Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone receptor α1-specific manner that requires TAK1 and p38 mitogen-activated protein kinase

Alterations in TR [thyroid hormone (TH) receptor] 1 isoform expression have been reported in models of both physiologic and pathologic cardiac hypertrophy as well as in patients with heart failure. In this report, we demonstrate that TH induces hypertrophy as a direct result of binding to the TR alpha(1) isoform and, moreover, that overexpression of TR alpha(1) alone is also associated with a hypertrophic phenotype, even in the absence of ligand. The mechanism of TH and TR alpha(1)-specific hypertrophy is novel for a nuclear hormone receptor and involves the transforming growth factor beta-activated kinase (TAK1) and p38. Mitigating TR alpha(1) effects, both TR alpha(2) and TR beta(1) attenuate TR alpha(1)-induced myocardial growth and gene expression by diminishing TAK1 and p38 activities, respectively. 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.