Abstract 20678: Cardiomyogenesis Prevents Cre-Induced Dilated Cardiomyopathy
The possibility to target gene expression to specific cell types and desired window of time has moved forward the field of molecular cardiology. However, tamoxifen-inducible myocyte-restricted Cre expression is accompanied by a dilated myopathy with heart failure and high animal mortality. The objective of this study was to determine the cellular processes responsible for the development of ventricular dysfunction and its reversibility in this model. We have previously documented that a comparable dilated myopathy occurs by inhibition of the Notch1 pathway and defective cardiomyogenesis as Notch1 promotes early commitment of cardiac stem cells to the myocyte lineage. Importantly, restoration of Notch1 function and myocyte formation rescues the failing heart. Therefore, double-transgenic α-MHC-MerCreMer-N1ICD (α-MHC-N1ICD) mice were employed to establish whether enhanced cardiomyogenesis can counteract Cre-cardiotoxicity which was determined in mice carrying the α-MHC-MerCreMer promoter (α-MHC-Cre) only. Wild-type mice were used as controls. The three groups of animals were injected with tamoxifen, or fed raloxifen, and studied during the treatment phase and at various time-points after its cessation. Over a 4 week period, 20% of transgenic mice died, but mortality was nearly 3-fold higher in α-MHC-Cre than α-MHC-N1ICD. At the end of treatment, α-MHC-Cre mice showed echocardiographic evidence of a dilated myopathy with increased chamber diameter, wall thinning and reduced ejection fraction. In contrast, modest changes in cardiac anatomy and function were found in α-MHC-N1ICD mice. The cardiac alterations were reversible with time but at a faster rate in mice overexpressing N1ICD. Myocyte proliferation was 5-fold higher in α-MHC-N1ICD than α-MHC-Cre, while myocyte apoptosis was 2-fold lower in α-MHC-N1ICD mice. Moreover, the functional, anatomical and cellular defects were more apparent in male than in female mice. Collectively, our findings indicate that the male heart is more susceptible to Cre-induced cardiotoxicity. Sustained cardiomyogenesis prevents largely the onset of a dilated myopathy and animal mortality, strengthening the relevance of myocyte formation for the anatomical and functional integrity of the adult heart.
- © 2010 by American Heart Association, Inc.