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Leptin modulates the negative inotropic effect of interleukin-1β in cardiac myocytes

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Abstract

Interleukin-1β (IL-1β) is a potent negative inotrope implicated in the functional abnormalities of heart failure. Because the adipokine, leptin, protects against some of the cardiovascular effects of endotoxin, we hypothesized that leptin may modulate the cardiosuppressive effects of IL-1β in isolated cardiomyocytes. Ventricular cardiac myocytes isolated from adult male Sprague Dawley rats were analyzed simultaneously for electrically stimulated contractility and calcium transients following 30 min exposure to IL-1β (10 ng/ml) with or without 60 min pretreatment with leptin (25 ng/ml). IL-1β decreased cell shortening, depressed maximal velocities of shortening and relengthening, and prolonged the time to 90% relaxation. The change in fura2-AM fluorescence ratio amplitude (Δ[Ca2+]) was significantly depressed and the time to return to baseline [Ca2+] was prolonged. The negative inotropic effects of IL-1β were blocked by the neutral sphingomyelinase inhibitor Manumycin A (5 μM) or the ceramidase inhibitor N-oleoyl ethanolamine (1 μM). Prior exposure of myocytes to leptin blocked IL-1β-induced cardiosuppression in conjunction with a blunting of IL-1β stimulated ceramide accumulation. These data suggest that leptin may modulate IL-1β signaling through the sphingolipid signaling pathway in cardiomyocytes.

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References

  1. Blum A, Miller H (2001) Pathophysiological role of cytokines in congestive heart failure. Annu Rev Med 52:15–27. doi:10.1146/annurev.med.52.1.15

    Article  PubMed  CAS  Google Scholar 

  2. Long CS (2001) The role of interleukin-1 in the failing heart. Heart Fail Rev 6:81–94. doi:10.1023/A:1011428824771

    Article  PubMed  CAS  Google Scholar 

  3. Favory R, Lancel S, Marchetti P, Mordon S, Chopin C, Formstecher P et al (2004) Endotoxin-induced myocardial dysfunction: Evidence for a role of sphingosine production. Crit Care Med 32:495–501. doi:10.1097/01.CCM.0000109452.36271.FA

    Article  PubMed  CAS  Google Scholar 

  4. Schreur KD, Liu S (1997) Involvement of ceramide in inhibitory effect of IL-1 beta on L-type calcium current in adult rat ventricular myocytes. Am J Physiol Heart Circ Physiol 272:H2591–H2598

    CAS  Google Scholar 

  5. Sweeney G (2002) Leptin signaling. Cell Signal 12:655–663. doi:10.1016/S0898-6568(02)00006-2

    Article  Google Scholar 

  6. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271. doi:10.1016/0092-8674(95)90151-5

    Article  PubMed  CAS  Google Scholar 

  7. Hoggard N, Mercer JG, Rayner DV, Moar K, Trayhurn P, Williams LM (1997) Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridization. Biochem Biophys Res Commun 232:383–387. doi:10.1006/bbrc.1997.6245

    Article  PubMed  CAS  Google Scholar 

  8. Nickola MW, Wold LE, Colligan PB, Wang G-J, Samson WK, Ren J (2000) Leptin attenuates cardiac contraction in rat ventricular myocytes. Role of NO. Hypertension 36:501–505

    PubMed  CAS  Google Scholar 

  9. Faggioni R, Moser A, Feingold KR, Grunfeld C (2000) Reduced leptin levels in starvation increase susceptibility to endotoxic shock. Am J Pathol 156:1781–1787

    PubMed  CAS  Google Scholar 

  10. Faggioni R, Fantuzzi G, Gabay C, Moser A, Dinarello CA, Feingold KR et al (1999) Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am J Physiol 276:R136–R142

    PubMed  CAS  Google Scholar 

  11. Wimsatt DK, Hohl CM, Brierley GP, Altschuld RA (1990) Calcium accumulation and release by the sarcoplasmic reticulum of digitonin-lysed adult mammalian ventricular cardiomyocytes. J Biol Chem 265:14849–14857

    PubMed  CAS  Google Scholar 

  12. Hohl CM, Altschuld RA (1991) Response of isolated adult canine cardiac myocytes to prolonged hypoxia and reoxygenation. Am J Physiol 260:C383–C391

