l-Thyroxine activates Akt signaling in the heart

Abstract

Hyperthyroidism causes physiological cardiac hypertrophy and enhanced function. Many of these effects have been traditionally attributed to changes in gene expression. However, the role of signal transduction pathways in the effects mediated by thyroid hormone (TH) have recently gained a significant amount of attention in non-cardiovascular cells and tissue. Whether signal transduction pathways are involved in the cardiac effects of TH is unknown. In this study, we treated Sprague Dawley rats with L-thyroxine (T4) or propylthiouracil (PTU) to determine whether there was modulation of signal transduction pathways in the left ventricle. Predictably, T4 increased heart weight, left ventricular systolic pressure, and dP/dT. T4 and PTU also had typical effects on expression of thyroid responsive genes such as α and β myosin heavy chain. T4 treatment caused phosphorylation of Akt and downstream signaling components such as GSK-3β, mTOR, and S6 kinase. In conclusion, activation of the Akt signaling pathway may contribute to the effects of TH on the heart. While this pathway is clearly activated, further work is needed to determine whether this is via a genomic or non-genomic mechanism.

Introduction

Thyroid hormone (TH) is known to have dramatic effects on the cardiovascular system. TH increases cardiac output through inotropic, chronotropic, and vasodilatory mechanisms [1]. Though the physiological effects of TH have been well documented the underlying mechanisms remain elusive. The effects of TH have been traditionally attributed to nuclear receptor mediated regulation of transcription. However, recent data suggests that TH also exerts actions independent of thyroid receptor regulated gene transcription [2], [3].

The classical mechanism through which TH exerts its action is by binding to receptors in the nucleus that regulate transcription of genes that contain thyroid response elements (TRE's). Some of the genes known to be regulated by T3 include SERCA, phospholamban, and α/β myosin heavy chain (MHC). These proteins are important in maintaining normal cardiovascular function and have been implicated in mediating many of the cardiovascular effects of TH. However, the inotropic and vasodilatory effect of TH is rapidly induced after T3 infusion and must therefore be, at least in part, mediated by a non-genomic mechanism [4].

TH causes physiological cardiac hypertrophy and enhanced function. The mechanisms of cardiac hypertrophy due to pressure overload or neurohormonal activation have been studied extensively and many signal transduction pathways and transcription factors have been implicated. TH-induced hypertrophy is less understood and it is unknown whether signal transduction pathways may contribute to the growth process. A study done by Lin et al. showed that l-thyroxine can activate ERK through a G-protein dependent mechanism in Hela and CV-1 cells [5]. Whether signaling pathways are activated by TH in the heart is not known.

The Akt signaling pathway has been implicated in regulating physiological cardiac growth and increased cardiac function [6]. Akt has been shown to be active both during developmental hypertrophy [7] and exercise hypertrophy [8]. Cardiac specific over-expression of constitutively active Akt resulted in concentric hypertrophy and enhanced cardiac contractility [9]. Recently, the Akt pathway was shown to be activated by TH in human skin fibroblasts [10] but no studies have investigated this phenomenon in the heart. Collectively, these data suggest that Akt is important in physiological hypertrophy and may play a role in some of the cellular effects of TH.

We hypothesized that T4 treatment in rats would activate signal transduction pathways implicated in physiological hypertrophy (i.e. Akt pathway). In this study, we investigated the effect of T4 on expression and phosphorylation of Akt and its downstream components.