Signaling pathways responsible for fetal gene induction in the failing human heart - Evidence for altered thyroid hormone receptor gene expression

Background-We have previously demonstrated that changes in myosin heavy cha in (MHC) isoforms that occur in failing human hearts resemble the pattern p roduced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypot hesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormo ne receptors (TRs). Methods and Results-To examine this hypothesis, we used RNase protection as say to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie, decreased expression of alpha -MHC with increased beta -MHC expression compared with left ventricles from age -matched controls. We detected expression of TR-alpha (1), -alpha (2), and -beta (1) isoforms in human left ventricles, In failing left ventricles, TR -alpha (1) was downregulated, whereas TR-alpha (2), a splice variant that d oes not bind thyroid hormone but inhibits responses to liganded TRs, was in creased. Expression levels of TR-beta (1) did not differ significantly betw een the 2 groups. According to linear regression analysis, expression level s of TR-alpha (1) and -alpha (2) were positively and negatively correlated with those of alpha -MHC, respectively. Conclusions-We conclude that decreases in TR-alpha (1) and increases in TR- alpha (2) may lead to local attenuation of thyroid hormone signaling in the railing human heart and that the resulting tissue-specific hypothyroidism is a candidate for the molecular mechanism that induces fetal gene expressi on in the failing human ventricle.