Mineralocorticoid receptor blockade attenuates disrupted glutathione-dependent antioxidant defense and elevated endoglin in the hearts of pregnant rats exposed to testosterone

Abstract

Elevated testosterone during late pregnancy has been linked to cardiac dysfunction and poor pregnancy outcomes. The role of mineralocorticoid receptor (MR) in testosterone-induced cardiac dysfunction has not been fully elucidated. The study was therefore designed to investigate the role of MR on gestational excess androgen-induced cardiac disrupted glutathione-dependent antioxidant system and elevated endoglin (Eng) linking it with pregnancy outcomes. Thirty-two pregnant Wistar rats were randomly allotted into four groups (n = 8/group) receiving (sc) olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with non-selective MR blocker (MRB), spironolactone (0.25 mg/kg; po) or selective MRB, and eplerenone (1.0 mg/kg; po) in late between gestational days 14 and 19. The results showed that testosterone exposure resulted in elevated fasting blood glucose, increased cardiac mass, free fatty acid, endoglin, malonaldehyde, oxidized glutathione, uric acid, and lactate production and cardiac injury marker enzymes. On the other hand, testosterone exposure caused reduction in cardiac adenosine, nitric oxide, glutathione, glutathione peroxidase, and glucose-6-phosphate dehydrogenase activities. However, MR blockade by spironolactone and or eplerenone attenuated the effects induced by testosterone exposure. Taken together, the findings from the current study demonstrates that lategestational testosterone induces poor pregnancy outcome that is accompanied by cardiac lipotoxicity,glutathione-dependent antioxidant defense depletion, increased endoglin, lactate and uric acid productionthrough MR activation.

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

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

References

  1. Acromite MT, Mantzorons CS, Leach RE, Hurwitz J, Dorey LG (1999) Androgens in preeclampsia. Am J Obstet Gynecol 180:60–63

    CAS  Article  Google Scholar 

  2. Aquilano K, Baldelli S, Ciriolo MR (2014) Glutathione: new roles in redox signaling for an old antioxidant. Front Pharmacol 5:196

    Article  Google Scholar 

  3. Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daunhauer R et al (2002) Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 89:12–17

    CAS  Article  Google Scholar 

  4. Blázquez-Medela AM, García-Ortiz L, Gómez-Marcos MA, Recio-Rodríguez JI, Angel Sánchez-Rodríguez A, López-Novoa JM (2010) Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients. BMC Med 8:86

    Article  Google Scholar 

  5. Buster JE, Chang RJ, Preston DL (1979) Interrelationships of circulating maternal steroid concentrations in the third trimester pregnancies. J Clin Endocrinol Metab 48:139–142

    CAS  Article  Google Scholar 

  6. Dalton TP, Chen Y, Schneider SN, Nebert DW, Shertzer HG (2004) Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radic Biol Med 37(10):1511-1526

  7. Deneke SM, Fanburg BL (1989) Regulation of cellular glutathione. Am J Phys 257:L163–L173

    CAS  Google Scholar 

  8. Dickhout JG, Hossain GS, Pozza LM, Zhou J, Lhotak S, Austin RC (2005) Peroxynitrite causes endoplasmic reticulum stress and apoptosis in human vascular endothelium: implications in atherogenesis. Arterioscler Thromb Vasc Biol 25:2623–2629

    CAS  Article  Google Scholar 

  9. Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33(7):829–837

    Article  Google Scholar 

  10. Jadhav AA, Jain A (2013) Adenosine deaminase activity in normal pregnancy and pregnancy associated disorders. Arch Physiol Biochem 119:88–91

    CAS  Article  Google Scholar 

  11. Jia G, Habibi J, Bostick PB (2015) Uric acid promotes left ventricular diastolic dysfunction in mice fed with western diet. Hypertension 65:531–539

    CAS  Article  Google Scholar 

  12. Kelley EE, Khoo NK, Hundley NJ, Malik UZ, Freeman BA, Tarpey MM (2010) Hydrogen peroxide is the major oxidant product of xanthine oxidase. Free Radic Biol Med 48:493–498

    CAS  Article  Google Scholar 

  13. Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids but not unsaturated fatty acids induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276:16683–16689

    CAS  Article  Google Scholar 

  14. Lee JG, Kang DG, Yu JR, Kim Y, Kim J, Koh G et al (2011) Changes in adenosine deaminase activity in patients with type 2 diabetes mellitus and effect of DPP-4 inhibitor treatment on ADA activity. Diabetes Metab J 35:149–158

    CAS  Article  Google Scholar 

  15. Liu PY, Death AK, Handelsman DJ (2003) Androgens and cardiovascular disease. Endocr Rev 24(3):313–340

    CAS  Article  Google Scholar 

  16. Luft FC (2006) Soluble endoglin (sEng) joins the soluble fms-like tyrosine kinase (sFLT) receptor as a pre-eclampsia molecule. Nephrol Dial Transplant 21:3052–3054

    CAS  Article  Google Scholar 

  17. Mandal AK, Mount DB (2015) The molecular physiology of uric acid homeostasis. Annu Rev Physiol 77:323–345

    CAS  Article  Google Scholar 

  18. Markey CM, Coombs MA, Sonnenschein C, Soto AM (2003) Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evol Dev 5:67–75

