMed  CAS  Article  Google Scholar 

  108. Rupp H, Wahl R, Hansen M. Influence of diet and carnitine toyltransferase I inhibition on myosin and sarcoplasmic reticulum. J Appl Physiol 1992; 72: 352–60

    PubMed  CAS  Google Scholar 

  109. Rupp H, Schulze W, Vetter R. Dietary medium chain triglycerides can prevent changes in myosin and SR due to CPT I inhibition by etomoxir. Am J Physiol 1995; 269: R630–40

    PubMed  CAS  Google Scholar 

  110. Dhalla NS, Golfman L, Liu X, et al. Subcellular remodeling and heart dysfunction in cardiac hypertrophy due to pressure overload. Ann N Y Acad Sci 1999; 874: 100–10

    PubMed  CAS  Article  Google Scholar 

  111. Hegardt FG, Siera D, Asins G. Influence of etomoxir on the expression of several genes in liver, testis and heart. Gen Pharmacol 1995; 126: 897–904

    Google Scholar 

  112. Turcani M, Rupp H. Modification of left ventricular hypertrophy by chronic etomoxir treatment. Br J Pharmacol 1999; 126: 501–7

    PubMed  CAS  Article  Google Scholar 

  113. Yonekura K, Eto Y, Yokoyama I, et al. Inhibition of carnitine synthesis modulates protein content of the cardiac sarcoplasmic reticulum Ca2+-ATPase and hexokinase type I in rat hearts with myocardial infarction. Basic Res Cardiol 2000; 95: 343–8

    PubMed  CAS  Article  Google Scholar 

  114. Pennock GD, Spooner PH, Summers CE, et al. Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3,5-diothyropropianic acid (DITPA). J Mol Cell Cardiol 2000; 32: 1939–53

    PubMed  CAS  Article  Google Scholar 

  115. Lullman H, Lullman-Rauch R, Wassermann O. Lipidosis induced by amphilic cationic drags. Biochem Pharmacol 1978; 27: 1103–8

    Article  Google Scholar 

  116. Litwin SE, Raya TE, Gay RG, et al. Chronic inhibition of fatty acid oxidation: a new model of diastolic function. Am J Physiol 1990; 258: H51–6

    PubMed  CAS  Google Scholar 

  117. Yotsumoto T, Naitoh T, Kitahara M, et al. Effects of carnitine palmitoyltransferase I inhibitors on hepatic hypertrophy. Eur J Pharmacol 2000; 398: 297–302

    PubMed  CAS  Article  Google Scholar 

  118. Randle PJ. Blood glucose homeostasis and glucose utilization. In: Ceras E, Luft R, editors. Pathogenesis of diabetic mellitus Nobel symposium. New York: John Wiley & Sons, 1970: 173–97

    Google Scholar 

  119. Randle PJ, Garland PB, Hales CN, et al. Interactions of metabolism and the physiological role of insulin. Recent Prog Horm Res 1966; 22: 1–44

    PubMed  CAS  Google Scholar 

  120. Ruderman NB, Toews CJ, Shafrir E. Role of free fatty acids in glucose homeostasis. Arch Intern Med 1969; 123: 299–313

    PubMed  CAS  Article  Google Scholar 

  121. Rupp H, Elimban V, Dhalla NS. Modification of myosin isozymes and SR Ca2+ pump ATPase of the diabetic rat heart by lipid lowering interventions. Mol Cell Biochem 1994; 132: 69–80

    PubMed  CAS  Article  Google Scholar 

  122. Kato K, Chapman DC, Rupp H, et al. Alterations of heart function and Na+-K+ ATPase activity by etomoxir in diabetic rats. J Appl Physiol 1999; 86: 812–8

    PubMed  CAS  Google Scholar 

  123. Tutwilier GF, Ryzlak MT. Inhibition of mitochondrial carnitine palmitoyltransferase by 2-tetraglycidic acid (McN-3802). Life Sci 1980; 26: 393–7

    Article  Google Scholar 

Download references

Author information

Affiliations

  1. St Boniface General Hospital Research Centre & Department of Physiology, Faculty of Medicine, Institute of Cardiovascular Sciences, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba, R2H 2A6, Canada

    Sushma A. Mengi &  Naranjan S. Dhalla

Authors
  1. Sushma A. Mengi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naranjan S. Dhalla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naranjan S. Dhalla.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mengi, S.A., Dhalla, N.S. Carnitine Palmitoyltransferase-I, a New Target for the Treatment of Heart Failure. Am J Cardiovasc Drugs 4, 201–209 (2004). https://doi.org/10.2165/00129784-200404040-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200404040-00001

Keywords

  • Carnitine
  • Sarcoplasmic Reticulum
  • Chain Fatty Acid
  • Cardiac Hypertrophy
  • Fatty Acid Oxidation