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.
Highlights
Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling
In light of the established roles of both FoxO1 and TH in disease-related cardiac remodeling, coupled with the interplay between them in some settings, we set out to address two major questions: (a) Does a FoxO–Dio[2] signaling axis contribute to stress-induced hypertrophic remodeling of cardiomyocytes? (b) Does FoxO activity govern deiodinase gene expression in cardiomyocytes to regulate TH metabolism? Here, we demonstrate that FoxO1 activity is essential for reciprocal regulation of Dio[2] and Dio[3] expression and that the FoxO1–Dio[2] signaling axis governs TH- and stress-induced cardiomyocyte hypertrophic growth and pathological remodeling of the heart
These observations support a specific role of FoxO1 in THinduced cardiomyocyte growth and are concordant with our previous study demonstrating that FoxO1 gain-of-function inhibits angiotensin II (Ang II)-induced neonatal rat ventricular myocytes (NRVMs) growth[21]
Summary
Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. 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–Dio[2] axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1–Dio[2] signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis. We have recently reported that FoxO1, but not FoxO3, activity is critically associated with metabolic stress-induced pathological remodeling of the heart[17] These observations support a specific role of FoxO1 in cardiovascular morphogenesis and metabolic stress-induced cardiac remodeling that cannot be compensated by other FoxO family members[18].
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