    CAS  Article  Google Scholar 

  19. McEwen B (1992) Steroid hormones: effect on brain development and function. Horm Res Paediatr 37:1–10

    CAS  Article  Google Scholar 

  20. Morgan D, Oliveira-Emilio HR, Keane D, Hirata AE, Santos da Rocha M, Bordin S (2007) Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia 50:359–369

    CAS  Article  Google Scholar 

  21. Nagoshi T, Yoshimura M, Rosano GMC, Lopaschuk GD, Mochizuki S (2011) Optimization of cardiac metabolism in heart failure. Curr Pharm Des 17(35):3846–3853

    CAS  Article  Google Scholar 

  22. Olatunji LA, Areola ED, Badmus OO (2018) Endoglin inhibition by sodium acetate and flutamide ameliorates cardiac defective G6PD-dependent antioxidant defense in gestational testosterone exposed rats. Biopha 107:1641–1647

    CAS  Google Scholar 

  23. Patinha D, Afonso J, Sousa T, Morato M, Albino-Teixeira A (2014) Activation of adenosine receptors improves renal antioxidant status in diabetic Wistar but not SHR rats. Ups J Med Sci 119:10–18

    Article  Google Scholar 

  24. Powe CE, Levine RJ, Karumanchi SA (2011) Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation 123:2856–2869

    Article  Google Scholar 

  25. Rickard AJ, Morgan J, Tesch G, Funder JW, Fuller PJ, Young MJ et al (2009) Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension 54:537–543

    CAS  Article  Google Scholar 

  26. Serin IS, Kula M, Basbug M, Unluhizarci K, Gucer S, Tayyar M (2001) Androgen levels of preeclamptic patients in the third trimester of pregnancy and six weeks after delivery. Acta Obstet Gynecol Scand 80:1009–1013

    CAS  Article  Google Scholar 

  27. Sowers JR, Whaley-Connell A, Epstein M (2004) Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Am J Physiol Ren Physiol 286:F1178–F1184

    Article  Google Scholar 

  28. Steegers EA, Von DP, Duvekot JJ, Pijnenborg R (2010) Pre-eclampsia. Lancet 376:631–644

    Article  Google Scholar 

  29. Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K (1995) Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 15:821–826

    CAS  Article  Google Scholar 

  30. Tirosh A, Garg R, Adler GK (2010) Mineralocorticoid receptor antagonists and the metabolic syndrome. Curr Hypertens Rep 12(4):252–257

    CAS  Article  Google Scholar 

  31. Tsybouleva N, Zhang L, Chen S, Patel R, Lutucuta S, Nemoto S, DeFreitas G, Entman M, Carabello BA, Roberts R, Marian AJ (2004) Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy. Circulation 109:1284–1291

    CAS  Article  Google Scholar 

  32. Ungerer JP, Oosthuizen HM, Bissbort SH, Vermaak WJ (1992) Serum adenosine deaminase: isoenzymes and diagnostic application. Clin Chem 38:1322–1326

    CAS  Article  Google Scholar 

  33. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12:642–649

    CAS  Article  Google Scholar 

  34. Xu Y, Wang Y, Yan S, Zhou Y, Yang Q, Pan Y, Zeng X, An X, Liu Z, Wang L, Xu J, Cao Y, Fulton DJ, Weintraub NL, Bagi Z, Hoda MN, Wang X, Li Q, Hong M, Jiang X, Boison D, Weber C, Wu C, Huo Y (2017) Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis. EMBO Mol Med 9(9):1263–1278

    CAS  Article  Google Scholar 

  35. Zhang Y, Handy DE, Loscalzo J (2005) Adenosine-dependent induction of glutathione peroxidase 1 in human primary endothelial cells and protection against oxidative stress. Circ Res 96:8317

    Google Scholar 

Download references

Acknowledgements

The authors wish to appreciate Pfizer Inc. for providing the eplerenone (PF-02845980) used in this study via the Compound Transfer Program (CTP), Request Number WI223005.

Funding

This study was supported by the International Society of Hypertension (ISH) through the ISH grant for mentors (2017).

Author information

Affiliations

Authors

Contributions

LAO and IKK conceived the research. LAO designed the research. TOU and OOB conducted the experiments. LAO and IKK provided the selective mineralocorticoid receptor antagonist used in the study. LAO, TOU, and OOB analyzed the data. LAO and OOB wrote the manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Lawrence A. Olatunji.

Ethics declarations

Conflict of interest

LAO received eplerenone (PF-02845980) used in this study from Pfizer Inc. (NY, USA) via the Compound Transfer Program (CTP).

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Usman, T.O., Badmus, O.O., Kim, I. et al. Mineralocorticoid receptor blockade attenuates disrupted glutathione-dependent antioxidant defense and elevated endoglin in the hearts of pregnant rats exposed to testosterone. Naunyn-Schmiedeberg's Arch Pharmacol 392, 773–784 (2019). https://doi.org/10.1007/s00210-019-01630-5

Download citation

Keywords

  • Androgen
  • Endoglin
  • Cardiac hypertrophy glutathione-antioxidant system
  • Pregnancy