Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase

Antje Buerger; Olga Rozhitskaya; Megan C Sherwood; Adam L Dorfman; Egbert Bisping; E Dale Abel; William T Pu; Seigo Izumo; Patrick Y Jay

doi:10.1016/j.cardfail.2006.03.002

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Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase

Journal article

Peer reviewed

Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase

Antje Buerger, Olga Rozhitskaya, Megan C Sherwood, Adam L Dorfman, Egbert Bisping, E Dale Abel, William T Pu, Seigo Izumo and Patrick Y Jay

Journal of cardiac failure, Vol.12(5), pp.392-398

06/2006

DOI: 10.1016/j.cardfail.2006.03.002

PMID: 16762803

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Abstract

Conditional gene inactivation in mice using the bacteriophage P1 Cre-loxP recombination system requires transgenic expression of Cre-recombinase driven by a tissue-specific or inducible promoter. Using the cardiac alpha-myosin-heavy-chain promoter, the most commonly used myocardial-specific transgenic promoter, we created transgenic mice expressing Cre-recombinase in the heart. Seven transgenic lines developed dilated cardiomyopathy and premature death from congestive heart failure. One founder line that survived long enough to propagate had extremely high-level Cre recombinase expression. Transgenic lines that expressed low levels remained healthy. The high-expressing strain developed heart failure over a very predictable and reproducible time course. Detailed examination of the high-expressing strain revealed important molecular, cellular, and pharmacologic hallmarks of cardiomyopathy. First, "fetal genes" such as atrial natriuretic factor and brain natriuretic protein were expressed, a marker of pathologic cardiac hypertrophy and heart failure. Second, an increased incidence of cardiac myocyte apoptosis was present. Third, treatment of mice with captopril or metoprolol, drugs that delay the progression of heart failure, improved survival. Cre-recombinase when expressed at high levels may cause organ dysfunction, which could be mistaken for an effect of conditional gene inactivation. In addition, the stereotypic cardiomyopathy and disease progression in the characterized, high-expressing transgenic strain suggests its utility as a model to study the effects of pharmacologic or genetic manipulations in heart failure.

Up-Regulation

Cardiomyopathy, Dilated - pathology

Captopril - pharmacology

Metoprolol - pharmacology

Male

Adrenergic beta-Antagonists - pharmacology

Integrases - metabolism

Angiotensin-Converting Enzyme Inhibitors - pharmacology

Heart Failure - etiology

Heart Failure - mortality

Biomarkers - metabolism

Heart - physiopathology

Gene Expression

Myocytes, Cardiac

Cardiomyopathy, Dilated - complications

Organ Size

Heart Failure - genetics

Mice, Transgenic

Myocardium - pathology

Heart Failure - metabolism

Mice, Inbred Strains

Myocardium - enzymology

Animals

Cardiomyopathy, Dilated - etiology

Cardiomyopathy, Dilated - physiopathology

Survival Analysis

Mice

Apoptosis

Details

Title: Subtitle: Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase
Creators: Antje Buerger - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
Olga Rozhitskaya
Megan C Sherwood
Adam L Dorfman
Egbert Bisping
E Dale Abel
William T Pu
Seigo Izumo
Patrick Y Jay
Resource Type: Journal article
Publication Details: Journal of cardiac failure, Vol.12(5), pp.392-398
DOI: 10.1016/j.cardfail.2006.03.002
PMID: 16762803
NLM abbreviation: J Card Fail
ISSN: 1071-9164
eISSN: 1532-8414
Publisher: United States
Grant note: T32 HL007572 / NHLBI NIH HHS
Language: English
Date published: 06/2006
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024401802771

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