Cortisol stimulates proliferation and apoptosis in the late gestation fetal heart: differential effects of mineralocorticoid and glucocorticoid receptors

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 305; no. 4; pp. R343 - R350
• Main Authors: Feng, Xiaodi, Reini, Seth A, Richards, Elaine, Wood, Charles E, Keller-Wood, Maureen
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.08.2013
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Canrenoic Acid - pharmacology; Cardiomegaly - chemically induced; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiovascular and Renal Integration; Caspase 3 - metabolism; Cell Proliferation - drug effects; Enzymes; Female; Fetal Heart - drug effects; Fetal Heart - metabolism; Fetal Heart - pathology; Gestational Age; Heart; Hormones; Hydrocortisone - administration & dosage; Hydrocortisone - pharmacology; Hydrocortisone - toxicity; Infusions, Intravenous; Ki-67 Antigen - metabolism; Mifepristone - pharmacology; Mineralocorticoid Receptor Antagonists - pharmacology; Pregnancy; Prenatal development; Proto-Oncogene Proteins c-kit - metabolism; Purkinje Fibers - drug effects; Purkinje Fibers - metabolism; Purkinje Fibers - pathology; Receptors, Glucocorticoid - drug effects; Receptors, Glucocorticoid - metabolism; Receptors, Mineralocorticoid - drug effects; Receptors, Mineralocorticoid - metabolism; Sheep; Stem cells; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - pathology; T cell receptors; stress; Purkinje fiber; sheep; cardiomyocyte; caspase-3
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00112.2013

We have previously found that modest chronic increases in maternal cortisol result in an enlarged fetal heart. To explore the mechanisms of this effect, we used intrapericardial infusions of a mineralocorticoid receptor (MR) antagonist (canrenoate) or of a glucocorticoid receptor (GR) antagonist (mifepristone) in the fetus during maternal infusion of cortisol (1 mg·kg⁻¹·day⁻¹). We have shown that the MR antagonist blocked the increase in fetal heart weight and in wall thickness resulting from maternal cortisol infusion. In the current study we extended those studies and found that cortisol increased Ki67 staining in both ventricles, indicating cell proliferation, but also increased active caspase-3 staining in cells of the conduction pathway in the septum and subendocardial layers of the left ventricle, suggesting increased apoptosis in Purkinje fibers. The MR antagonist blocked the increase in cell proliferation, whereas the GR antagonist blocked the increased apoptosis in Purkinje fibers. We also found evidence of activation of caspase-3 in c-kit-positive cells, suggesting apoptosis in stem cell populations in the ventricle. These studies suggest a potentially important role of corticosteroids in the terminal remodeling of the late gestation fetal heart and suggest a mechanism for the cardiac enlargement with excess corticosteroid exposure.