Skip to main content
SpringerLink
Log in

Effect of Chronic CPT-1 Inhibition on Myocardial Ischemia-Reperfusion Injury (I/R) in a Model of Diet-Induced Obesity

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

By increasing circulating free fatty acids and the rate of fatty acid oxidation, obesity decreases glucose oxidation and myocardial tolerance to ischemia. Partial inhibition of fatty acid oxidation may improve myocardial tolerance to ischemia/reperfusion (I/R) in obesity. We assessed the effects of oxfenicine treatment on post ischemic cardiac function and myocardial infarct size in obese rats.

Methods

Male Wistar rats were fed a control diet or a high calorie diet which resulted in diet induced obesity (DIO) for 16 weeks. Oxfenicine (200 mg/kg/day) was administered to control and DIO rats for the last 8 weeks. Isolated hearts were perfused and infarct size and post ischemic cardiac function was assessed after regional or global ischemia and reperfusion. Cardiac mitochondrial function was assessed and myocardial expression and activity of CPT-1 (carnitine palmitoyl transferase-1) and IRS-1 (insulin receptor substrate-1) was assessed using Western blot analysis.

Results

In the DIO rats, chronic oxfenicine treatment improved post ischemic cardiac function and reduced myocardial infarct size after I/R but had no effect on the cardiac mitochondrial respiration. Chronic oxfenicine treatment worsened post ischemic cardiac function, myocardial infarct size and basal mitochondrial respiration in control rat hearts. Basal respiratory control index (RCI) values, state 2 and state 4 respiration rates and ADP phosphorylation rates were compromised by oxfenicine treatment.

Conclusion

Chronic oxfenicine treatment improved myocardial tolerance to I/R in the obese rat hearts but decreased myocardial tolerance to I/R in control rat hearts. This decreased tolerance to ischemia of oxfenicine treated controls was associated with adverse changes in basal and reoxygenation mitochondrial function. These changes were absent in oxfenicine treated hearts from obese rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Mathieu P, Pibarot P, Larose E, Poirier P, Marette A, Despés JP. Visceral obesity and the heart. Int J Biochem Cell Biol. 2008;40:821–36.

    Article  PubMed  CAS  Google Scholar 

  2. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation and effect of weight loss: an update of the 1997 American Heart Association scientific statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity and metabolism. Circulation. 2006;113:898–918.

    Article  PubMed  Google Scholar 

  3. Diniz YS, Burneiko RM, Seiva FRF, Almeida FQA, Galhardi CM, Filho JL. Diet compounds, glycemic index and obesity-related cardiac effects. Int J Cardiol. 2008;124:92–9.

    Article  PubMed  Google Scholar 

  4. Kobayashi H, Nakamura T, Miyaoka K, Nishida M, Funahashi T, Yamashita S, et al. Visceral fat accumulation contributes to insulin resistance, small sized low-density lipoprotein and progression of coronary artery disease in middle-aged non-obese Japanese men. Jpn Circ J. 2001;65:193–9.

    Article  PubMed  CAS  Google Scholar 

  5. Thim T, Bentzon JF, Kristiansen SB, Simonsen U, Anderson HL, Wassermann K, et al. Size of myocardial infarction induced by ischemia/reperfusion is unaltered in rats with metabolic syndrome. Clin Sci. 2006;110:665–71.

    Article  PubMed  Google Scholar 

  6. Hegarty BD, Turner N, Cooney GJ, Kraegen EW. Insulin resistance and fuel homeostasis: the role of AMP-activated protein kinase. Acta Physiol. 2009;196:129–45.

    Article  CAS  Google Scholar 

  7. Lopaschuk GD, Ussher JR, Folmes CL, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207–58.

    Article  PubMed  CAS  Google Scholar 

  8. Lopaschuk GD, Folmes CD, Stanley WC. Cardiac energy metabolism in obesity. Circ Res. 2007;101:335–47.

    Article  PubMed  CAS  Google Scholar 

  9. Carley AN, Severson DL. Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochim ET Biophys Acta. 2005;1734:112–26.

    CAS  Google Scholar 

  10. Opie LH. The heart: physiology and metabolism, second edition Raven Press 1991.

  11. Calvani M, Reda E, Arrigoni-Martelli E. Regulation of carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions. Basic Res Cardiol. 2000;95:2.

