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 TR alpha 1. 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.
United States Department of Health & Human Services National Institutes of Health (NIH) - USA HL-120732 HL-128215 HL-126012 HL-147933 HD-101006 HD-087351 American Heart Association 14SFRN20740000 19TPA34920001 19CDA34680003 18POST34060230 CPRIT RP110486P3 Leducq Foundation 11CVD04 Comision Nacional de Investigacion Cientifica y Tecnologica de Chile Fondo de Financiamiento de Centros de Investigacion en Areas Prioritarias (FONDAP) 15130011 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1161156 Scientist Development Grant (SDG) from the AHA 14SDG18440002 American Heart Association 14PRE19770000
Artículo de publicación ISI
Quote ItemNature Communications Volumen: 11 Número: 1 May 21 2020
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