Adeno-associated virus-mediated expression of thyroid hormone receptor isoforms-alpha1 and -beta1 improves...

Pressure overload-induced cardiac hypertrophy leads to decreased contractile performance, frequently progressing to heart failure. Cardiac hypertrophy and heart failure can be accompanied by the so-called sick thyroid syndrome, resulting in decreased serum T(3) levels along with decreased expression of thyroid hormone receptors (TRalpha1 and TRbeta1) and sarco(endo)plasmic reticulum Ca-ATPase (SERCA). Because the binding of T(3) occupied receptors to the thyroid response elements in the SERCA promotor can increase gene expression, we wanted to determine whether increasing TR expression in the hypertrophied heart could also improve SERCA expression and cardiac function. Mice subjected to aortic constriction to generate pressure overload-induced hypertrophy were also subjected to gene therapy using adeno-associated virus (AAV) expressing either TRalpha1 or TRbeta1, with LacZ expressing AAV serving as control. After 8 wk of aortic constriction, a similar degree of hypertrophy was observed in all three groups; however, mice treated with TRalpha1 or TRbeta1 showed improved contractile function. Administration of a physiological dose of T(3) increased serum T(3) levels only into the lower range of normal. This T(3) dose, with or without AAV TR treatment, did not result in any significant increase in contractile performance. Calcium transients measured in isolated myocytes also exhibited an enhanced rate of decay associated with TRalpha1 or TRbeta1 treatment. Western blot analysis showed increased SERCA expression in the TRalpha1- or TRbeta1-treated groups relative to the LacZ-treated control group. These results demonstrate that increasing TR expression in the hypertrophied heart is associated with an improvement in contractile function and increased SERCA expression.