FoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth

Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show that Dio2 is a direct transcriptional target of FoxO1, and the FoxO1–Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restricted FoxO1 knockout mice, we unveil an essential role for the FoxO1–Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1–Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.


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Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: -Accession codes, unique identifiers, or web links for publicly available datasets -A list of figures that have associated raw data -A description of any restrictions on data availability NCOMMS-19-20354-T 2020/02/24 Sonos 5500 system, VisualSonics The data supporting the findings of this study are available within the paper and its Supplementary  No statistical analysis was used to predetermine sample size. Estimates were made based on our previous experience, experimental approach, availability and feasibility required to obtain statistically significant results.
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Data reported in this manuscript were reproduced over numerous independent experiments with sufficient cells/animals per group to demonstrate statistical significance.
Mice were randomly assigned to each experimental/control group.
Investigators were blinded to the genotypes of the individual animals during the experiments and outcome assessments.
All of antibodies were validated by vendors. We based specificity on their provided data sheets. For FoxO1 and Dio2 antibodies we performed the target validation using specific siRNAs.

Mycoplasma detection was tested negative
None