Glucocorticoid receptor is required for foetal heart maturation

Eva A. Rog-Zielinska, Adrian Thomson, Christopher J. Kenyon, David G. Brownstein, Carmel M. Moran, Dorota Szumska, Zoi Michailidou, Jennifer Richardson, Elizabeth Owen, Alistair Watt, Harris Morrison, Lesley M. Forrester, Shoumo Bhattacharya, Megan C. Holmes, Karen E. Chapman

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Glucocorticoids are vital for the structuralandfunctional maturation of foetalorgans, yetexcessive foetalexposure is detrimental to adult cardiovascular health. To elucidate the role of glucocorticoid signalling in late-gestation cardiovascular maturation, we have generated mice with conditional disruption of glucocorticoid receptor (GR) in cardiomyocytes and vascular smooth muscle cells using smooth muscle protein 22-driven Cre recombinase (SMGRKO mice) and compared them with mice with global deficiency in GR (GR-/-). Echocardiography shows impaired heart function in both SMGRKO and GR-/- mice at embryonic day (E)17.5, associated with generalized oedema. Cardiac ultrastructure is markedly disrupted in both SMGRKO andGR-/- mice at E17.5, with short, disorganized myofibrilsandcardiomyocytes that fail to align in the compact myocardium. Failure to induce critical genes involved in contractile function, calcium handling and energy metabolism underpins this common phenotype. However, although hearts of GR-/- mice are smaller, with 22% reduced ventricularvolumeat E17.5,SMGRKOhearts are normally sized. Moreover, while levels ofmRNAencoding atrial natriuretic peptide are reduced in E17.5GR-/- hearts, they are normal in foetal SMGRKOhearts. These data demonstrate that structural, functional and biochemical maturation of the foetal heart is dependent on glucocorticoid signalling within cardiomyocytes and vascular smooth muscle, though some aspects of heart maturation (size, ANP expression) are independent of GR at these key sites.

Original languageEnglish
Pages (from-to)3269-3282
Number of pages14
JournalHuman Molecular Genetics
Volume22
Issue number16
DOIs
Publication statusPublished - Aug 2013
Externally publishedYes

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