Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, 75390-8573, USA.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8573, USA.
Nat Commun. 2020 May 21;11(1):2551. doi: 10.1038/s41467-020-16345-y.
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.
叉头框 O（FoxO）蛋白和甲状腺激素（TH）在心血管形态发生和重塑中具有明确的作用。然而，个体 FoxO 家族成员在应激诱导的心肌细胞生长和重塑中的特定作用仍不清楚。在这里，我们报告 FoxO1 而不是 FoxO3 的活性对于 II 型和 III 型甲状腺素脱碘酶（分别为 Dio2 和 Dio3）的相互调节是必需的，Dio2 和 Dio3 是参与细胞内 TH 代谢的关键酶。我们进一步表明，Dio2 是 FoxO1 的直接转录靶标，FoxO1-Dio2 轴控制 TH 诱导的体外和体内新生心肌细胞的肥大生长。利用横主动脉缩窄作为野生型和心肌细胞特异性 FoxO1 敲除小鼠血流动力学应激的模型，我们揭示了 FoxO1-Dio2 轴在负荷诱导的病理性心脏重塑和 TRα1 的激活中的重要作用。这些发现表明在应激诱导的心肌细胞生长和重塑以及细胞内 TH 动态平衡中存在一个以前未被认识的 FoxO1-Dio2 信号轴。
