Glucocorticoids and programming of the microenvironment in heart

Abstract

Glucocorticoids are primary stress hormones and can improve neonatal survival when given to pregnant women threatened by preterm birth or to preterm infants. It has become increasingly apparent that glucocorticoids, primarily by interacting with glucocorticoid receptors, play a critical role in late gestational cardiac maturation. Altered glucocorticoid actions contribute to the development and progression of heart disease. The knowledge gained from studies in the mature heart or cardiac damage is insufficient but a necessary starting point for understanding cardiac programming including programming of the cardiac microenvironment by glucocorticoids in the fetal heart. This review aims to highlight the potential roles of glucocorticoids in programming of the cardiac microenvironment, especially the supporting cells including endothelial cells, immune cells and fibroblasts. The molecular mechanisms by which glucocorticoids regulate the various cellular and extracellular components and the clinical relevance of glucocorticoid functions in the heart are also discussed.

Keywords: cardiac development; glucocorticoid; microenvironment; programming.

Figure 1.. Illustration of the routes by which maternal stress/hypoxia-modified glucocorticoid signaling alter cardiac development and the susceptibility to adult heart disease.

Maternal stress/hypoxia induces an excessive release of glucocorticoids which can diffuse across the placenta to enter into the fetal circulation. Activation of the glucocorticoid receptor (GR) by glucocorticoids results in both genomic and nongenomic effects. The glucocorticoid/receptor complex formed in the cytosol could migrate into the nucleus to alter gene expression through transactivation or transrepression (genomic effects). The binding of glucocorticoids to GR in the membrane could activate other cellular signaling pathways (i.e., MAPK, src, and PI3K) to elicit rapid responses (nongenomic effects). Maternal stress/hypoxia can also regulate GR expression via epigenetic mechanisms to alter glucocorticoid-induced genomic and non-genomic effects. Moreover, the binding of glucocorticoids to GR in the fetal heart can alter cardiac epigenome (e.g., DNA methylation, histone acetylation, miRNAs and lncRNAs). Together, genomic, nongenomic and epigenetic mechanisms alter fine-tuning proliferation-, maturation- and apoptosis-related proteins and Ca2+ handling proteins, resulting in modification of the activities and functions of cardiomyocytes and supporting cells including endothelial cells, immune cells, and fibroblasts in the cardiac microenvironment. Consequently, the cardiac developmental disorder occurs and the susceptibility to heart disease increases in adult offspring.