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Physiol. Genomics 22: 118-126, 2005. First published March 29, 2005; doi:10.1152/physiolgenomics.00016.2005
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Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression

¹ Department of Radiology, University of California, San Francisco
² Department of Medicine, University of California, San Francisco
³ Department of Cardiovascular Research Institute, University of California, San Francisco
⁴ Department of Gladstone Institute of Cardiovascular Disease, University of California, San Francisco
⁵ Department of Veterans Affairs Medical Center, San Francisco, California

The cardiac-specific tetracycline-regulated gene expression system (tet-system) is a powerful tool using double-transgenic mice. The cardiac -myosin heavy chain promoter (MHC) drives lifetime expression of a tetracycline-inhibited transcription activator (tTA). Crossing MHC-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 MHC-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 MHC-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 MHC-tTA mice. Compared with WT littermates, MHC-tTA mice had a greater heart-to-body weight ratio (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 MHC-tTA with WT myocardium. These findings demonstrate that introduction of the MHC-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 MHC-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 MHC-tTA myocardium.

calcium; trabeculae; tet-system; cardiomyopathy; mouse

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