Skip to main content
SpringerLink
Log in

Dexamethasone-induced cardiac deterioration is associated with both calcium handling abnormalities and calcineurin signaling pathway activation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Dexamethasone is a potent and widely used anti-inflammatory and immunosuppressive drug. However, recent evidences suggest that dexamethasone cause pathologic cardiac remodeling, which later impairs cardiac function. The mechanism behind the cardiotoxic effect of dexamethasone is elusive. The present study aimed to verify if dexamethasone-induced cardiotoxicity would be associated with changes in the cardiac net balance of calcium handling protein and calcineurin signaling pathway activation. Wistar rats (~400 g) were treated with dexamethasone (35 µg/g) in drinking water for 15 days. After dexamethasone treatment, we analyzed cardiac function, cardiomyocyte diameter, cardiac fibrosis, and the expression of proteins involved in calcium handling and calcineurin signaling pathway. Dexamethasone-treated rats showed several cardiovascular abnormalities, including elevated blood pressure, diastolic dysfunction, cardiac fibrosis, and cardiomyocyte apoptosis. Regarding the expression of proteins involved in calcium handling, dexamethasone increased phosphorylation of phospholamban at threonine 17, reduced protein levels of Na+/Ca2+ exchanger, and had no effect on protein expression of Serca2a. Protein levels of NFAT and GATA-4 were increased in both cytoplasmic and nuclear faction. In addition, dexamethasone increased nuclear protein levels of calcineurin. Altogether our findings suggest that dexamethasone causes pathologic cardiac remodeling and diastolic dysfunction, which is associated with impaired calcium handling and calcineurin signaling pathway activation.

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
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Cherrington AD (1999) Banting lecture 1997. Control of glucose uptake and release by the liver in vivo. Diabetes 48(5):1198–1214

    Article  CAS  PubMed  Google Scholar 

  2. Naves A (2010) Nutrição Clínica Funcional: Modulação Hormonal, 1st edn. VP Editora, São Paulo

    Google Scholar 

  3. Severino C, Brizzi P, Secchi G, Maioli M, Tonolo G (2002) Low-dose dexamethasone in the rat: a model to study insulin resistance. Am J Physiol Endocrinol Metab 283(2):E367–E373

    Article  CAS  PubMed  Google Scholar 

  4. Barnes PJ, Adcock I (1993) Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol Sci 14(12):436–441

    Article  CAS  PubMed  Google Scholar 

  5. Romanholi DJ, Salgado LR (2007) Exogenous Cushing’s syndrome and glucocorticoid withdrawal. Arq bras endocrinol metab 51(8):1280–1292

    Google Scholar 

  6. Qi D, Rodrigues B (2007) Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism. Am J Physiol Endocrinol Metab 292(3):E654–E667

    Article  CAS  PubMed  Google Scholar 

  7. Van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C (2000) Use of oral corticosteroids in the United Kingdom. QJM: Mon J Assoc Physicians 93(2):105–111

    Article  Google Scholar 

  8. Bernal-Mizrachi C, Weng S, Feng C, Finck BN, Knutsen RH, Leone TC et al (2003) Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice. Nat Med 9(8):1069–1075

    Article  CAS  PubMed  Google Scholar 

  9. Iannoli P, Miller JH, Ryan CK, Sax HC (1998) Glucocorticoids upregulate intestinal nutrient transport in a time-dependent and substrate-specific fashion. J Gastrointest Surg 2(5):449–457

    Article  CAS  PubMed  Google Scholar 

  10. Stahn C, Buttgereit F (2008) Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol 4(10):525–533

    Article  CAS  PubMed  Google Scholar 

  11. Walker BR (2007) Glucocorticoids and cardiovascular disease. Eur J Endocrinol 157(5):545–559

    Article  CAS  PubMed  Google Scholar 

  12. Bal MP, de Vries WB, Steendijk P, Homoet-van der Kraak P, van der Leij FR, Baan J et al (2009) Histopathological changes of the heart after neonatal dexamethasone treatment: studies in 4-, 8-, and 50-week-old rats. Pediatr Res 66(1):74–79

