Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice

Melissa C. Colbert, D. Greg Hall, Thomas R. Kimball, Sandra A. Witt, John N. Lorenz, Margaret L. Kirby, Timothy E. Hewett, Raisa Klevitsky, Jeffrey Robbins

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Retinoids play a critical role in cardiac morphogenesis. To examine the effects of excessive retinoid signaling on myocardial development, transgenic mice that overexpress a constitutively active retinoic acid receptor (RAR) controlled by either the α- or β-myosin heavy chain (MyHC) promoter were generated. Animals carrying the α-MyHC-RAR transgene expressed RAPs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast β-MyHC-RAR animals where expression was activated in fetal ventricles, developed a dilated cardiomyopathy that varied in severity with transgene copy number. Characteristic postmortem lesions included biventricular chamber dilation and left atrial thrombosis: the incidence and severity of these lesions increased with increasing copy number Transcript analyses showed that molecular markers of hypertrophy α-skeletal actin, atrial natriuretic factor and β-MyHC, were upregulated. Cardiac performance of transgenic hearts was evaluated using the isolated perfused working heart model as well as in vivo, by transthoracic M- mode echocardiography. Both analyses showed moderate to severe impairment of left ventricular function and reduced cardiac contractility. Thus, expression of a constitutively active RAR in developing atria and/or in postnatal ventricles is relatively benign, while ventricular expression during gestation can lead to significant cardiac dysfunction.

Original languageEnglish (US)
Pages (from-to)1958-1968
Number of pages11
JournalJournal of Clinical Investigation
Volume100
Issue number8
DOIs
StatePublished - Oct 15 1997

Keywords

  • Dilated cardiomyopathy
  • Heart failure
  • Left ventricular function
  • Retinoic acid receptors
  • Transgenic mice

ASJC Scopus subject areas

  • Medicine(all)

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