The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling.
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.
Skurk
Carsten
C
Boston University School of Medicine, Whitaker Cardiovascular Institute, Boston, Massachusetts 02118, USA.
Izumiya
Yasuhiro
Y
Maatz
Henrike
H
Razeghi
Peter
P
Shiojima
Ichiro
I
Sandri
Marco
M
Sato
Kaori
K
Zeng
Ling
L
Schiekofer
Stephan
S
Pimentel
David
D
Lecker
Stewart
S
Taegtmeyer
Heinrich
H
Goldberg
Alfred L
AL
Walsh
Kenneth
K
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
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