title: Avoidance of transient cardiomyopathy in cardiomyocyte-targeted tamoxifen-induced MerCreMer gene deletion models.
abstract: Cardiac myocyte targeted MerCreMer transgenic mice expressing tamoxifen-inducible Cre driven by the alpha-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-alpha, peroxisome proliferator-activated alpha, 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.
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Ari L
authors.initials: AL
authors.lastname: Zaiman
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Manling
authors.initials: M
authors.lastname: Zhang
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology*; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D019426:Integrases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases