Published online before print June 11, 2009, doi: 10.1161/CIRCRESAHA.109.198416
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Submitted on April 1, 2009
Revised on May 26, 2009
Accepted on June 1, 2009
Avoidance of Transient Cardiomyopathy in Cardiomyocyte-Targeted Tamoxifen-Induced MerCreMer Gene Deletion Models
Norimichi Koitabashi ;
From the Divisions of Cardiology (N.K., M.Z., E.T., D.A.K.) and Pulmonary and Critical Care Medicine (A.L.Z.), Department of Medicine; and Division of Comparative Medicine (D.B., K.L.G.), Johns Hopkins Medical Institutions, Baltimore, Md; and University of Amsterdam (Y.M.P.), Heart Failure Research Center, The Netherlands.
* To whom correspondence should be addressed. E-mail: dkass{at}jhmi.edu.
Cardiac myocyte targeted MerCreMer transgenic mice expressing tamoxifen-inducible Cre driven by the 
-myosin heavy chain promoter are increasingly used to control gene expression in the adult heart. Here, we show tamoxifen-mediated MerCreMer (MCM) nuclear translocation can induce severe transient dilated cardiomyopathy in mice with or without loxP transgenes. The cardiomyopathy is accompanied by marked reduction of energy/metabolism and calcium-handling gene expression (eg, PGC1-, peroxisome proliferator-activated , SERCA2A), all fully normalized with recovery. MCM-negative/flox-positive controls display no dysfunction with tamoxifen. Nuclear Cre translocation and equally effective gene knockdown without cardiomyopathy is achievable with raloxifene, suggesting toxicity is not simply from Cre. Careful attention to controls, reduced tamoxifen dosing and/or use of raloxifene is advised with this model.
Key words: mouse • cardiac • conditional knockout • Cre recombinase • ventricular function • tamoxifen • raloxifene