n the heart development in the earlier embryonic stage remains an interesting question for further investigation. Heart growth occurs by one of two methods, hyperplasia or hypertrophy, and fetal glucocorticoid AMI-1 
exposure was noted to induce both hyperplasic and hypertrophic growth. In neonates, complicated and sometimes contradictory accounts have also been noted. Studies have revealed that the glucocorticoid treatment is associated with hyperplasic, hypertrophic or no effect on the growth of cardiomyocytes, as analyzed by the 15 / 20 Dexamethasone and Heart Development protein to DNA ratio. Formation of binucleated myocardial cells is regarded as an early indicator of transition of hyperplasia to hypertrophic growth, indicating ceasing of proliferation of cardiomyocytes. Mounting evidence has shown that arrest of the cell cycle, and thereby locking of cells in either G1 or G0 phase stop myocyte proliferation. Poolman and colleagues studied the profile of the cell cycle in cardiomyocytes in postnatal rats from P2 to P5, and found that the percentage of G0/G1 phase cells was increased during the early neonatal development. These studies suggested that cell cycle dependent molecules, such as cyclins, cyclin-dependent kinase and CDK inhibitors, may control the transition from hyperplasia to hypertrophic growth of myocytes. Indeed, CDI p21 was up-regulated during the switch of cardiac myocyte from hyperplasia to hypertrophic growth in rats. G1 phase acting proteins, CDK4 and CDK6 were also up-regulated in this process and were associated with hypertrophic growth of myocytes. It is possible that increased exposure to glucocorticoids during the critical window of the heart development may alter the expression or activities of these key regulating proteins of the cell cycle. The primary mechanism of glucocorticoid activity is via the GR, an intracellular ligand dependent transcription factor. The GR plays a critical role in fetal heart maturation and cardiovascular health and disease. Knockout of the GR gene in cardiomyocytes results in impaired cardiac structure and function that can be observed at embryonic PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19777456 day 17.5, and the offspring die prematurely from spontaneous cardiovascular disease. In glucocorticoid null fetal mice hyper-proliferation was reported, implicating the GR as an important regulator of cell proliferation. Several lines of evidence suggest the role of glucocorticoids in regulating the cell cycle. It has been shown that dexamethasone suppresses rat epithelial cell growth by blocking a specific cell cycle of either G1 or G0 phase, and dexamethasone withdrawal increases the expression of G1 marker genes, including c-Myc and cyclin D1. In addition, glucocorticoid signaling arrests cell cycle activity by either transcriptional repression of G1 phase kinases CDK4/6 or enhanced transcription of CDK endogenous inhibitor, CDIs p21 and p27. Moreover, a recent study has shown that dexamethasone up-regulates CDI p21 and inhibits osteoblastic cell proliferation and these effects are blocked by the GR antagonist Ru486 or specific silencing of GR, demonstrating a GR-dependent mechanism. Further studies PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19776277 are needed to investigate the effect of dexamethasone on the cell cycle regulating molecules in cardiomyocytes of the development heart. Although the mechanisms by which perinatal dexamethasone treatment causes long-term effects are still not known, increasing evidence indicates that epigenetic modifications, such as DNA methylation, play an
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