    Article  Google Scholar 

  12. Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Research. 1997;34:25–33.

    Article  CAS  Google Scholar 

  13. Rupp H, Rupp TP, Maisch B. Fatty acid oxidation inhibition with PPAR-α activation (FOXIB/PPARα) for normalizing gene expression in heart failure? Cardiovasc Research. 2005;66:423–6.

    Article  CAS  Google Scholar 

  14. Taegtmeyer H, Wilson CR, Razeghi P, Sharma S. Metabolic energetics and genetics in the heart. Ann New York Acad Sci. 2005;1047:208–18.

    Article  CAS  Google Scholar 

  15. Hafstad AD, Khalid AM, How OJ, Larsen TS, Aasum E. Glucose and insulin improve cardiac efficiency and post-ischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice. Am J Physiol Endorinol Metab. 2007;292:E1288–94.

    Article  CAS  Google Scholar 

  16. Rupp H, Zarain-Herzberg A, Maisch B. The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure. Urban Vogel. 2002;27:621–36.

    Google Scholar 

  17. Beadle RM, Frenneaux M. Modification of myocardial substrate utilisation: a new therapeutic paradigm in cardiovascular disease. Heart. 2010;96:824–30.

    Article  PubMed  CAS  Google Scholar 

  18. Opie LH, Knuuti J. The adrenergic-fatty acid load in heart failure. J Am Coll Cardiol. 2009;54:1637–46.

    Article  PubMed  CAS  Google Scholar 

  19. Stephens TW, Higgins AJ, Cook GA, Harris RA. Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem J. 1985;227:651–60.

    PubMed  CAS  Google Scholar 

  20. Burges RA, Gardiner DG, Higgins AJ. Protection of the ischemic dog heart by oxfenicine. Life Sci. 1981;29:1847–85.

    Article  PubMed  CAS  Google Scholar 

  21. Stanley WC. Partial fatty acid oxidation inhibitors for stable angina. Expert Opin Investig Drugs. 2002;11:615–29.

    Article  PubMed  CAS  Google Scholar 

  22. Okere IC, Chandler MP, McElfresh TA, Rennison JH, Kung TA, Hoit BD, et al. Carnitine palmitoyl transferase-I inhibition is not associated with cardiac hypertrophy in rats fed a high – fat diet. Clin Exp Pharmacol Physiol. 2007;34:113–9.

    Article  PubMed  CAS  Google Scholar 

  23. Bachmann E, Weber E. Biochemical mechanisms of oxfenicine cardio toxicity. Pharmacol. 1988;36:238–48.

    Article  CAS  Google Scholar 

  24. Jodalen H, Ytrehus K, Moen P, Hokland B, Mjøs OD. Oxfenicine-induced accumulation of lipid in the rat myocardium. J Mol Cell Cardiol. 1988;20:277–82.

    Article  PubMed  CAS  Google Scholar 

  25. Greaves P, Martin J, Michel MC, Mompon P. Cardiac hypertrophy in the dog and rat induced by oxfenicine, an agent which modifies muscle metabolism. Arch Toxicol. 1984;7:488–93.

    Article  CAS  Google Scholar 

  26. Chang KC, Tseng CD, Lu SC, Liang JT, Wu MS, Tsai MS, et al. Effects of acetyl-L-carnitine and oxfenicine on aorta stiffness in diabetic rats. Eur J Clin Invest. 2010;40:1–9.

    Google Scholar 

  27. Chavez PN, Stanley WC, McElfresh TA, Huang H, Sterk JP, Chandler ME. Effect of hyperglycemia and fatty acid oxidation inhibition during aerobic conditions and demand-induced ischemia. Am J Physiol Heart Circ Physiol. 2003;284:H1521–7.

    PubMed  CAS  Google Scholar 

  28. Chandler MP, Chavez PN, McElfresh TA, Huang H, Harmon CS, Stanley WC. Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia. Cardiovasc Research. 2003;59:143–51.

