Avoidance of Transient Cardiomyopathy in Cardiomyocyte-Targeted Tamoxifen-Induced MerCreMer Gene Deletion Models

作者：Koitabashi Norimichi; Bedja Djahida; Zaiman Ari L; Pinto Yigal M; Zhang Manling; Gabrielson Kathleen L; Takimoto Eiki; Kass David A^*

来源：Circulation Research, 2009, 105(1): 12-U38.

DOI：10.1161/CIRCRESAHA.109.198416

• inducible transgenic
• Cre recombinase
• selective estrogen receptor modulator
• ventricular function
• mouse models

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.

• 出版日期2009-7-2