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Foxo3a inhibits cardiomyocyte hypertrophy through transactivating catalase
Wei-Qi Tan1, Kun Wang, Dao-Yuan Lv
1Division of Cardiovascular Research, National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
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.
Insights
Forkhead transcription factor Foxo3a inhibits cardiomyocyte hypertrophy by activating catalase. This process reduces reactive oxygen species (ROS) and downregulates myocardin, revealing a key mechanism against cardiac enlargement.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Transcription Factor Regulation
Background:
- Cardiomyocyte hypertrophy is a significant risk factor for heart failure.
- The forkhead transcription factor Foxo3a is known to inhibit cardiac hypertrophy, but its precise molecular pathways are unclear.
- Reactive oxygen species (ROS) play a critical role in mediating hypertrophic signaling.
Purpose of the Study:
- To elucidate the molecular mechanism by which Foxo3a inhibits cardiomyocyte hypertrophy.
- To investigate the role of catalase and ROS in insulin-induced cardiac hypertrophy.
- To identify downstream targets of Foxo3a in the context of cardiac hypertrophy.
Main Methods:
- Investigated the effect of insulin on cardiomyocyte hypertrophy and ROS levels.
- Assessed the expression and activity of Foxo3a and catalase under various conditions.
- Utilized chromatin immunoprecipitation (ChIP) to determine Foxo3a binding to the catalase promoter.
- Examined the role of myocardin as a downstream mediator.
Main Results:
- Insulin induced cardiomyocyte hypertrophy and increased ROS levels, which were attenuated by antioxidants.
- Catalase levels decreased upon insulin treatment, while Foxo3a phosphorylation increased, inhibiting its activity.
- Foxo3a directly bound to and transactivated the catalase promoter, establishing catalase as a transcriptional target.
- Foxo3a inhibited hypertrophy by upregulating catalase, reducing ROS, and subsequently downregulating myocardin expression.
Conclusions:
- Foxo3a inhibits cardiomyocyte hypertrophy primarily through the transcriptional activation of catalase.
- This Foxo3a-catalase pathway serves as a crucial antioxidant defense mechanism against hypertrophic stimuli.
- Myocardin acts as a downstream effector of ROS in insulin/IGF-1-induced hypertrophic signaling, negatively regulated by Foxo3a.
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