    Article  CAS  Google Scholar 

  29. Lionetti V, Linke A, Chandler MP, Young ME, Penn MS, Gupte S, et al. Carnitine palmitoyl transferase-I inhibition prevents ventricular remodelling and delays decompensation in pacing-induced heart failure. Cardiovasc Research. 2005;66:454–61.

    Article  CAS  Google Scholar 

  30. Pickavance LC, Tadayyon M, Widdowson PS, Buckingham RE, Wilding JPH. Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution. Brit J Pharmacol. 1999;128:1570–6.

    Article  CAS  Google Scholar 

  31. Du Toit EF, Smith W, Muller C, Strijdom H, Stouthammer B, Woodiwiss AJ, et al. Myocardial susceptibility to ischemic-reperfusion injury in a pre-diabetic model of dietary-induced obesity. Am J Physiol Heart Circ Physiol. 2008;294:H2336–43.

    Article  PubMed  Google Scholar 

  32. Lindenmayer GE, Sordahl LA, Schwartz A. Re-evaluation of oxidative phosphorylation in cardiac mitochondria from normal animals and animals in heart failure. Circ Res. 1968;23:439–50.

    PubMed  CAS  Google Scholar 

  33. Lanza IR, Nair KS. Functional assessment of isolated mitochondria in vitro. Methods Enzymol. 2009;457:349–72.

    Article  PubMed  CAS  Google Scholar 

  34. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951;193:265–75.

    PubMed  CAS  Google Scholar 

  35. Bradford MM. A rapid sensitive method for quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;71:248–54.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  37. Higgins AJ, Morville M, Burges RA. Mechanism of action of oxfenicine on muscle metabolism. Biochem Biophys Res Comm. 1981;100:291–6.

    Article  PubMed  CAS  Google Scholar 

  38. Molaparast-Sales F, Liedtke AJ, Nellis SH. Effects of the fatty acid blocking agents, oxfenicine and 4-bromocrotonic acid, on performance in aerobic and ischemic myocardium. J Mol Cell Cardiol. 1987;19:509–20.

    Article  Google Scholar 

  39. Essop MF, Chan WYA, Valle A, García-Palmer FJ, Du Toit EF. Impaired contractile function and mitochondrial respiratory capacity in response to oxygen deprivation in a rat model of pre-diabetes. Acta Physiol. 2009;197:289–96.

    Article  CAS  Google Scholar 

  40. Zhou L, Huang H, Yuan CL, Keung W, Lopaschuk GD, Stanley WC. Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2008;294:H954–60.

    Article  PubMed  CAS  Google Scholar 

  41. Broderick TL, Glick B. Effect of gender and fatty acids on ischemic recovery of contractile and pump function in the rat heart. Gend Med. 2004;1:86–99.

    Article  PubMed  Google Scholar 

  42. Carregal M, Varela A, Dalamon V, Sacks S, Savino EA. Beneficial effects of oxfenicine on the hypoxic rat atria. Arch Physiol Biochem. 1995;103:45–9.

    Article  PubMed  CAS  Google Scholar 

  43. Prendes MGM, Garcia JV, Testoni G, Fernandez MA, Perazzo JC, Savino EA, et al. Influence of fasting on the effects of dimethylamiloride and oxfenicine on ischemic–reperfused rat hearts. Arch Physiol Biochem. 2006;112:31–6.

    Article  CAS  Google Scholar 

  44. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785–9.

    Article  PubMed  CAS  Google Scholar 

  45. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabet Metab. 1998;14:263–83.

    Article  CAS  Google Scholar 

  46. Guo L, Tabrizchi R. Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance. Pharmacol Therap. 2006;111:147–73.

    Article  Google Scholar 

  47. King KL, Opie LH. Glucose and glycogen utilization in myocardial ischemia-changes in metabolism and consequences for the myocyte. Mol Cell Biochem. 1998;180:3–26.

    Article  PubMed  CAS  Google Scholar 

  48. Apstein CS, Opie LH. Glucose-insulin-potassium (GIK) for acute myocardial infarction: a negative study with a positive value. Cardiovasc Drugs Ther. 1999;13:185–9.

