Avoidance of transient cardiomyopathy in Cardiomyocyte-targeted Tamoxifen-induced mercremer gene deletion models

Norimichi Koitabashi, Djahida Bedja, Ari L. Zaiman, Yigal M. Pinto, Manling Zhang, Kathleen L. Gabrielson, Eiki Takimoto, David A. Kassz

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiac myocyte targeted MerCreMer transgenic mice expressing tamoxifen-inducible Cre driven by the α-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-α, peroxisome proliferator-activated α, 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.

Original languageEnglish (US)
Pages (from-to)12-15
Number of pages4
JournalCirculation research
Volume105
Issue number1
DOIs
StatePublished - Jul 2 2009

Keywords

  • Cre recombinase
  • Inducible transgenic
  • Mouse models
  • Selective estrogen receptor modulator
  • Ventricular function

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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