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

• Published in: The Journal of biological chemistry Vol. 280; no. 21; pp. 20814 - 20823
• Main Authors: Skurk, Carsten, Izumiya, Yasuhiro, Maatz, Henrike, Razeghi, Peter, Shiojima, Ichiro, Sandri, Marco, Sato, Kaori, Zeng, Ling, Schiekofer, Stephan, Pimentel, David, Lecker, Stewart, Taegtmeyer, Heinrich, Goldberg, Alfred L., Walsh, Kenneth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-05-2005; American Society for Biochemistry and Molecular Biology
• Subjects: Angiotensin II - pharmacology; Animals; Animals, Newborn; Cardiomegaly - genetics; Cell Size; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Enzyme Activation; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression - drug effects; Gene Expression Regulation; Growth Hormone - metabolism; Heart Ventricles; Insulin - pharmacology; Insulin-Like Growth Factor I - pharmacology; Mechanoreceptors - physiology; Mice; Mice, Knockout; Microarray Analysis; Muscle Proteins - genetics; Mutagenesis; Myocytes, Cardiac - chemistry; Myocytes, Cardiac - cytology; Nerve Tissue Proteins; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-akt; Rats; Receptor, Insulin - deficiency; Receptor, Insulin - physiology; RNA, Messenger - analysis; Signal Transduction - drug effects; SKP Cullin F-Box Protein Ligases - genetics; Transcription Factors - genetics; Transcription Factors - physiology; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M500528200

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, insulin-like 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.