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Reduction of palmitate-induced cardiac apoptosis by fenofibrate

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Abstract

The objective of this study was to test the hypothesis that a strategy based on alteration of lipid metabolism would moderate the cellular toxicity of the C16:0 saturated fatty acid-palmitate. Cardiomyocytes from neonatal mice and embryonic chicks were treated with palmitate and both oncotic and apoptotic death were observed. Fenofibrate pretreatment, 1 μM, 24 h prior to palmitate, significantly (p < 0.05) reduced palmitate-induced apoptosis. In contrast, fenofibrate had no significant effect on palmitate-induced apoptosis when fenofibrate treatment was concomitant with palmitate. The protective effect of fenofibrate was restricted to the apoptotic population. The more potent and specific PPARα agonist WY 14643, 1 μM, also reduced palmitate-induced apoptosis but to a smaller extent than fenofibrate. The long pretreatment time, 24 h, was necessary to show fenofibrate's effect on apoptosis, suggesting an increase in gene transcription and protein expression. Indeed, fenofibrate increased PPARα expression that was mainly demonstrated in the nucleus. These data suggest a novel approach to the reduction of cardiac apoptosis by the chronic treatment with the PPARα agonist fenofibrate.

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References

  1. Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T: Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem 272: 3324–3329, 1997

    Google Scholar 

  2. De Vries JE, Vork MM, Roemen THM, De Jong YF, Cleutjens JPM, Van der Vusse GJ, Van Bilsen M: Saturated but not mono-unsaturated fatty acids induce apoptotic cell death in neonatal rat ventricular myocytes. J Lipid Res 38: 1384–1394, 1997

    Google Scholar 

  3. Shimabukuro M, Zhoum YT, Levim M, Unger RH: Fatty acid-induced beta cell apoptosis: A link between obesity and diabetes. Proc Natl Acad Sci USA 95: 2498–2502, 1998

    Google Scholar 

  4. Rabkin SW, Huber M, Krystal G: Modulation of palmitate-induced cardiomyocyte cell death by alteration of intracellular calcium. Prost Leuk Essent Fatty Acids 61: 195–201, 1999

    Google Scholar 

  5. Kong JY, Rabkin SW: Palmitate-induced apoptosis in cardiomyocytes is mediated through alterations in mitochondria: Prevention by cyclosporin. Biochim Biophys Acta 55608: 1–11, 2000

    Google Scholar 

  6. Oliver MF, Kurien A, Greenwood W: Relation between serum free fatty acids and arrhythmias and death after acute myocardial infarction. Lancet 1: 71–75, 1968

    Google Scholar 

  7. Opie LH, Tansey M, Kennelly BM: Proposed metabolic vicious cycle in patients with large myocardial infarcts and high plasma free fatty acid concentrations. Lancet 2: 899–892, 1977

    Google Scholar 

  8. Vik-Mo H, Mjos OD: Influence of free fatty acids on myocardial oxygen consumption and ischemic injury. Am J Cardiol 48: 361–365, 1981

    Google Scholar 

  9. Kong JY, Rabkin SW: Cardiac apoptosis induced by palmitate is mediated through carnitine palmitoyltransferase 1. Am J Physiol 282: H717–H725, 2002

    Google Scholar 

  10. Mannaerts GP, van Veldhoven PP: Metabolic pathways in mammalian peroxisomes. Biochimie 75: 147–158, 1993

    Google Scholar 

  11. Chu C, Mao LF, Schulz H: Estimation of peroxisomal beta-oxidation in rat heart by a direct assay of acyl-CoA oxidase. Biochem J 302: 23–29, 1994

    Google Scholar 

  12. Veerkamp JH, van Moerkerk HT: Peroxisomal fatty acid oxidation in rat and human tissues. Effect of nutritional state, clofibrate treatment and postnatal development in the rat. Biochim Biophys Acta. 875: 301–310, 1986

    Google Scholar 

  13. Piot C, Veerkamp JH, Bauchart D, Hocquette JF: Contribution of mitochondria and peroxisomes to palmitate oxidation in rat and bovine tissue. Com Biochem Physiol 121: 185–194, 1998

    Google Scholar 

  14. Skorin C, Necochea C, Johow V, Soto U, Grau M, Breme J, Leighton F: Peroxisomal fatty acid oxidation and inhibitors of the mitochondrial carnitine palmitoyltransferase I in isolated rat hepatocytes. Biochem J 281: 561–567, 1992

    Google Scholar 

  15. Norseth J, Thomassen MS: Stimulation of microperoxisomal beta-oxidation in rat heart by high-fat diets. Biochim Biophys Acta 751: 312–320, 1983

