FOXO1 silence aggravates oxidative stress-promoted apoptosis in cardiomyocytes by reducing autophagy

Abstract

-Mechanisms underlining oxidative stress-induced injury to cardiomyocytes during myocardial infarction (MI) or acute ischemia/reperfusion (I/R) are not well recognized. Forkhead box O (FOXO) transcription factors have been defined as critical mediators of oxidative stress resistance in multiple cell types, but their cardioprotective functions have not been reported previously. In the present study, we investigated the promotion to FOXO1 by the treatment with hydrogen peroxide (H 2 O 2 ) during the H 2 O 2 -induced apoptosis in cardiomyocyte H9c2 cells. We then silenced FOXO1 with FOXO1-specific siRNA, and re-evaluated the H 2 O 2 -induced apoptosis. In addition, we also examined the H 2 O 2 -induced autophagy and the autophagy induction post FOXO1 silence. Results demonstrated that H 2 O 2 induced a significantly high level of apoptosis in H9c2 cells. Interestingly, the FOXO1 in both mRNA and protein levels were not significantly regulated, however, the phosphorylated form of FOXO1 was significantly promoted in the H 2 O 2 -treated H9c2 cells. On the other hand, post the significant knockout of FOXO1 with the transfection with FOXO1-specific siRNA, the apoptosis induction was more significant in H9c2 cells subjected to H 2 O 2 . In addition, we found a significantly higher level of autophagy induction in the H 2 O 2 -treated H9c2 cells. However, the autophagy was markedly reduced by the knockout of FOXO1. In summary, these data support the critical role for FOXO1 in promoting cardiomyocytes against oxidative stress probably through inducing autophagy.

RETRACTED ARTICLE: Association of the polymorphisms in FOXO1 gene and diabetic nephropathy risk

“…Another function of FOXO1 is the resistance for oxidative stress. An in vitro study which was executed by Ning et al showed that in cardiomyocytes, FOXO1 might induce autophagy against the oxidative stress [11]. In addition, it was suggested that FOXO1 inhibitors are probably used as novel medicines for obesity and metabolic disorders [12,24].…”

“…FOXO1 directly or indirectly mediates many biological responses. Recent researches found that FOXO1 involve in the regulation of proliferation and the response for oxidative stress [9][10][11]. In addition, other researches found that FOXO1 regulates adipogenesis and glucose metabolism [12,13].…”

Overexpression of BAG3 Attenuates Hypoxia-Induced Cardiomyocyte Apoptosis by Inducing Autophagy

“…There are three different types of interplay with autophagy and apoptosis: the partner, the enabler, and the antagonist [27]. Researches have reported that inducing autophagy could inhibit oxidative stress and high-fat dietinduced apoptosis [29,30]. However, Zhang et al [31] indicated that autophagy in hypoxia/ reoxygenation injury promoted cardiomyocyte apoptosis.…”

Preventive effect of hesperidin modulates inflammatory responses and antioxidant status following acute myocardial infarction through the expression of PPAR‑γ and Bcl‑2 in model mice

“…Cell apoptosis is eventually induced through activating downstream caspase-3 and other cells (15). This indicates that decreasing the activity or reducing the expression levels of caspase-3 and caspase-9 protease can effectively inhibit myocardial cell apoptosis (16). The Bcl-2 family can regulate the release of cytochrome c in the mitochondria.…”