The FOXO3a Transcription Factor Regulates Cardiac Myocyte Size Downstream of AKT Signaling

Abstract

Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulinlike growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes "atrogenes," including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth.Cardiac hypertrophy occurs during normal physiological growth of the organism and as an adaptive response to pressure or volume stress, mutations in cardiac proteins, or metabolic perturbations (1). Hypertrophy is characterized by an increase in cell size, enhanced protein synthesis and, in some cases, reorganization of the sarcomere. In pathological hypertrophy, the increase in cardiac myocyte size is thought to be a compensatory mechanism to diminish wall stresses that result from hypertension, valvular heart disease, or myocardial infarction. Ventricular hypertrophy is associated with a significantly increased risk of heart failure and malignant arrhythmias (2).Multiple signaling pathways contribute to the hypertrophic phenotype (3, 4). A number of studies have shown that the serine-threonine kinase Akt (protein kinase B) is an important regulator of myocyte growth (5) and survival (6). Many stimuli activate Akt including the growth factors insulin and IGF 1 (7), angiotensin II (8), and mechanical stress (9). Constitutive overexpression of Akt in transgenic mice can lead to enhanced contractility (10), cytoprotection (11), and pathological cardiac hypertrophy (12, 13). Akt signaling is also an important determinant of physiological heart growth and coordinates heart size with body size as the nutritional status of the organism varies (7). The growth factor/Akt signaling pathway up-regulates protein expression through mechanisms involving the activation of the mammalian target of rapamycin (13), eukaryotic initiation factor 4E-binding proteins (14), p70S6k (7), and the inhibition of GSK3␤ (15).Relatively little is known about the mechanisms that negatively regulate the hypertrophic phenotype. Hearts undergo a reduction in size in response to a...

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“…Interestingly, we observed normal cardiac expression of calmodulin, H11 kinase, serotonin 5-HT 2B receptor, and FoxO3a transcription factor (Fig. 4), all of which are essential for the development of hypertrophy in cardiomyocytes (Nebigil et al, 2000;Depre et al, 2002;Colomer et al, 2004;Skurk et al, 2005).…”

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

“…It has been demonstrated that FoxO3a is expressed in the heart and skeletal muscle 33, 34. And recent studies have showed that FoxO3a activation can induce skeletal muscle atrophy by causing transcription of the ubiquitin ligase atrogin‐1 promoter 33. Li et al.…”

FoxO Transcription Factors Promote Autophagy in Cardiomyocytes

“…The FoxO subfamily of transcription factors consists of FoxO1, FoxO3, and FoxO4, which are subject to inhibition by growth factors, including insulin and insulin-like growth factor-1 (25). During growth factor limitation, the inhibition of FoxO activity by phosphatidylinositol 3-kinase/AKT is relieved, and the dephosphorylated FoxO transcription factors are activated and become localized to the nucleus (23,26,27). Sirt1, a mammalian ortholog of NAD ϩ -dependent protein deacetylase, Sir2, promotes the activity of FoxO transcription factors by deacety-lation under conditions of oxidative stress (24).…”

“…Sirt1, a mammalian ortholog of NAD ϩ -dependent protein deacetylase, Sir2, promotes the activity of FoxO transcription factors by deacety-lation under conditions of oxidative stress (24). FoxO target genes are involved in atrophy in skeletal and cardiac myocytes (26,28), autophagy in skeletal myocytes (29,30), differentiation in skeletal and smooth muscle (31), or inhibition of cell cycle progression in neonatal cardiomyocytes (27). FoxO1 null mice die at E10.5 from vascular defects, and FoxO3 null mice develop cardiac hypertrophy as adults, suggesting a possible role for FoxO3 in regulating cardiomyocyte cell size (32,33).…”