    Google Scholar 

  16. Orton TC, Parker GL: The effect of hypolipidemic agents on the hepatic microsomal drug-metabolizing enzyme system of the rat. Induction of cytochrome(s) P-450 with specificity toward terminal hydroxylation of lauric acid. Drug Metab Dispos 10: 110–115, 1982

    Google Scholar 

  17. Isseman I, Green S: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645–650, 1990

    Google Scholar 

  18. Amri EZ, Bonino F, Ailhaud G, Abumrad NA, Grimaldi PA: Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem 270: 2367–2371, 1995

    Google Scholar 

  19. Beck F, Plummer S, Senior PV, Byrne S, Green S, Brammer WJ: The ontogeny of peroxisome proliferator activated receptor gene expression in the mouse and rat. Proc Roy Soc Lond 247: 83–86, 1992

    Google Scholar 

  20. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC: Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circ 98: 2088–2093, 1998

    Google Scholar 

  21. Schoonjans K, Staels B, Auwerx J: Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 37: 907–925, 1996

    Google Scholar 

  22. Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W: Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci USA 90: 2160–2164, 1993

    Google Scholar 

  23. Gulick T, Cresci S, Caira T, Moore DD, Kelly DP: The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci 91: 11012–11016, 1994

    Google Scholar 

  24. Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J: Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators. J Biol Chem 272: 28210–28217, 1997

    Google Scholar 

  25. Motojima K, Passilly P, Peters JM, Gonzalez FJ, Latruffe N: Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue-and inducer-specific manner. J Biol Chem 273: 16710–16714, 1998

    Google Scholar 

  26. Kong JY, Rabkin SW: Angiotensin II does not induce apoptosis but rather prevents apoptosis in cardiomyocytes. Peptides 21: 237–247, 2000

    Google Scholar 

  27. Rabkin SW, Kong JY: Nitroprusside induces cardiomyocyte death: Interaction with hydrogen peroxide. Am J Physiol 279: H3089–H3100, 2000

    Google Scholar 

  28. Darzynkiewicz Z, Bruno S, Del Bino G, Gorczyca W, Hotz MA, Lassota P, Traganos F: Features of apoptotic cells measured by flow cytometry. Cytometry 13: 795–808, 1992

    Google Scholar 

  29. Reid E, Williamson R: Centrifugation. Meth Enzymol 31: 713–733, 1974

    Google Scholar 

  30. Richieri GY, Klienfeld AM: Unbound free fatty acid levels in human serum. J Lipid Res 36: 229–240, 1995

    Google Scholar 

  31. Isseman I, Prince RA, Tugwood JT, Green S: The peroxisome proliferator activated receptor: Retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidemic drugs. J Mol Endocrinol 11: 37–47, 1993

    Google Scholar 

  32. Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB: A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis. Am J Physiol 279: H2124–H2132, 2000

    Google Scholar 

  33. Levin S, Bucci TJ, Cohen SM, Fix AS, Hardisty JF, LeGrand EK, Maronpot RR, Trump BF: The nomenclature of cell death: Recommendations of an ad hoc committee of the society of toxicologic pathologists. Toxicol Pathol 27: 484–490, 1999

    Google Scholar 

  34. Bartkowiak D, Hogner S, Baust H, Nothdurft W, Rottinger EM: Comparative analysis of apoptosis in HL60 detected by annexin-V and fluorescein-diacetate. Cytometry 37: 191–196, 1999

    Google Scholar 

  35. Zhou S, Wallace KB: The effect of peroxisome proliferators on mitochondrial bioenergetics. Toxicol Sci 48: 82–89, 1999

    Google Scholar 

  36. Yamazaki K, Kuromitsu J, Tanaka I: Microarray analysis of gene expression changes in mouse liver induced by peroxisome proliferator-activated receptor alpha agonists. Biochem Biophys Res Commun 290: 114–122, 2002

    Google Scholar 

  37. Christensen JG, Gonzalez AJ, Cattley RC, Goldsworthy TL: Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoixic carcijnogens. Cell Growth Differ 9: 815–825, 1998

    Google Scholar 

  38. James NH, Gill JH, Brindle R: Peroxisome proliferator-activated receptor (PPAR) alpha-regulated growth responses and their importance to hepatocarcinogenesis. Toxicol Lett 102/103: 91–96, 1998

    Google Scholar 

  39. Roberts RA, James NH, Woodyatt NJ, Macdonald N, Tugwood JD: Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPARα). Carcinogenesis 19: 43–48, 1998

    Google Scholar 

  40. Diep QN, Touyz RM, Schiffrin EL: Docosahexaenoic acid, a peroxisome proliferator-activated receptor-alpha ligand, induces apoptosis in vascular smooth muscle cells by stimulation of p38 mitogen-activated protein kinase. Hypertension 36: 851–855, 2000

