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.