Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression

Physiol Genomics. 2005 Jun 16;22(1):118-26. doi: 10.1152/physiolgenomics.00016.2005. Epub 2005 Mar 29.


The cardiac-specific tetracycline-regulated gene expression system (tet-system) is a powerful tool using double-transgenic mice. The cardiac alpha-myosin heavy chain promoter (alphaMHC) drives lifetime expression of a tetracycline-inhibited transcription activator (tTA). Crossing alphaMHC-tTA mice with mice containing a tTA-responsive promoter linked to a target gene yields double-transgenic mice having tetracycline-repressed expression of the target gene in the heart. Using the tet-system, some studies use nontransgenic mice for the control group, whereas others use single-transgenic alphaMHC-tTA mice. However, previous studies found that high-level expression of a modified activator protein caused cardiomyopathy. Therefore, we tested whether cardiac expression of tTA was associated with altered function of alphaMHC-tTA mice compared with wild-type (WT) littermates. We monitored in vivo and in vitro function and gene expression profiles for myocardium from WT and alphaMHC-tTA mice. Compared with WT littermates, alphaMHC-tTA mice had a greater heart-to-body weight ratio (approximately 10%), ventricular dilation, and decreased ejection fraction, suggesting mild cardiomyopathy. In vitro, submaximal contractions were greater compared with WT and were associated with greater myofilament Ca2+ sensitivity. Gene expression profiling revealed that the expression of 153 genes was significantly changed by >20% when comparing alphaMHC-tTA with WT myocardium. These findings demonstrate that introduction of the alphaMHC-tTA construct causes significant effects on myocardial gene expression and major functional abnormalities in vivo and in vitro. For studies using the tet-system, these results suggest caution in the use of controls, since alphaMHC-tTA myocardium differs appreciably from WT. Furthermore, the results raise the possibility that the phenotype conferred by a target gene may be influenced by the modified genetic background of alphaMHC-tTA myocardium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Animals
  • Body Weight
  • Calcium / metabolism
  • Cytosol / metabolism
  • Doxycycline / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Genotype
  • Heart / drug effects*
  • Heart / physiology*
  • Mice
  • Mice, Transgenic
  • Myocardium / metabolism*
  • Organ Size
  • Phenotype
  • Tetracycline / pharmacology*
  • Trans-Activators / metabolism*
  • Ventricular Myosins / genetics
  • Ventricular Myosins / metabolism


  • Trans-Activators
  • Ventricular Myosins
  • Tetracycline
  • Doxycycline
  • Calcium