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Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic
Maresha S Gay1, Yong Li1, Fuxia Xiong1
1Center 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.
Insights
Dexamethasone exposure in newborn rats alters heart development, increasing binucleated cardiomyocytes and decreasing proliferation. DNA methylation plays a key role in these adverse effects on developing cardiac cells.
Area of Science:
- Developmental Biology
- Cardiovascular Research
- Pharmacology
Background:
- The impact of synthetic glucocorticoids like dexamethasone on the developing heart is not fully understood.
- Investigating potential adverse effects on cardiomyocyte development is crucial for neonatal care and treatment protocols.
Purpose of the Study:
- To examine the effects of dexamethasone on cardiomyocyte proliferation and binucleation in newborn rat hearts.
- To evaluate the role of DNA methylation as a mechanism underlying dexamethasone's impact on cardiac development.
Main Methods:
- Newborn rats received dexamethasone with or without a glucocorticoid receptor antagonist (Ru486).
- DNA methylation inhibitor (5-aza-2'-deoxycytidine, 5-AZA) was used to assess its mechanistic role.
- Cardiomyocyte proliferation, binucleation, cell number, and gene expression (cyclin D2, p27) were analyzed at different postnatal days.
Main Results:
- Dexamethasone increased binucleated cardiomyocytes, decreased proliferation, reduced cell number, and increased heart-to-body weight ratio.
- The glucocorticoid receptor antagonist Ru486 and DNA methylation inhibitor 5-AZA counteracted dexamethasone's effects.
- Dexamethasone reduced cyclin D2 expression, an effect blocked by 5-AZA, indicating gene-specific DNA methylation involvement.
Conclusions:
- Dexamethasone adversely affects developing cardiomyocyte proliferation and differentiation through glucocorticoid receptors.
- Increased DNA methylation is a key mechanism mediating dexamethasone's detrimental effects on the developing heart.
- Findings highlight the importance of considering cardiac developmental impacts when using dexamethasone in neonates.
