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.
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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.
This study was supported by the International Society of Hypertension (ISH) through the ISH grant for mentors (2017).
Conflict of interest
LAO received eplerenone (PF-02845980) used in this study from Pfizer Inc. (NY, USA) via the Compound Transfer Program (CTP).
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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
- Cardiac hypertrophy glutathione-antioxidant system