title: Transcription factor Foxo3a prevents apoptosis by regulating calcium through the apoptosis repressor with caspase recruitment domain.
abstract: Apoptosis can occur in the myocardium under a variety of pathological conditions, including myocardial infarction and heart failure. The forkhead family of transcription factor Foxo3a plays a pivotal role in apoptosis; however, its role in regulating cardiac apoptosis remains to be fully elucidated. We showed that enforced expression of Foxo3a inhibits cardiomyocyte apoptosis, whereas knockdown of endogenous Foxo3a sensitizes cardiomyocytes to undergo apoptosis. The apoptosis repressor with caspase recruitment domain (ARC) is a potent anti-apoptotic protein. Here, we demonstrate that it attenuates the release of calcium from the sarcoplasmic reticulum and inhibits calcium elevations in the cytoplasm and mitochondria provoked by oxidative stress in cardiomyocytes. Furthermore, Foxo3a is shown to maintain cytoplasmic and mitochondrial calcium homeostasis through ARC. We observed that Foxo3a knock-out mice exhibited enlarged myocardial infarction sizes upon ischemia/reperfusion, and ARC transgenic mice demonstrated reduced myocardial infarction and balanced calcium levels in mitochondria and sarcoplasmic reticulum. Moreover, we showed that Foxo3a activates ARC expression by directly binding to its promoter. This study reveals that Foxo3a maintains calcium homeostasis and inhibits cardiac apoptosis through trans-activation of the ARC promoter. These findings provided novel evidence that Foxo3a and ARC constitute an anti-apoptotic pathway that regulates calcium homeostasis in the heart.
authors: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Daoyuan
authors: D
authors: Lu
authors: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Jinping
authors: J
authors: Liu
authors: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Jianqin
authors: J
authors: Jiao
authors: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Bo
authors: B
authors: Long
authors: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Qian
authors: Q
authors: Li
authors: Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Weiqi
authors: W
authors: Tan
authors: College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612. Electronic address: peifli@uic.edu.
authors: Peifeng
authors: P
authors: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D051017:Apoptosis Regulatory Proteins; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009124:Muscle Proteins; C491788:Nol3 protein, rat; D016877:Oxidants; D006861:Hydrogen Peroxide; D049410:Luciferases, Renilla; C505410:Casp3 protein, rat; D053148:Caspase 3; D002118:Calcium
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