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Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications.

Gay MS, Li Y, Xiong F, Lin T, Zhang L - PLoS ONE (2015)

Bottom Line: Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups.Ru486 abrogated the effects of dexamethasone.In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts.

View Article: PubMed Central - PubMed

Affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda, California, 92350, United States of America.

ABSTRACT
The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1), 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner.

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5-AZA inhibits dexamethasone (DEX)-mediated effects on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of 5-AZA during the first three days of postnatal life. 5-AZA was administered 30 minutes prior to the DEX treatment. Heart and body weights were determined in day 4 (P4), day 7 (P7) and day 14 (P14) neonatal rats. Data are mean ± SEM, n = 5–21. * p<0.05, DEX vs. Saline; # p<0.05, +5-AZA vs. -5-AZA.
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pone.0125033.g005: 5-AZA inhibits dexamethasone (DEX)-mediated effects on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of 5-AZA during the first three days of postnatal life. 5-AZA was administered 30 minutes prior to the DEX treatment. Heart and body weights were determined in day 4 (P4), day 7 (P7) and day 14 (P14) neonatal rats. Data are mean ± SEM, n = 5–21. * p<0.05, DEX vs. Saline; # p<0.05, +5-AZA vs. -5-AZA.

Mentions: Given that epigenetic modifications play an important role in the heart development and the activation of GR has been noted to alter the methylation pattern of multiple genes, we determined whether heightened methylation played a role in dexamethasone-induced effects on the heart development in neonatal rats. The effects of dexamethasone was evaluated in the absence or presence of a methylation inhibitor 5-AZA. Although 5-AZA treatment alone had no significant effects on either heart weight or body weight in P4 and P7 pups, it caused a significant but symmetric decrease in both heart and body weight in P14 pups (Figs 5A and 5B). Interestingly, although it had no significant effects on either heart or body weight in P7 pups, it significantly increased the heart to body ratio in P7 pups (Fig 5C). Of importance, in the presence of 5-AZA, effects of dexamethasone on heart weight, body weight and the heart to body weight ration were abrogated (Fig 5), suggesting DNA methylation as a critical mechanism of dexamethasone effects.


Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications.

Gay MS, Li Y, Xiong F, Lin T, Zhang L - PLoS ONE (2015)

5-AZA inhibits dexamethasone (DEX)-mediated effects on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of 5-AZA during the first three days of postnatal life. 5-AZA was administered 30 minutes prior to the DEX treatment. Heart and body weights were determined in day 4 (P4), day 7 (P7) and day 14 (P14) neonatal rats. Data are mean ± SEM, n = 5–21. * p<0.05, DEX vs. Saline; # p<0.05, +5-AZA vs. -5-AZA.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4414482&req=5

pone.0125033.g005: 5-AZA inhibits dexamethasone (DEX)-mediated effects on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of 5-AZA during the first three days of postnatal life. 5-AZA was administered 30 minutes prior to the DEX treatment. Heart and body weights were determined in day 4 (P4), day 7 (P7) and day 14 (P14) neonatal rats. Data are mean ± SEM, n = 5–21. * p<0.05, DEX vs. Saline; # p<0.05, +5-AZA vs. -5-AZA.
Mentions: Given that epigenetic modifications play an important role in the heart development and the activation of GR has been noted to alter the methylation pattern of multiple genes, we determined whether heightened methylation played a role in dexamethasone-induced effects on the heart development in neonatal rats. The effects of dexamethasone was evaluated in the absence or presence of a methylation inhibitor 5-AZA. Although 5-AZA treatment alone had no significant effects on either heart weight or body weight in P4 and P7 pups, it caused a significant but symmetric decrease in both heart and body weight in P14 pups (Figs 5A and 5B). Interestingly, although it had no significant effects on either heart or body weight in P7 pups, it significantly increased the heart to body ratio in P7 pups (Fig 5C). Of importance, in the presence of 5-AZA, effects of dexamethasone on heart weight, body weight and the heart to body weight ration were abrogated (Fig 5), suggesting DNA methylation as a critical mechanism of dexamethasone effects.

Bottom Line: Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups.Ru486 abrogated the effects of dexamethasone.In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts.

View Article: PubMed Central - PubMed

Affiliation: Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda, California, 92350, United States of America.

ABSTRACT
The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1), 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner.

Show MeSH
Related in: MedlinePlus