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

• Published in: The Journal of clinical investigation 1997-10, Vol.100 (8), p.1958-1968
• Main Authors: Colbert, M C, Hall, D G, Kimball, T R, Witt, S A, Lorenz, J N, Kirby, M L, Hewett, T E, Klevitsky, R, Robbins, J
• Format: Article
• Language: English
• Subjects: Animals; Cardiomyopathy, Dilated - genetics; Echocardiography; Female; Gene Dosage; Gene Expression; Gene Targeting - methods; Heart - embryology; Heart - growth & development; Heart Defects, Congenital - genetics; Heart Failure - genetics; Male; Mice; Mice, Transgenic; Myocardium - pathology; Myosin Heavy Chains - genetics; Promoter Regions, Genetic; Receptors, Retinoic Acid - genetics; Ventricular Function, Left
• ISSN: 0021-9738
• DOI: 10.1172/JCI119727

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 alpha- or beta-myosin heavy chain (MyHC) promoter were generated. Animals carrying the alpha-MyHC-RAR transgene expressed RARs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast, beta-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, alpha-skeletal actin, atrial natriuretic factor and beta-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.