Glucocorticoid receptor in the early life programming of cardiac resilience

Glucocorticoid receptor in the early life programming of cardiac resilience

Left image: a whole mount heart from an E14.5 R26Fucci2a mouse fetus showing mCherry (red, non-proliferating) and mVenus (green, proliferating) cells. Centre image: a whole mount E10.5 mouse fetus, with blue staining indicating where glucocorticoid receptor is expressed Right image: section through the left ventricle of an adult mouse heart stained with wheat germ agglutinin (red, plasma membrane), isolectin B4 (green, vasculature) and dapi (blue, nuclei).

In the time shortly before and after birth (the first few months of life), the vital organs, including the heart and the lungs, undergo remarkable changes that are essential for the baby to survive once it is born. The changes that occur in the heart before birth set the foundations for later life, and influence the risk of developing heart disease in adulthood. Glucocorticoids, an important class of steroid hormone produced by the body, play a vital role in these maturational changes. We utilise this clinically in premature babies (or when premature birth appears likely) with the routine administration of potent synthetic glucocorticoids to improve lung function and neonatal survival. This antenatal corticosteroid therapy (ACT) has been assumed to be very safe for pregnant women and their unborn babies. However, there is convincing evidence from animal studies and in humans that prolonged exposure to higher than normal levels of glucocorticoids before birth predisposes an individual to a host of later life diseases, including heart disease. It may even increase the risk of late fetal or infant death. The reasons why are incompletely understood, but may reflect a wrongly timed or excessive response to the normal maturational effects of glucocorticoids.

To be able to understand the harmful effects that glucocorticoids are capable of and which have their origins in the time before birth, we are investigating what they do normally before birth in the heart. Glucocorticoids regulate gene expression by interacting with specific glucocorticoid receptors (GR) that allow them to initiate responses in target tissues. We generated genetically altered mice that lack GR in cardiomyocytes and vascular smooth muscle cells. These mice have hearts that appear grossly normal but the myofibrils appear immature and the heart does not contract as it should. This might be why up to half of these mice die shortly after birth. We found that glucocorticoids increase mitochondrial capacity in fetal cardiomyocytes and that this is important for glucocorticoids to improve myofibril structure in these cells. This is intriguing, as the same oxygen-utilising systems cause cessation of cardiomyocyte proliferation shortly after birth. This suggests that glucocorticoids help prepare, or mature the heart, ready for birth, but at the same time regulate the number of cells in the heart after birth. A reduced cardiomyocyte endowment because of excessive glucocorticoid action before birth is likely to make the adult heart more vulnerable to insult in later life.

We are currently testing this hypothesis. We are investigating whether mitochondrial  mechanisms underpin other maturational effects of glucocorticoids upon fetal and neonatal cardiomyocytes. We are testing whether ACT in mice alters the timing and extent to which cardiomyocytes proliferate and also binucleate before and shortly after birth and the role that GR plays in this. We are determining whether cardiomyocyte endowment in adult mice is altered by transient fetal or neonatal manipulation of the level of GR expression. This will allow us to test if the different effects of glucocorticoids upon the heart, manifest in newborns and adults and including any effects on cell number, all have their origins in prenatal life.

This research will provide important new understanding of the benefits and risks of antenatal glucocorticoid actions upon the immature heart. It will enable us to establish, in theory, areas for future refinement in therapy, for example, to avoid over treatment of babies and to limit adverse effects, whilst optimising the benefits of treatment.