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 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.
Colbert
M C
MC
Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA. melissa.colbert@chmcc.org
Hall
D G
DG
Kimball
T R
TR
Witt
S A
SA
Lorenz
J N
JN
Kirby
M L
ML
Hewett
T E
TE
Klevitsky
R
R
Robbins
J
J
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D004452:Echocardiography; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D018390:Gene Targeting / Q000379:methods; D006321:Heart / Q000196:embryology / Q000254:growth & development; D006330:Heart Defects, Congenital / Q000235:genetics*; D006333:Heart Failure / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D016277:Ventricular Function, Left
D018168:Receptors, Retinoic Acid; D018995:Myosin Heavy Chains