Foxo3a Inhibits Cardiomyocyte Hypertrophy through Transactivating Catalase

被引:161
作者
Tan, Wei-Qi [1 ]
Wang, Kun [1 ]
Lv, Dao-Yuan [1 ]
Li, Pei-Feng [1 ,2 ]
机构
[1] Chinese Acad Sci, Div Cardiovasc Res, Natl Key Lab Biomembrane & Membrane Biotechnol, Inst Zool, Beijing 100101, Peoples R China
[2] Univ Illinois, Coll Med, Chicago, IL 60612 USA
基金
中国国家自然科学基金;
关键词
D O I
10.1074/jbc.M805514200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:29730 / 29739
页数:10
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