Canonical and noncanonical contribution of thyroid hormone receptor isoforms alpha and beta to cardiac hypertrophy and heart rate in male mice

Abstract

AbstractBackgroundStimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determinein vivowhich TH receptor (TR), α or β, and which mode of TR action, canonical gene expression or DNA-binding independent noncanonical action, mediate these effects.Material and methodsWe compared global TRα and TRβ knockout mice (TRαKO; TRβKO) with WT mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA- binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRβGS). Hearts were studied with echocardiography at baseline and after seven weeks T3-treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice.ResultsT3 induced ventricular hypertrophy in WT and TRβKOmice, but not in TRαKOmice. Hypertrophy was also induced in TRαGSmice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression ofMhy7occurred in WT and TRαGSmice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3-treatment as well as expression of pacemaker geneHcn2were still preserved in TRαKOmice, demonstrating that TRβ could compensate for absence of TRα.ConclusionT3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRβ could substitute for canonical, but not noncanonical TRα action.