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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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Effect of dexamethasone (DEX) on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of Ru486 during the first three days of postnatal life. Ru486 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 = 10–21. * p<0.05, DEX vs. Saline; # p<0.05, +Ru486 vs.-Ru486.
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pone.0125033.g001: Effect of dexamethasone (DEX) on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of Ru486 during the first three days of postnatal life. Ru486 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 = 10–21. * p<0.05, DEX vs. Saline; # p<0.05, +Ru486 vs.-Ru486.

Mentions: Newborn pups of P1 to P3 were treated with tapered dose of dexamethasone or saline. At P4, P7 and P14, heart weight, body weight and the heart to body weight ratio were evaluated. As shown in Fig 1, in the saline control animals, heart and body weight increased as pups grew, albeit the heart to body weight ratio stayed relatively constant. The dexamethasone treatment increased heart weight in P7 and P14 pups (Fig 1A), but body weight only at P7 pups (Fig 1B), resulting in a significant increase in the heart to body ratio in P14 pups (Fig 1C). To determine the role of glucocorticoid receptor (GR) in the dexamethasone-mediated effects, Ru486 was administered 30 minutes prior to dexamethasone. While Ru486 treatment alone had no significant effects on heart weight, body weight or heart to body weight ratio in P4 and P7 pups, it caused a significant decrease in both heart and body weight in P14 pups (Fig 1). In the presence of Ru486, the effects of dexamethasone were abrogated (Fig 1), suggesting a GR-mediated effect of dexamethasone.


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)

Effect of dexamethasone (DEX) on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of Ru486 during the first three days of postnatal life. Ru486 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 = 10–21. * p<0.05, DEX vs. Saline; # p<0.05, +Ru486 vs.-Ru486.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4414482&req=5

pone.0125033.g001: Effect of dexamethasone (DEX) on heart development in neonatal rats.Newborn rats were treated with tapered dose of DEX in the absence or presence of Ru486 during the first three days of postnatal life. Ru486 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 = 10–21. * p<0.05, DEX vs. Saline; # p<0.05, +Ru486 vs.-Ru486.
Mentions: Newborn pups of P1 to P3 were treated with tapered dose of dexamethasone or saline. At P4, P7 and P14, heart weight, body weight and the heart to body weight ratio were evaluated. As shown in Fig 1, in the saline control animals, heart and body weight increased as pups grew, albeit the heart to body weight ratio stayed relatively constant. The dexamethasone treatment increased heart weight in P7 and P14 pups (Fig 1A), but body weight only at P7 pups (Fig 1B), resulting in a significant increase in the heart to body ratio in P14 pups (Fig 1C). To determine the role of glucocorticoid receptor (GR) in the dexamethasone-mediated effects, Ru486 was administered 30 minutes prior to dexamethasone. While Ru486 treatment alone had no significant effects on heart weight, body weight or heart to body weight ratio in P4 and P7 pups, it caused a significant decrease in both heart and body weight in P14 pups (Fig 1). In the presence of Ru486, the effects of dexamethasone were abrogated (Fig 1), suggesting a GR-mediated effect of dexamethasone.

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