Published online before print July 25, 2008, doi: 10.1161/CIRCRESAHA.108.181487
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Submitted on July 2, 2007
Revised on June 16, 2008
Accepted on July 10, 2008
Increased FOG-2 in Failing Myocardium Disrupts Thyroid Hormone–Dependent SERCA2 Gene Transcription
Rosanne Rouf ;
From the MCRI Center for Translational Genomics (R.R., S.G., E.C.W., J.W., J.B., R.D.P., G.S.H.), Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Mass; Cardiology Unit (M.P.), Massachusetts General Hospital, Boston, Mass; Department of Medicine (E.C.S.), University of Chicago, Ill; and Division of Endocrinology and Metabolism (W.H.D.), University of California, San Diego.
* To whom correspondence should be addressed. E-mail: ghuggins{at}tuftsmedicalcenter.org.
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-
1 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.
Key words: friend of GATA-2 • thyroid hormone receptor • sarcoplasmic reticulum calcium-activated ATPase-2 • heart failure