June 1, 1998Journal of Clinical Investigation250 citationsOpen Access
Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart.
Key Result
Transgenic mice expressing a dominant-negative CREB transcription factor in the heart developed progressive dilated cardiomyopathy with over 40% mortality by 20 weeks compared to 0% in controls.
Structured PICO
P
Population
Transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac myocyte-specific alpha-MHC promoter
I
Intervention
Expression of dominant-negative CREB (CREBA133)
O
Outcome
Development of dilated cardiomyopathy
This study establishes a transgenic mouse model of dilated cardiomyopathy by expressing a dominant-negative CREB transcription factor, implicating CREB as an important regulator of cardiac myocyte function.
Main Result
Absolute Event Rate: 40% vs 0%
p-value: p=<0.000005
Limitations
- Low levels of cardiomyocyte apoptosis or very early apoptosis might not have been detected by the TUNEL assays used.
- The specific CREB target genes responsible for the dilated cardiomyopathy phenotype were not identified.
Abstract
Idiopathic-dilated cardiomyopathy (IDC) is a common primary myocardial disease of unknown etiology characterized by progressive biventricular failure, cardiac dilatation, and premature mortality. Here we show that transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac myocyte-specific alpha-MHC promoter develop dilated cardiomyopathy that closely resembles many of the anatomical, physiological, and clinical features of human IDC. Between 2 and 20 wk of age, these mice develop four chamber cardiac dilatation, decreased systolic and diastolic left ventricular function, and attenuated contractile responses to the beta-adrenergic agonist, isoproterenol. Histologically, the CREBA133 hearts demonstrated both atrophic and hypertrophied fibers as well as significant interstitial fibrosis. These anatomical and hemodynamic changes were associated with hepatic congestion and peripheral edema, intracardiac thrombi, and premature mortality. Taken together, these results implicate CREB as an important regulator of cardiac myocyte function and provide a genetic model of dilated cardiomyopathy which should facilitate studies of both the pathogenesis and therapy of this clinically important disorder.