Related Experiment Video
Updated: May 5, 2026
Delivery of Modified mRNA in a Myocardial Infarction Mouse Model
Published on: June 11, 2020
Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart
R C Fentzke1, C E Korcarz, R M Lang
1Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
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.
Insights
Transgenic mice with a dominant-negative CREB (CREBA133) developed dilated cardiomyopathy, mimicking human idiopathic dilated cardiomyopathy (IDC). This study provides a valuable genetic model for IDC research.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics
Background:
- Idiopathic dilated cardiomyopathy (IDC) is a significant cause of heart failure with unknown etiology.
- Characterized by biventricular failure, cardiac dilation, and high mortality.
- Understanding the molecular mechanisms underlying IDC is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of the CREB transcription factor in cardiac function.
- To develop a genetic mouse model that recapitulates key features of human IDC.
- To explore CREB's potential as a therapeutic target in dilated cardiomyopathy.
Main Methods:
- Generation of transgenic mice expressing a dominant-negative CREB (CREBA133) under the alpha-MHC promoter.
- Longitudinal assessment of cardiac anatomy and function (echocardiography, in vivo hemodynamics).
- Histological analysis of cardiac tissue for structural changes and fibrosis.
Main Results:
- CREBA133 mice exhibited progressive biventricular dilation and impaired systolic/diastolic function.
- Reduced contractile response to beta-adrenergic stimulation (isoproterenol).
- Histopathology revealed myocyte hypertrophy/atrophy, interstitial fibrosis, and intracardiac thrombi, leading to premature mortality.
Conclusions:
- CREB is a critical regulator of cardiac myocyte function and survival.
- The CREBA133 mouse model accurately mimics human IDC, offering a platform for pathogenesis and therapeutic studies.
- Targeting CREB signaling may hold potential for treating dilated cardiomyopathy.
Related Concept Videos
01:30Cardiomyopathy II: Dilated Cardiomyopathy
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:29Cardiomyopathy IV: Restrictive Cardiomyopathy