Foxo3a Inhibits Cardiomyocyte Hypertrophy through Transactivating Catalase

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.Myocardial hypertrophy is a compensatory response to increased hemodynamic load. It is often associated with poor clinical outcomes, including the development of cardiac systolic and diastolic dysfunction and ultimately heart failure (1-7). Hyperinsulinemia and cardiac hypertrophy are closely related. For example, insulin treatment can induce hypertrophy in cultured cardiomyocytes (8). In the animal model, chronic hyperinsulinemia leads to cardiac hypertrophy (9). In particular, hypertensive patients with left ventricular hypertrophy have a higher degree of hyperinsulinemia than hypertensive patients without left ventricular hypertrophy (10). Insulin-like growth factor-1 (IGF-1) 3 also is a potent hypertrophic stimulus both in vitro and in vivo (11). To prevent and/or reverse myocardial hypertrophy, it is necessary to identify and characterize the molecules that are involved in the hypertrophic cascades of insulin and IGF-1.The forkhead family of transcription factors are characterized by the presence of a conserved 100-amino acid DNA binding domain and participate in regulating diverse cellular functions such as apoptosis, differentiation, metabolism, proliferation, and survival (12). The Foxo (Forkhead bOX-containing protein, O sub-family) subgroup contains four members (Foxo1, Foxo3a, Foxo4, and Foxo6). It has been shown that Foxo1 and Foxo3a are expressed in the heart and ske...

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“…Li et al. demonstrated that myocardin expression can be stimulated by ROS, and FoxO3a negatively regulates myocardin expression through controlling ROS levels 27. Recently, there were several reports suggesting that FoxO3a was closely controlled by miR‐155 28, 29.…”

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