Abstract
The causes of hypertension are complex and involve both genetic and environmental factors. Environment changes during fetal development have been linked to adult diseases including hypertension. Studies show that timed in utero exposure to the synthetic glucocorticoid (GC) dexamethasone (Dex) results in the development of hypertension in adult rats. Evidence suggests that in utero stress can alter patterns of gene expression, possibly a result of alterations in the topology of the genome by epigenetic markers such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). The objective of this study was to determine the effects of epigenetic regulators in the fetal programming and the development of adult hypertension. Specifically, this research examined the effects of the HDAC inhibitor valproic acid (VPA) and the DNMT inhibitor 5-aza-2′-deoxycytidine (5aza2DC) on blood pressure (BP) and gene expression in prenatal Dex-programmed rats. Data suggest that both VPA and 5aza2DC attenuated the Dex-mediated development of hypertension and restored BP to control levels. Epigenetic DNMT inhibition (DNMTi) or HDAC inhibition (HDACi) also successfully attenuated elevations in the majority of altered catecholamine (CA) enzyme expression, phenylethanolamine N-methyltransferase (PNMT) protein, and elevated epinephrine (Epi) levels in males. Although females responded to HDACi similar to males, DNMTi drove increased glucocorticoid receptor (GR) and PNMT expression and elevations in circulating Epi in females despite showing normotensive BP.
Highlights
Despite many advances in hypertension research, factors contributing to the development of the disease continue to emerge
This study aims to investigate the role of DNA methyltransferases (DNMTs) or histone deacetylases (HDACs) inhibition in GC-mediated fetal programming of hypertension
The epigenetic inhibitors 5aza2DC and valproic acid (VPA) were effective in attenuating elevated blood pressure (BP) induced by prenatal Dex exposure in adult offspring for both sexes (Figures 3(a) and 3(b)). 5aza2DC administration in Dex-programmed male offspring decreased mean arterial pressure (MAP) from 155 mmHg at week 11 to 117 mmHg by week 14 compared to Dex-Control animals which displayed a MAP of 140 mmHg by the end of week 14 (Figure 3(a)). 5aza2DC alone did not affect BP compared to Saline-Control (Figure 3(a))
Summary
Despite many advances in hypertension research, factors contributing to the development of the disease continue to emerge. Of particular interest is the role of GCs in fetal development and programming [1]. GCs can stimulate tissue maturation and fetal development; in times of stress, excess production of maternal GCs can negatively impact the fetus, promoting premature tissue development and programing for disease [1]. Previous research has highlighted a role for ROS in programming; epigenetic modifications such as DNA methylation and histone acetylation are suspected to propagate these fetal insults to postnatal health. Increased fetal GC exposure may mediate programming through alteration of gene DNA methylation status; studies show increased global DNA methylation status in specific tissues, including the adrenal glands following betamethasone administration in guinea pigs [3]. Many genes suspected to be implicated in the development of hypertension are regulated via promoter methylation by DNMTs and are present
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