Systolic dysfunction in cardiac-specific ligand-inducible MerCreMer transgenic mice

The Cre-loxP system is a useful tool to study the physiological effects of gene knockout in the heart. One limitation with using this system in the heart is the toxic effect of chronic expression of the Cre recombinase. To circumvent this limitation, a widely used inducible cardiac-specific model, Myh6-MerCreMer (Cre), using tamoxifen (TAM) to activate Cre has been developed. The current study examined cardiac function in Cre-positive C57B/J6 mice exposed to one, three, or five daily doses of a 40 mg/kg TAM to induce Cre activity specifically in the heart. Echocardiography demonstrated no statistically significant differences in systolic function (SF) at baseline as assessed by fractional shortening. In mice exposed to five injections, a significant fall in all determinants of SF was observed 6 days after TAM was initiated. However, SF returned to baseline levels 10 days after TAM initiation although the hearts exhibited significant hypertrophy. Heart weight-to-tibia length ratios were 73 ± 3, 78.5 ± 6, and 87.6 ± 9 mg/cm for one, three, and five TAM injections, respectively. TAM had no effect on cardiac function or hypertrophy in Cre-negative mice. Cre-positive mice receiving five TAM injections had significant reductions in cardiac mitochondrial ATP and significant reductions in the expression of proteins important for the regulation of cardiac oxidative phosphorylation including peroxisome proliferator-activated receptor-γ coactivator-1α and pyruvate dehydrogenase kinase-4. Thus inducible cardiac-specific activation of Cre recombinase caused a transient decline in SF that was dependent on the number of TAM doses and associated with significant hypertrophy and alterations in mitochondrial ATP and important proteins involved in the regulation of cardiac oxidative phosphorylation.