    Article  CAS  PubMed  Google Scholar 

  13. Saad MJ, Folli F, Araki E, Hashimoto N, Csermely P, Kahn CR (1994) Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. Effects of differentiation, insulin, and dexamethasone. Mol Endocrinol 8(5):545–557

    CAS  PubMed  Google Scholar 

  14. Taliari KRS (2004) The dexamethasone action in creatine supplement muscle. Saude book. 10:4

  15. Maxwell SR, Moots RJ, Kendall MJ (1994) Corticosteroids: do they damage the cardiovascular system? Postgrad Med J 70(830):863–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sicard RE, Werner JC (1995) Biochemical correlates of dexamethasone-induced relative cardiomegaly in neonatal rats. In vivo 9(1):75–79

    CAS  PubMed  Google Scholar 

  17. Rao MK, Xu A, Narayanan N (2001) Glucocorticoid modulation of protein phosphorylation and sarcoplasmic reticulum function in rat myocardium. Am J Physiol Heart Circ Physiol 281(1):H325–H333

    CAS  PubMed  Google Scholar 

  18. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y et al (2003) Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Investig 111(3):419–426

    Article  PubMed  PubMed Central  Google Scholar 

  19. Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. Lancet 367(9522):1605–1617

    Article  CAS  PubMed  Google Scholar 

  20. Herrera EA, Verkerk MM, Derks JB, Giussani DA (2010) Antioxidant treatment alters peripheral vascular dysfunction induced by postnatal glucocorticoid therapy in rats. PLoS ONE 5(2):e9250

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zack R (1995) Molecular mechanisms of cardiac hypertrophy. In: Haber E (ed) Scientific American Molecular Cardiovascular Medicine. Scientific American Inc., New York, pp 177–192

    Google Scholar 

  22. Bueno OF, Wilkins BJ, Tymitz KM, Glascock BJ, Kimball TF, Lorenz JN, Molkentin JD (2002) Impaired cardiac hypertrophic response in calcineurin Abeta-deficient mice. Proc Natl Acad Sci USA 99:4586–4591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wilkins BJ, De Windt LJ, Bueno OF, Braz JC, Glascock BJ, Kimball TF, Molkentin JD (2002) Target disruption of NFATc3, but not NFATc4, reveals an intrinsic defect in calcineurin-mediates cardiac hypertrophic growth. Mol Cell Biol 22:7603–7613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Diedrichs H, Hagemeister J, Chi M, Boelck B, Muller-Ehmsen J, Schneider CA (2007) Activation of the calcineurin/NFAT signaling cascade starts early in human hypertrophic myocardium. J Int Med Res 35:803–818

    Article  CAS  PubMed  Google Scholar 

  25. Saruta T (1996) Mechanism of glucocorticoid-induced hypertension. Hypertens Res 19(1):1–8

    Article  CAS  PubMed  Google Scholar 

  26. Roy SG, De P, Mukherjee D, Chander V, Konar A, Bandyopadhyay D et al (2009) Excess of glucocorticoid induces cardiac dysfunction via activating angiotensin II pathway. Cell Physiol Biochem 24(1–2):1–10

    Article  CAS  PubMed  Google Scholar 

  27. Sahn DJ, DeMaria A, Kisslo J, Weyman A (1978) Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 58(6):1072–1083

    Article  CAS  PubMed  Google Scholar 

  28. Litwin SE, Katz SE, Morgan JP, Douglas PS (1994) Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation 89(1):345–354

    Article  CAS  PubMed  Google Scholar 

  29. Ferreira JC, Bacurau AV, Evangelista FS, Coelho MA, Oliveira EM, Casarini DE, Krieger JE, Brum PC (2008) The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice. Am J Physiol Regul Integr Comp Physiol 294(1):R26–R32

    Article  CAS  PubMed  Google Scholar 

  30. Tice RR, Argurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, Miyamae Y, Rojas E, Ryu JC, Sasaki YF (2000) Single cell gel/comet assay, guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35(3):206–221

