TY - JOUR
T1 - Dilated Cardiomyopathy Resulting From High-Level Myocardial Expression of Cre-Recombinase
AU - Buerger, Antje
AU - Rozhitskaya, Olga
AU - Sherwood, Megan C.
AU - Dorfman, Adam L.
AU - Bisping, Egbert
AU - Abel, E. Dale
AU - Pu, William T.
AU - Izumo, Seigo
AU - Jay, Patrick Y.
N1 - Funding Information:
Supported by the Deutsche Akademie der Naturforscher Leopoldina (A.B.), Charles H. Hood Foundation, and NIH. P.Y.J. is a Scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (K12-HD001487).
PY - 2006/6
Y1 - 2006/6
N2 - Background: 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. Methods and Results: Using the cardiac α-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. Conclusion: 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.
AB - Background: 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. Methods and Results: Using the cardiac α-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. Conclusion: 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.
KW - Apoptosis
KW - Dilated cardiomyopathy
KW - Fetal gene expression
KW - Heart failure
KW - Mouse
UR - http://www.scopus.com/inward/record.url?scp=33744548947&partnerID=8YFLogxK
U2 - 10.1016/j.cardfail.2006.03.002
DO - 10.1016/j.cardfail.2006.03.002
M3 - Article
C2 - 16762803
AN - SCOPUS:33744548947
SN - 1071-9164
VL - 12
SP - 392
EP - 398
JO - Journal of cardiac failure
JF - Journal of cardiac failure
IS - 5
ER -