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(Circulation. 2001;103:1089.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Signaling Pathways Responsible for Fetal Gene Induction in the Failing Human Heart
Evidence for Altered Thyroid Hormone Receptor Gene Expression
Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-507).
From the Division of Cardiology (K.K., W.A.M., M.F.T., B.A.L., M.R.B.) and Division of Endocrinology, Metabolism, and Diabetes (W.M.W., E.C.R.), University of Colorado Health Sciences Center, and the Cardiology Section, Denver Health Medical Center (C.S.L.), Denver, Colo; and the Metabolic Research Unit, University of California, San Francisco (J.D.B., R.C.J.R.).
Correspondence to Michael R. Bristow, MD, PhD, Head, Division of Cardiology, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Campus Box B139, Denver, CO 80262. E-mail michael.bristow{at}uchsc.edu
Background—We have previously demonstrated that changes in myosin heavy chain (MHC) isoforms that occur in failing human hearts resemble the pattern produced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypothesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormone receptors (TRs).
Methods and Results—To
examine this hypothesis, we used RNase protection assay to measure mRNA
levels of TRs in failing left ventricles that exhibited a fetal pattern
of gene expression, ie, decreased expression of 
-MHC with increased
ß-MHC expression compared with left ventricles from age-matched
controls. We detected expression of TR-1,
-2, and -ß1 isoforms
in human left ventricles. In failing left ventricles,
TR-1 was downregulated, whereas
TR-2, a splice variant that does not bind
thyroid hormone but inhibits responses to liganded TRs, was increased.
Expression levels of TR-ß1 did not differ
significantly between the 2 groups. According to linear regression
analysis, expression levels of TR-1 and
-2 were positively and negatively correlated
with those of -MHC, respectively.
Conclusions—We conclude
that decreases in TR-1 and increases in
TR-2 may lead to local attenuation of thyroid
hormone signaling in the failing human heart and that the resulting
tissue-specific hypothyroidism is a candidate for the molecular
mechanism that induces fetal gene expression in the failing human
ventricle.
Key Words: thyroid • hormones • receptors • myosin • heart failure
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