Cardiac fibrosis in mice expressing an inducible myocardial-specific Cre driver

• Published in: Disease models & mechanisms Vol. 6; no. 6; pp. 1470 - 1476
• Main Authors: Lexow, Jonas, Poggioli, Tommaso, Sarathchandra, Padmini, Santini, Maria Paola, Rosenthal, Nadia
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.11.2013; The Company of Biologists Limited; The Company of Biologists
• Subjects: Animals; Cardiac function; Cardiomyocytes; Cardiovascular disease; Cytokines; Ejection fraction; Estrogens; Gene expression; Genetic engineering; Genotype & phenotype; Heart; Integrases - metabolism; Mice; Morphology; Myocardium - enzymology; Physiology; Research Report
• ISSN: 1754-8403; 1754-8411; 1754-8411
• DOI: 10.1242/dmm.010470

Tamoxifen-inducible Cre-mediated manipulation of animal genomes has achieved wide acceptance over the last decade, with numerous important studies heavily relying on this technique. Recently, a number of groups have reported transient complications of using this protocol in the heart. In the present study we observed a previously unreported focal fibrosis and depressed left-ventricular function in tamoxifen treated αMHC-MerCreMer-positive animals in a Tβ4shRNAflox x αMHC-MerCreMer cross at 6-7 weeks following standard tamoxifen treatment, regardless of the presence of the floxed transgene. The phenotype was reproduced by treating mice from the original αMHC-MerCreMer strain with tamoxifen. In the acute phase after tamoxifen treatment, cell infiltration into the myocardium was accompanied by increased expression of pro-inflammatory cytokines (IL-1β, IL-6, TNFα, IFNγ, Ccl2) and markers of hypertrophy (ANF, BNP, Col3a1). These observations highlight the requirement for including tamoxifen-treated MerCreMer littermate controls to avert misinterpretation of conditional mutant phenotypes. A survey of the field as well as the protocols presented here suggests that controlling the parameters of tamoxifen delivery is important in avoiding the chronic MerCreMer-mediated cardiac phenotype reported here.