    Google Scholar 

  41. Yang WL, Frucht H: Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. Carcinogenesis 22: 1379–1383, 2001

    Google Scholar 

  42. Djouadi F, Brandt JM, Weinheimer CJ, Leone TC, Gonzalez FJ, Kelly DP: The role of the peroxisome proliferator-activated receptor alpha (PPAR alpha) in the control of cardiac lipid metabolism. Prostagland Leukotr 60: 339–343, 1999

    Google Scholar 

  43. Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B: Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 273: 25573–25580, 1998

    Google Scholar 

  44. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz KL: Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15: 3012–3022, 1995

    Google Scholar 

  45. Peters JM, Aoyama T, Cattley RC, Usuda M, Hashimoto T, Gonzalez FJ: Role of peroxisome proliferator-activated receptor-alpha in altered cell cycle regulation in mouse liver. Carcinogenesis 19: 1989–1994, 1998

    Google Scholar 

  46. Johnson TI, Holloway MK, Vogel R, Rutledge SJ, Perkins JJ, Rodan GA: Structural requirements and cell-type specificity for ligand activation of peroxisome proliferator-activated receptors. J Steroid Biochem Mol Biol 63: 1–8, 1997

    Google Scholar 

  47. Marcus SL, Miyata KS, Rachubinski RA, Capone JP: Transactivation by PPAR/RXR heterodimers in yeast is potentiated by exogenous fatty acids via a pathway requiring intact peroxisomes. Gene Expr 4: 227–239, 1995

    Google Scholar 

  48. Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahli W, Meier CA, Desvergne B: DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. J Biol Chem 272: 25252–25259, 1997

    Google Scholar 

  49. James NH, Roberts RA: Species differences in response to peroxisome proliferation correlate in vitro with induction of DNA synthesis rather than suppression of apoptosis. Carcinogenesis 17: 1623–1632, 1996

    Google Scholar 

  50. Nilsson L, Takemura T, Eriksson P, Hamsten A: Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells. Arterioscler Thromb Vasc Biol 19: 1577–1581, 1999

    Google Scholar 

  51. Gebel T, Arand M, Oesch F: Induction of the peroxisome proliferator activated receptor by fenofibrate in rat liver. FEBS Lett 309: 37–40, 1992

    Google Scholar 

  52. Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B: Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 275: 16638–16642, 2000

    Google Scholar 

  53. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Wilson TM, Kliewer SA, Milburn MV: Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3: 397–403, 1999

    Google Scholar 

  54. Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM: Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res 51: 304–312, 2001

    Google Scholar 

  55. Olivetti G. Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P: Apoptosis in the failing human heart. New Engl J Med 336: 1131–1141, 1997

    Google Scholar 

  56. Kong JY, Rabkin SW: Thapsigargin enhances camptothecin-induced apoptosis in cardiomyocytes. Pharmacol Toxicol 85: 212–220, 1999

    Google Scholar 

  57. Kong JY, Rabkin SW: Palmitate induces structural alterations in nuclei of cardiomyocytes. Tissue Cell 31: 473–479, 1999

    Google Scholar 

  58. Kong JY, Rabkin SW: Lovastatin does not accentuate but is rather additive to palmitate-induced apoptosis in cardiomyocytes. Prostagland Leukotr Essent Fatty Acids (in press)

  59. Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R: In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: A cautionary note. Hepatology 21: 1465–1468, 1995

    Google Scholar 

  60. Labat-Moleur F, Guillermet C, Lorimier P, Robert C, Lantuejoul S, Brambilla E, Negoescu A: TUNEL apoptotic cell detection in tissue sections: Critical evaluation and improvement. J Histochem Cytochem 46: 327–334, 1998

    Google Scholar 

  61. Kong JY, Rabkin SW: Mechanisms of palmitate-induced cardiomyocyte apoptosis. In: P.K. Singal et al. (ed.). Cardiac Remodeling and Failure. Kluwer Academic Publishers, Boston, MA, 2002, pp 435–458

    Google Scholar 

  62. Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H, Kawamura S, Kimura M, Ikeda Y, Iwatate M, Matsuzaki M: Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. Cardiovasc Res 45: 642–650, 2000

    Google Scholar 

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  1. Department of Medicine, University of British Columbia, Vancouver, Canada

    Jennifer Y. Kong & Simon W. Rabkin

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Kong, J.Y., Rabkin, S.W. Reduction of palmitate-induced cardiac apoptosis by fenofibrate. Mol Cell Biochem 258, 1–13 (2004). https://doi.org/10.1023/B:MCBI.0000012811.89386.a8

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  • DOI: https://doi.org/10.1023/B:MCBI.0000012811.89386.a8

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