title: Cortisol stimulates proliferation and apoptosis in the late gestation fetal heart: differential effects of mineralocorticoid and glucocorticoid receptors.
abstract: 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.
authors.affiliation: Departments of Pharmacodynamics, and Physiology and Functional Genomics, University of Florida, Gainesville, Florida.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Feng
authors.forename: Seth A
authors.initials: SA
authors.lastname: Reini
authors.forename: Elaine
authors.initials: E
authors.lastname: Richards
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
authors.forename: Maureen
authors.initials: M
authors.lastname: Keller-Wood
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002191:Canrenoic Acid / Q000494:pharmacology; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005318:Fetal Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005865:Gestational Age; D006854:Hydrocortisone / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007262:Infusions, Intravenous; D019394:Ki-67 Antigen / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000378:metabolism; D012756:Sheep; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D019394:Ki-67 Antigen; D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D015735:Mifepristone; D002191:Canrenoic Acid; D019009:Proto-Oncogene Proteins c-kit; D053148:Caspase 3; D006854:Hydrocortisone
keywords: Purkinje fiber; cardiomyocyte; caspase-3; sheep; stress