    Article  PubMed  CAS  Google Scholar 

  49. Bergmann SR, Weinheimer CJ, Markham J, Herrero P. Quantitation of myocardial fatty acid metabolism using PET. J Nucl Med. 1996;37:1723–30.

    PubMed  CAS  Google Scholar 

  50. Drake-Holland AJ, Passingham JE. The effect of oxfenicine on cardiac carbohydrate metabolism is intact dogs. Bas Res Cardiol. 1983;78:19–27.

    Article  CAS  Google Scholar 

  51. Barr RL, Lopaschuk GD. Direct measurement of energy metabolism in the isolated working rat heart. JPM. 1997;38:11–7.

    CAS  Google Scholar 

  52. Lochner A, Du Toit EF, Huisamen B, Koeslag JH, Moolman JA. Cellular injury in ischemia. Cardiovasc Journ of South Africa. 2004;15:205–6.

    CAS  Google Scholar 

  53. Taegtmeyer H. Metabolism — the lost child of cardiology. J Am Coll Cardiol. 2000;36:1386–8.

    Article  PubMed  CAS  Google Scholar 

  54. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline in chronic heart failure a randomized, controlled trial of short-term use of a novel treatment. Circ Res. 2005;112:3280–8.

    CAS  Google Scholar 

  55. Aasum E, Khalid AM, Gudbrandsen OA, How OJ, Berge RK, Larsen TS. Fenofibrate modulates cardiac and hepatic metabolism and increases ischemic tolerance in diet-induced obese mice. J Mol Cell Cardiol. 2008;44:201–9.

    Article  PubMed  CAS  Google Scholar 

  56. Belke DD, Larsen TS, Gibbs EM, Severson DL. Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab. 2000;279:E1104–13.

    PubMed  CAS  Google Scholar 

  57. Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab. 2009;297:E578–91.

    Article  PubMed  CAS  Google Scholar 

  58. Dyck JRB, Cheng JF, Stanley WC, Barr R, Chandler MP, Brown S, et al. Malonyl-Coenzyme A decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ Res. 2004;94:e78–84.

    Article  PubMed  CAS  Google Scholar 

  59. Liu Q, Docherty JC, Rendell JCT, Clanachan AS, Lopaschuk GD. High levels of fatty acids delay the recovery of intracellular pH and cardiac efficiency in post-ischemic hearts by inhibiting glucose oxidation. J Am Coll Cardiol. 2002;39:718–25.

    Article  PubMed  CAS  Google Scholar 

  60. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The anti angina drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation inhibiting mitochondrial long chain 3-Ketoacyl Coenzyme A Thiolase. Circ Res. 2000;86:580–8.

    PubMed  CAS  Google Scholar 

  61. Bielefeld DR, Vary TC, Neely JR. Inhibition of Carnitine Palmitoyl-CoA Transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscle. Mol Cell Cardiol. 1985;17:619–25.

    Google Scholar 

Download references

Acknowledgments

This study was financially supported by the South African National Research Foundation (Prof. E.F. Du Toit and Dr. E. Marais). We would also like to thank Prof. A. Lochner and Prof. B. Huisamen for expert advice and guidance.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Departments of Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa

    Gerald Maarman, Erna Marais & Amanda Lochner

  2. Heart Foundation Research Center, School of Medical Science, Gold Coast Campus, Griffith University, Queensland, Australia

    Eugene F du Toit

  3. Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Room 4.05, Medical Campus, Cape Town, Western Cape, South Africa

    Gerald Maarman

Authors
  1. Gerald Maarman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erna Marais
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amanda Lochner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eugene F du Toit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald Maarman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maarman, G., Marais, E., Lochner, A. et al. Effect of Chronic CPT-1 Inhibition on Myocardial Ischemia-Reperfusion Injury (I/R) in a Model of Diet-Induced Obesity. Cardiovasc Drugs Ther 26, 205–216 (2012). https://doi.org/10.1007/s10557-012-6377-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-012-6377-1

Key words

Search

Navigation