    Article  CAS  PubMed  Google Scholar 

  31. Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts AC, Leufkens HG, Walker BR (2004) Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart 90(8):859–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Muangmingsuk S, Ingram P, Gupta MP, Arcilla RA, Gupta M (2000) Dexamethasone induced cardiac hypertrophy in newborn rats is accompanied by changes in myosin heavy chain phenotype and gene transcription. Mol Cell Biochem 209(1–2):165–173

    Article  CAS  PubMed  Google Scholar 

  33. Ruzzin J, Wagman AS, Jensen J (2005) Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor. Diabetologia 48(10):2119–2130

    Article  CAS  PubMed  Google Scholar 

  34. Carnicelli V, Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R (2008) Short-term effects of pressure overload on the expression of genes involved in calcium homeostasis. Mol Cell Biochem 313(1–2):29–36

    Article  CAS  PubMed  Google Scholar 

  35. Nakayama H, Otsu K, Yamaguchi O, Nishida K, Date MO, Hongo K et al (2003) Cardiac-specific overexpression of a high Ca2+ affinity mutant of Serca 2a attenuates in vivo pressure overload cardiac hypertrophy. FASEB J 17(1):61–63

    CAS  PubMed  Google Scholar 

  36. Molkentin JD, Olson EN (1997) GATA4: a novel transcriptional regulator of cardiac hypertrophy? Circulation 96(11):3833–3835

    CAS  PubMed  Google Scholar 

  37. Vega RB, Bassel-Duby R, Olson EN (2003) Control of cardiac growth and function by calcineurin signaling. J Biol Chem 278(39):36981–36984

    Article  CAS  PubMed  Google Scholar 

  38. Lakshmi RT, Priyanka T, Meenakshi J, Mathangi KR, Jeyaraman V, Babu M (2011) Low molecular weight heparin mediated regulation of nitric oxide synthase during burn wound healing. Ann Burns Fire Disasters 24(1):24–29

    CAS  PubMed  PubMed Central  Google Scholar 

  39. De P, Roy SG, Kar D, Bandyopadhyay A (2011) Excess of glucocorticoid induces myocardial remodeling and alteration of calcium signaling in cardiomyocytes. J Endocrinol 209(1):105–114

    Article  CAS  PubMed  Google Scholar 

  40. Hajjar RJ, Muller FU, Schimitz P, Bohm M (1998) Molecular aspects of adrenergic signal transduction in cardiac failure. J Mol Med 76(11):747–755

    Article  CAS  PubMed  Google Scholar 

  41. Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, Kuwajima G, Mikoshiba K, Just H, Hasenfuss G et al (1995) Alterations of sarcoplasmatic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92(4):778–784

    Article  CAS  PubMed  Google Scholar 

  42. Schwinger RH, Munch G, Bolck B, Karczewski P, Krause EG, Erdmann E (1999) Reduced Ca2+- sensitivity of Serca 2a in failing human myocardium due to reduce serin-16 phospholamban phosphorylation. J Mol Cell Cardiol 31(3):479–491

    Article  PubMed  Google Scholar 

  43. Kiss E, Ball NA, Kranias EG, Walsh RA (1995) Differential changes in cardiac phospholamban and sarcoplasmatic reticular Ca2+—ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure. Circ Res 77(4):759–764

    Article  CAS  PubMed  Google Scholar 

  44. Dash R, Kadambi V, Schmidt AG, Tepe NM, Biniakiewicz D, Gerst MJ, Canning AM, Abraham WT, Hoit BD, Liggett SB, Lorenz JN, Dorn GW 2nd, Kranias EG (2001) Interactions between phospholamban and beta-adrenergic drive may lead to cardiomyopathy and early mortality. Circulation 103(6):889–896

    Article  CAS  PubMed  Google Scholar 

  45. Lu L, Mei DF, Gu AG, Wang S, Lentzner B, Gutstein DE, Zwas D, Homma S, Yi GH, Wang J (1999) Exercise training normalizes altered calcium-handling proteins during development of heart failure. Am J Cardiol 83(8):1201–1205

