Foxo3a inhibits cardiomyocyte hypertrophy through transactivating catalase.
The forkhead transcription factor Foxo3a is able to inhibit cardiomyocyte hypertrophy. However, its underlying molecular mechanism remains to be fully understood. Our present study demonstrates that Foxo3a can regulate cardiomyocyte hypertrophy through transactivating catalase. Insulin was able to induce cardiomyocyte hypertrophy with an elevated level of reactive oxygen species (ROS). The antioxidant agents, including catalase and N-acetyl-L-cysteine, could inhibit cardiomyocyte hypertrophy induced by insulin, suggesting that ROS is necessary for insulin to induce hypertrophy. Strikingly, we observed that the levels of catalase were decreased in response to insulin treatment. The transcriptional activity of Foxo3a depends on its phosphorylation status with the nonphosphorylated but not phosphorylated form to be functional. Insulin treatment led to an increase in the phosphorylated levels of Foxo3a. To understand the relationship between Foxo3a and catalase in the hypertrophic pathway, we characterized that catalase was a transcriptional target of Foxo3a. Foxo3a bound to the promoter region of catalase and stimulated its activity. The inhibitory effect of Foxo3a on cardiomyocyte hypertrophy depended on its transcriptional regulation of catalase. Finally, we identified that myocardin was a downstream mediator of ROS in conveying the hypertrophic signal of insulin or insulin-like growth factor-1. Foxo3a could negatively regulate myocardin expression levels through up-regulating catalase and the consequent reduction of ROS levels. Taken together, our results reveal that Foxo3a can inhibit hypertrophy by transcriptionally targeting catalase.
Tan
Wei-Qi
WQ
Division of Cardiovascular Research, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Wang
Kun
K
Lv
Dao-Yuan
DY
Li
Pei-Feng
PF
D000818:Animals; D002374:Catalase / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D000099251:Myocardin
D002374:Catalase; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007334:Insulin-Like Growth Factor I; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D000099251:Myocardin; C499517:FOXO3 protein, human; C499515:FOXO3 protein, rat
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