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PMID: 9616213 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart.

The Journal of clinical investigation ·Vol. 101 ·No. 11 ·1998-06-01 ·Pages 2415-26

Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM

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.

MeSH Terms
Animals Apoptosis Cardiomyopathy, Dilated/etiology,metabolism,pathology Cyclic AMP Response Element-Binding Protein/physiology Echocardiography Gene Expression Regulation Heart Failure/etiology Male Mice Mice, Transgenic Myocardium/metabolism Myosin Heavy Chains/genetics Ventricular Function, Left
Chemicals
Cyclic AMP Response Element-Binding Protein Myosin Heavy Chains
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fentzke R C
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Korcarz C E
Lang R M
Lin H
Leiden J M
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI2950
Published
1998-06-01
Pages
2415-26
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC508831
Subset
IM
Grants
NHLBI NIH HHS · HL54592 · United States
External Links
PubMed source DOI: 10.1172/JCI2950 PMC Full Text View journal details
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