    PubMed  CAS  Google Scholar 

  13. Bergman MR, Holycross BJ (1996) Pharmacological modulation of myocardial tumor necrosis factor α production by phosphodiesterase inhibitors. J Pharmacol Exp Ther 279:247–254

    PubMed  CAS  Google Scholar 

  14. Houle MS, Altschuld RA, Billman GE (2001) Enhanced in vivo and in vitro contractile responses to β2-adrenergic receptor stimulation in dogs susceptible to lethal arrhythmias. J Appl Physiol 91:1627–1637

    PubMed  CAS  Google Scholar 

  15. Hensley J, Billman GE, Johnson JD, Hohl CM, Altschuld RA (1997) Effects of calcium channel antagonists on Ca2+ transients in rat and canine cardiomyocytes. J Mol Cell Cardiol 29:1037–1043. doi:10.1006/jmcc.1996.0348

    Article  PubMed  CAS  Google Scholar 

  16. Dasgupta S, Hogan EL (2001) Chromatographic resolution and quantitative assay of CNS tissue sphingoids and sphingolipids. J Lipid Res 42:301–307

    PubMed  CAS  Google Scholar 

  17. Bishcel MD, Austin JH (1963) A modified benzidine method for the chromatographic detection of sphingolipids and acid polysaccharides. Biochim Biophys Acta 70:598–600. doi:10.1016/0006-3002(63)90800-X

    Article  Google Scholar 

  18. Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K (2000) Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta 1485:63–99

    PubMed  CAS  Google Scholar 

  19. Liu SJ, Kennedy RH (2003) Positive inotropic effect of ceramide in adult ventricular myocytes: mechanisms dissociated from its reduction in Ca++ influx. Am J Physiol Heart Circ Physiol 285:H735–H744

    PubMed  CAS  Google Scholar 

  20. Relling DP, Hintz KK, Ren J (2003) Acute exposure of ceramide enhances cardiac contractile function in isolated ventricular myocytes. Br J Pharmacol 140:1163–1168. doi:10.1038/sj.bjp.0705510

    Article  PubMed  CAS  Google Scholar 

  21. Viani P, Giussani P, Brioschi L, Bassi R, Anelli V, Tettamanti G et al (2003) Ceramide in nitric oxide inhibition of glioma cell growth. Evidence for the involvement of ceramide traffic. J Biol Chem 278:9592–9601. doi:10.1074/jbc.M207729200

    Article  PubMed  CAS  Google Scholar 

  22. Franzen R, Fabbro D, Aschrafi A, Pfeilschifter J, Huwiler A (2002) Nitric oxide induces degradation of the neutral ceramidase in rat renal mesangial cells and is couterrregulated by protein kinase C. J Biol Chem 277:46184–46190. doi:10.1074/jbc.M204034200

    Article  PubMed  CAS  Google Scholar 

  23. Zhang Y, Scarpace PJ (2006) The role of leptin in leptin resistance and obesity. Physiol Behav 88:249–256. doi:10.1016/j.physbeh.2006.05.038

    Article  PubMed  CAS  Google Scholar 

  24. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D et al (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 97:1784–1789. doi:10.1073/pnas.97.4.1784

    Article  PubMed  CAS  Google Scholar 

  25. Chabowski A, Zmijewska M, Gorski J, Bonen A, Kaminski K, Winnicka MM (2007) Effect of IL-6 deficiency on myocardial expression of fatty acid transporters and intracellular lipid deposits. J Physiol Pharmacol 58:73–82

    PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from the American Heart Association, Ohio Valley Affiliate, and The Ohio State University Canine Research Fund. We wish to thank Toni Hoepf for technical assistance.

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Authors and Affiliations

  1. Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH, 43210, USA

    M. Judith Radin

  2. The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, 43210, USA

    Bethany J. Holycross, Cristian Dumitrescu & Robert Kelley

  3. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, 43210, USA

    Ruth A. Altschuld

Authors
  1. M. Judith Radin
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  2. Bethany J. Holycross
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  3. Cristian Dumitrescu
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  4. Robert Kelley
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  5. Ruth A. Altschuld
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Correspondence to M. Judith Radin.

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Radin, M.J., Holycross, B.J., Dumitrescu, C. et al. Leptin modulates the negative inotropic effect of interleukin-1β in cardiac myocytes. Mol Cell Biochem 315, 179–184 (2008). https://doi.org/10.1007/s11010-008-9805-6

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  • DOI: https://doi.org/10.1007/s11010-008-9805-6

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