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

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

26 Scopus citations

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 (US)
Article number	2551
Pages (from-to)	2551
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16345-y
State	Published - May 21 2020
Externally published	Yes

Keywords

Animals
Animals, Newborn
Cardiomegaly/metabolism
Cells, Cultured
Forkhead Box Protein O1/genetics
Gene Expression Regulation
Iodide Peroxidase/antagonists & inhibitors
Mice
Mice, Knockout
Myocytes, Cardiac/metabolism
Rats
Signal Transduction
Thyroid Hormones/metabolism
Ventricular Remodeling

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-020-16345-y

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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), 2551. Article 2551. https://doi.org/10.1038/s41467-020-16345-y

Ferdous, A, Wang, ZV, Luo, Y, Li, DL, Luo, X, Schiattarella, GG, Altamirano, F, May, HI, Battiprolu, PK, Nguyen, A, Rothermel, BA, Lavandero, S, Gillette, TG & Hill, JA 2020, 'FoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth', Nature Communications, vol. 11, no. 1, 2551, pp. 2551. https://doi.org/10.1038/s41467-020-16345-y

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title = "FoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth",

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.",

keywords = "Animals, Animals, Newborn, Cardiomegaly/metabolism, Cells, Cultured, Forkhead Box Protein O1/genetics, Gene Expression Regulation, Iodide Peroxidase/antagonists & inhibitors, Mice, Mice, Knockout, Myocytes, Cardiac/metabolism, Rats, Signal Transduction, Thyroid Hormones/metabolism, Ventricular Remodeling",

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.}",

note = "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 Cient{\'i}fico 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: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = may,

day = "21",

doi = "10.1038/s41467-020-16345-y",

language = "English (US)",

volume = "11",

pages = "2551",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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 - 2020/5/21

Y1 - 2020/5/21

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.

KW - Animals

KW - Animals, Newborn

KW - Cardiomegaly/metabolism

KW - Cells, Cultured

KW - Forkhead Box Protein O1/genetics

KW - Gene Expression Regulation

KW - Iodide Peroxidase/antagonists & inhibitors

KW - Mice

KW - Mice, Knockout

KW - Myocytes, Cardiac/metabolism

KW - Rats

KW - Signal Transduction

KW - Thyroid Hormones/metabolism

KW - Ventricular Remodeling

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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

SP - 2551

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2551

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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