    Article  Google Scholar 

  46. Mace LC, Palmer BM, Brown DA, Jew KN, Lynch JM, Glunt JM, Parsons TA, Cheung JY, Moore RL (2003) Influence of age and run training on cardiac NA+/Ca2+ exchange. J Appl Physiol 95(5):1994–2003

    Article  CAS  PubMed  Google Scholar 

  47. Yao A, Su Z, Nonaka A, Zubair I, Spitzer KW, Bridge JH, Muelheims G, Ross J Jr, Barry WH (1998) Abnormal myocyte Ca2+ homeostasis in rabbits with pacing-induced heart failure. Am J Physiol 274(4):H1441–H1448

    Google Scholar 

  48. Marks AR (2000) Cardiac intracellular calcium release channels: role in heart failure. Circ Res 87(1):8–11

    Article  CAS  PubMed  Google Scholar 

  49. Diedrichs H, Hagemeister J, Chi M, Boelck B, Muller-Ehmsen J, Schneider CA (2007) Activation of the calcineurin/NFAT signalling cascade starts early in human hypertrophic myocardium. J Int Med Res 35:803–817

    Article  CAS  PubMed  Google Scholar 

  50. Lim HW, De Windt LJ, Steinberg L, Taigen T, Witt SA, Kimball TR, Molkentin JD (2000) Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy. Circulation 101:2431–2437

    Article  CAS  PubMed  Google Scholar 

  51. Lim HW, Molkentin JD (1999) Calcineurin and human heart failure. Nat Med 5:246–247

    Article  CAS  PubMed  Google Scholar 

  52. Diedrichs H, Chi M, Boelck B, Mehlhorn U, Schwinger RH (2004) Increased regulatory activity of the calcineurin/NFAT pathway in human heart failure. Eur J Heart Fail 6:3–9

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP (#2011/04699-3).

Author information

Author notes

    Authors and Affiliations

    1. Biosciences Department, Federal University of Sao Paulo, Silva Jardim, 136-Vl. Mathias, Santos, SP, 11015-020, Brazil

      Fabiana de Salvi Guimarães, Wilson Max Almeida Monteiro de Moraes, Daniel Araki Ribeiro & Alessandra Medeiros

    2. School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil

      Luis Henrique Marchesi Bozi & Patricia Chakur Brum

    3. Faculty of Medicine, University of São Paulo, São Paulo, Brazil

      Pâmela R. Souza

    4. Cardio-Physiology and Pathophysiology Laboratory, Federal University of Sao Paulo, São Paulo, Brazil

      Ednei Luiz Antonio, Danilo Sales Bocalini & Paulo José Ferreira Tucci

    5. Department of Post-Graduation in Physical Education, São Judas Tadeu University, São Paulo, Brazil

      Danilo Sales Bocalini

    Authors
    1. Fabiana de Salvi Guimarães
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Wilson Max Almeida Monteiro de Moraes
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Luis Henrique Marchesi Bozi
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Pâmela R. Souza
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ednei Luiz Antonio
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Danilo Sales Bocalini
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Paulo José Ferreira Tucci
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Daniel Araki Ribeiro
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Patricia Chakur Brum
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Alessandra Medeiros
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Alessandra Medeiros.

    Ethics declarations

    Conflict of interest

    The authors declare no conflict of interests.

    Additional information

    Fabiana de Salvi Guimarães, Wilson Max Almeida Monteiro de Moraes, Luis Henrique Marchesi Bozi, and Pâmela R. Souza have contributed equally to this study.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    de Salvi Guimarães, F., de Moraes, W.M.A.M., Bozi, L.H.M. et al. Dexamethasone-induced cardiac deterioration is associated with both calcium handling abnormalities and calcineurin signaling pathway activation. Mol Cell Biochem 424, 87–98 (2017). https://doi.org/10.1007/s11010-016-2846-3

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11010-016-2846-3

    Keywords

    Search

    Navigation