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

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.