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

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Animal Models

Background:

• The tetracycline-regulated gene expression system (tet-system) is widely used in transgenic mice for controlled gene expression.
• The cardiac alpha-myosin heavy chain promoter (alphaMHC) drives expression of the tetracycline-inhibited transcription activator (tTA) in the heart.
• Previous studies suggest potential cardiac dysfunction with high-level activator protein expression.

Purpose of the Study:

• To investigate whether cardiac expression of tTA in alphaMHC-tTA mice leads to functional alterations compared to wild-type (WT) littermates.
• To assess the impact of the alphaMHC-tTA construct on myocardial gene expression and cardiac function.
• To evaluate the suitability of alphaMHC-tTA mice as controls in tet-system studies.

Main Methods:

• In vivo and in vitro functional assessments of hearts from WT and alphaMHC-tTA mice.
• Measurement of heart-to-body weight ratio, ventricular dimensions, and ejection fraction.
• Gene expression profiling of myocardial tissue from both groups.

Main Results:

• AlphaMHC-tTA mice exhibited a higher heart-to-body weight ratio, ventricular dilation, and reduced ejection fraction, indicating mild cardiomyopathy.
• In vitro studies showed increased submaximal contractions and heightened myofilament Ca2+ sensitivity in alphaMHC-tTA myocardium.
• Gene expression profiling revealed significant changes (>20%) in 153 genes in alphaMHC-tTA myocardium compared to WT.

Conclusions:

• The alphaMHC-tTA construct significantly impacts myocardial gene expression and cardiac function, causing abnormalities in vivo and in vitro.
• Caution is advised when using alphaMHC-tTA mice as controls in tet-system studies due to their distinct myocardial characteristics.
• The genetic background of alphaMHC-tTA mice may influence the observed phenotype of target genes in experimental studies.