title: 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, 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.
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Boston, Massachusetts 02118, USA.
authors.forename: Carsten
authors.initials: C
authors.lastname: Skurk
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Henrike
authors.initials: H
authors.lastname: Maatz
authors.forename: Peter
authors.initials: P
authors.lastname: Razeghi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.forename: Ling
authors.initials: L
authors.lastname: Zeng
authors.forename: Stephan
authors.initials: S
authors.lastname: Schiekofer
authors.forename: David
authors.initials: D
authors.lastname: Pimentel
authors.forename: Stewart
authors.initials: S
authors.lastname: Lecker
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics; D048429:Cell Size; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000378:metabolism; D006352:Heart Ventricles; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008465:Mechanoreceptors / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009124:Muscle Proteins / Q000235:genetics; D016296:Mutagenesis; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000166:cytology*; D009419:Nerve Tissue Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011972:Receptor, Insulin / Q000172:deficiency / Q000502:physiology; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D000071161:Forkhead Box Protein O1
chemical_list: D000804:Angiotensin II; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D013006:Growth Hormone; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011972:Receptor, Insulin; D044843:SKP Cullin F-Box Protein Ligases; D014157:Transcription Factors; C474033:FoxO3 protein, mouse; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C486691:Fbxo32 protein, mouse; C494920:Akt1 protein, rat