Tamoxifen-mediated MerCreMer nuclear translocation induced severe transient dilated cardiomyopathy in transgenic mice, which was avoided by using raloxifene for gene knockdown.
In MerCreMer transgenic mice, tamoxifen induces transient cardiomyopathy, which can be avoided by using raloxifene or reduced tamoxifen dosing.
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.
Koitabashi et al. (2009) studied Transient dilated cardiomyopathy. Tamoxifen vs. MCM-negative/flox-positive controls and raloxifene was evaluated on Severe transient dilated cardiomyopathy. Tamoxifen-mediated MerCreMer nuclear translocation induced severe transient dilated cardiomyopathy in transgenic mice, which was avoided by using raloxifene for gene knockdown.
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