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

Anwarul Ferdous; Zhao V. Wang; Yuxuan Luo; Dan L. Li; Xiang Luo; Gabriele G. Schiattarella; Francisco Altamirano; Herman I. May; Pavan K. Battiprolu; Annie Nguyen; Beverly A. Rothermel; Sergio Lavandero; Thomas G. Gillette; Joseph A. Hill

doi:10.1038/s41467-020-16345-y

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

Anwarul Ferdous, Zhao V. Wang, Yuxuan Luo, Dan L. Li, Xiang Luo, Gabriele G. Schiattarella, Francisco Altamirano, Herman I. May, Pavan K. Battiprolu, Annie Nguyen, Beverly A. Rothermel, Sergio Lavandero, Thomas G. Gillette, Joseph A. Hill

Universidad de Chile

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

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.

Original language	English
Article number	2551
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16345-y
Publication status	Published - Dec 1 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

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).

Funders	Funder number
FON-DECYT	grant1161156
National Institutes of Health	HD-101006, HL-147933, HD-087351
National Heart, Lung, and Blood Institute	R01HL128215, HL-120732, HL-126012
American Heart Association	19TPA34920001, 14SFRN20740000, 18POST34060230, 19CDA34680003
American Historical Association	14PRE19770000, 14SDG18440002
Cancer Prevention and Research Institute of Texas	RP110486P3
Fondation Leducq	11CVD04
Fondo Nacional de Desarrollo Científico y Tecnológico
Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias	15130011

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-020-16345-y

Cite this

Ferdous, A., Wang, Z. V., Luo, Y., Li, D. L., Luo, X., Schiattarella, G. G., Altamirano, F., May, H. I., Battiprolu, P. K., Nguyen, A., Rothermel, B. A., Lavandero, S., Gillette, T. G., & Hill, J. A. (2020). FoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth. Nature Communications, 11(1), Article 2551. https://doi.org/10.1038/s41467-020-16345-y

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abstract = "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.",

author = "Anwarul Ferdous and Wang, {Zhao V.} and Yuxuan Luo and Li, {Dan L.} and Xiang Luo and Schiattarella, {Gabriele G.} and Francisco Altamirano and May, {Herman I.} and Battiprolu, {Pavan K.} and Annie Nguyen and Rothermel, {Beverly A.} and Sergio Lavandero and Gillette, {Thomas G.} and Hill, {Joseph A.}",

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

Abstract

Bibliographical note

Funding

ASJC Scopus Subject Areas

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