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

• Published in: Nature communications Vol. 11; no. 1; pp. 2551 - 13
• Main Authors: Ferdous, Anwarul, Wang, Zhao V., Luo, Yuxuan, Li, Dan L., Luo, Xiang, Schiattarella, Gabriele G., Altamirano, Francisco, May, Herman I., Battiprolu, Pavan K., Nguyen, Annie, Rothermel, Beverly A., Lavandero, Sergio, Gillette, Thomas G., Hill, Joseph A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 38/15; 38/39; 64/60; 692/163/2743/1841; 692/4019/592/1540; Animals; Animals, Newborn; Aorta; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiomyocytes; Cells, Cultured; Coronary artery disease; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Forkhead protein; FOXO1 protein; FOXO3 protein; Gene Expression Regulation; Heart diseases; Hemodynamics; Homeostasis; Humanities and Social Sciences; Hypertrophy; Intracellular; Intracellular signalling; Iodide Peroxidase - antagonists & inhibitors; Iodide Peroxidase - genetics; Iodide Peroxidase - metabolism; Iodothyronine Deiodinase Type II; Metabolism; Mice; Mice, Knockout; Morphogenesis; multidisciplinary; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neonates; Rats; Science; Science (multidisciplinary); Signal Transduction; Signaling; Thyroid; Thyroid gland; Thyroid Hormones - metabolism; Transcription; Ventricular Remodeling
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16345-y

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. Disease stress-induced cardiac hypertrophy is a major mechanism of pathological cardiac remodeling. Here, the authors unveil a previously unrecognized role of a FoxO1–Dio2 signaling axis in maladaptive, afterload-induced cardiac hypertrophy and intracellular thyroid hormone homeostasis.