Fork Head Box Class O1 (FOXO1) Activates Bim Expression to Mediate Cardiac Apoptosis in Chronic Intermittent Hypoxia-Induced Cardiac Hypertrophy

Background: Obstructive sleep apnea syndrome (OSAS) is characterized by chronic intermittent episodes of upper-airway obstruction with hypoxia and is associated with increased risk of cardiovascular diseases, including myocardial hypertrophy. Chronic intermittent hypoxia (CIH) has been shown to induce apoptosis in cardiomyocytes. However, the mechanisms of cardiomyocytes apoptosis under CIH largely remain unclear. Material/Methods: We used male Sprague-Dawley rats and human cardiomyocyte cell line H9C2, and Annexin V/PI, Western blot analysis, co-immunoprecipitation, RT-PCR, immunohistochemistry, and TUNEL assay were carried out. Results: We show that Bim was significantly up-regulated by CIH in cardiomyocytes, and the function of Bim in CIHinduced apoptosis was supported by the genetic suppression of Bim with si-RNA. We also observed that CIHmotivated expression of Bim was directly related to fork head box class O1 (FOXO1), which is increased in CIH. Genetic ablation and pharmacological inhibition of FOXO1 in cardiomyocytes attenuated CIH-induced apoptosis, hypertrophy, and features of perivascular fibrosis in cardiomyocytes in vitro and in vivo. Conclusions: FOXO1 is a key integrator of the apoptosis signal transduction pathway, driving chronic intermittent hypoxiainduced cardiac hypertrophy, and inhibition of FOXO1 provides a potential target for the treatment of OSAS with cardiac hypertrophy.