TY - JOUR
T1 - FoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth
AU - Ferdous, Anwarul
AU - Wang, Zhao V.
AU - Luo, Yuxuan
AU - Li, Dan L.
AU - Luo, Xiang
AU - Schiattarella, Gabriele G.
AU - Altamirano, Francisco
AU - May, Herman I.
AU - Battiprolu, Pavan K.
AU - Nguyen, Annie
AU - Rothermel, Beverly A.
AU - Lavandero, Sergio
AU - Gillette, Thomas G.
AU - Hill, Joseph A.
N1 - Funding Information:
We thank the entire Hill lab for constructive discussions. We thank the Histology Core and Diana C. Canseco for help with immunohistochemistry and Dr. Yauk of Carleton University, Ontario, Canada, for reagents. The work was supported by grants from the NIH (HL-120732; HL-128215; HL-126012; HL-147933 to J.A.H.; HD-101006 to B.A.R; HD-087351 to B.A.R.), American Heart Association (14SFRN20740000 to J.A.H.; 19TPA34920001 to B.A.R.; 19CDA34680003 to F.A.; 18POST34060230 to G.G.S.), CPRIT (RP110486P3 to J.A.H.), the Leducq Foundation (11CVD04 to J.A.H.), the Comision Nacional de Investigacion Cientifica y Tecnologica de Chile Fondo de Financiamiento de Centros de Investigacion en Areas Prioritarias (FONDAP; grant 15130011 to S.L.), and Fondo Nacional de Desarrollo Científico y Tecnologico (FON-DECYT grant1161156 to S.L.); ZVW was supported by a Scientist Development Grant (SDG) from the AHA (14SDG18440002). D.L.L. was supported by a predoctoral fellowship from the AHA (14PRE19770000).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-020-16345-y
DO - 10.1038/s41467-020-16345-y
M3 - Article
C2 - 32439985
AN - SCOPUS:85085156539
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2551
ER -