title: FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress.
abstract: Transcriptional regulatory mechanisms of cardiac oxidative stress resistance are not well defined. FoxO transcription factors are critical mediators of oxidative stress resistance in multiple cell types, but cardioprotective functions have not been reported previously. FoxO function in oxidative stress resistance was investigated in cultured cardiomyocytes and in mice with cardiomyocyte-specific combined deficiency of FoxO1 and FoxO3 subjected to myocardial infarction (MI) or acute ischemia/reperfusion (I/R) injury. Induction of oxidative stress in cardiomyocytes promotes FoxO1 and FoxO3 nuclear localization and target gene activation. Infection of cardiomyocytes with a dominant-negative FoxO1(Δ256) adenovirus results in a significant increase in reactive oxygen species and cell death, whereas increased FoxO1 or FoxO3 expression reduces reactive oxygen species and cell death. Mice generated with combined conditional deletion of FoxO1 and FoxO3 specifically in cardiomyocytes were subjected to I/R or MI. Loss of FoxO1 and FoxO3 in cardiomyocytes results in a significant increase in infarct area with decreased expression of the antiapoptotic molecules, PTEN-induced kinase1 (PINK1) and CBP/P300-interacting transactivator (CITED2). Expressions of the antioxidants catalase and manganese superoxide dismutase-2 (SOD2) and the autophagy-related proteins LC3II and Gabarapl1 also are decreased following I/R compared with controls. Mice with cardiomyocyte-specific FoxO deficiency subjected to MI have reduced cardiac function, increased scar formation, induction of stress-responsive signaling, and increased apoptotic cell death relative to controls. These data support a critical role for FoxOs in promoting cardiomyocyte survival during conditions of oxidative stress through induction of antioxidants and cell survival pathways.
authors.affiliation: Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Arunima
authors.initials: A
authors.lastname: Sengupta
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Yutzey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006861:Hydrogen Peroxide; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D010100:Oxygen; D048051:p38 Mitogen-Activated Protein Kinases; C499515:FOXO3 protein, rat; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins; C074639:Foxo1 protein, rat