Although previously felt to represent the euthyroid-sick syndrome rather than frank hypothyroidism, recent data suggest that a primary change in the myocardial response to thyroid hormone might underlie some of the alterations in myocardial form and function seen in the failing heart. IT IS WELL accepted that alterations in thyroid function occur in patients with heart failure ( 1– 4). These findings refine our previous observations on TR expression in the hypertrophied and failing heart and suggest that manipulation of thyroid hormone signaling in an isoform-specific manner may be a relevant therapeutic target for altering the pathologic myocardial program. Mitigating TRα 1 effects, both TRα 2 and TRβ 1 attenuate TRα 1-induced myocardial growth and gene expression by diminishing TAK1 and p38 activities, respectively. The mechanism of TH and TRα 1-specific hypertrophy is novel for a nuclear hormone receptor and involves the transforming growth factor β-activated kinase (TAK1) and p38. In this report, we demonstrate that TH induces hypertrophy as a direct result of binding to the TRα 1 isoform and, moreover, that overexpression of TRα 1 alone is also associated with a hypertrophic phenotype, even in the absence of ligand.
Alterations in TR 1 isoform expression have been reported in models of both physiologic and pathologic cardiac hypertrophy as well as in patients with heart failure.
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