Reduced expression of sarcoplasmic reticulum calcium ATPase (SERCA)2 and other 
genes in the adult cardiac gene program has raised consideration of an impaired 
responsiveness to thyroid hormone (T3) that develops in the advanced failing 
heart. Here, we show that human and murine cardiomyopathy hearts have increased 
expression of friend of GATA (FOG)-2, a cardiac nuclear hormone receptor 
corepressor protein. Cardiac-specific overexpression of FOG-2 in transgenic mice 
led to depressed cardiac function, activation of the fetal gene program, 
congestive heart failure, and early death. SERCA2 transcript and protein levels 
were reduced in FOG-2 transgenic hearts, and FOG-2 overexpression impaired 
T3-mediated SERCA2 expression in cultured cardiomyocytes. FOG-2 physically 
interacts with thyroid hormone receptor-alpha1 and abrogated even high levels of 
T3-mediated SERCA2 promoter activity. These results demonstrate that SERCA2 is 
an important target of FOG-2 and that increased FOG-2 expression may contribute 
to a decline in cardiac function in end-stage heart failure by impaired T3 
signaling.