Abstract 37: Genetic Profile and Modifiers of Transient Cardiomyopathy from Tamoxifen-Induced Cardiomyocyte Expression of Mutated Estrogen Receptor-Cre Fusion Protein
The Myh6-MerCreMer (MCM) transgenic mouse is used to conditionally augment or reduce targeted gene expression in cardiomyocytes in vivo. Studies report transient cardiomyopathy upon tamoxifen exposure in the MCM mouse itself; however, this varies among investigators despite their using seemingly similar protocols and mouse strain. To better understand this model and apparent variable response, we studied the transcriptome-function relationship during the initial days of tamoxifen therapy, and tested if a genetic background involving gene deletion for nicotinamide nucleotide transhydrogenase (Nnt) found in C57BL/6J (common strain in MCM studies) influences the severity of transient cardiac dysfunction. MCM+/- mice (pure C57BL/6J, all Nnt-/-) received intra-peritoneal injections of tamoxifen (40 mg/kg/day for 5 days). LV function remained normal until Day 2 after tamoxifen, yet qtPCR and microarray analysis in MCM+/- mice revealed markedly reduced expression of metabolic and calcium handling genes (Pgc1a, Pgc1b, Plb, Atp2a2) and upregulation of sarcomere protein skeletal isoforms by Day 2. This transcriptome subsequently evolved to one typical of cardiomyopathy (initial highlighted metabolic/Ca2+ genes remaining low) that correlated with LV dysfunction. Purchased MCM+/+ mice (sv129xC57BL/6J) were Nnt heterozygotes. After 7-10 days following tamoxifen dosing, offspring lacking Nnt developed worse cardiodepression than those with at least one Nnt allele. The MCM mouse exhibits marked changes in transcription profile 2 days after tamoxifen suggesting potential causal mechanisms for subsequent cardiomyopathy. The severity of dysfunction is influenced by background genetics in part related to Nnt.
- © 2012 by American Heart Association, Inc.