Several cardiac genes possess thyroid hormone (TH) response elements regulated by TH receptors. Mutation in TR-β gene causes the human syndrome of resistance to TH, which is characterized by elevated serum concentration of T4 and T3 and variable degrees of insensitivity to TH. It is unclear, however, whether a mutant TR-β could function as a dominant negative in the heart when expressed from the endogenous locus. A well-described resistance to TH (Δ337T) was either introduced into germline of mice (KI-mut) or expressed as a transgene in the heart using a cardiac-specific promoter (KS-mut). Mice were studied at baseline, after 5-propyl-2-thiouracil (PTU) or after PTU and T3 treatment (PTU + T3). PTU + T3 treatment significantly increased left ventricular mass in all groups compared with baseline measurements, although the increase in left ventricular mass was significantly less in KI-mut animals. Baseline heart rates (HRs) were similar in wild-type (WT) and KI-mut but were lower in KS-mut animals. After TH deprivation (PTU), HR decreased in WT and KI-mut animals; similarly, HR increased in WT and KI-mut after PTU + T 3. In contrast, HR in KS-mut animals did not change after either treatment. Except for cardiac hypertrophy, the presence of a germline TR-β mutation had surprisingly little effect on cardiac function.
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