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Background:  PI3K/AKT pathway plays major roles in regulating cardiomyocyte metabolism. The roles of PI3K/AKT pathway and FOXO3a in mediating high glucose-induced apoptosis in cardiomyocytes remain unclear.    Objectives:  In this experimental study, we investigated the mechanisms of the PI3K/AKT pathway and FOXO3a in mediating hyperglycemia-induced apoptosis in neonatal rat ventricular myocytes (NRVMs).    Materials and Methods:  NRVMs were adopted as the cell model to investigate the roles of PI3K/AKT and FOXO3a in mediating hyperglycemia-induced apoptosis in cardiomyocytes. Annexin-V-FITC staining and PI staining were used to evaluate the apoptosis in NRVMs under indicated conditions of serum starvation, high glucose exposure, and pharmacological or genetic manipulations on the expressions of PI3K/AKT and FOXO3a. Western blotting was conducted to evaluate the cytoplasmic/nuclear localization of FOXO3a in NRVMs exposed to high glucose. FOXO3a transcriptional activity was measured by luciferase reporter assay.    Results:  High glucose (30 mM) induced significant apoptosis in serum-starved NRVMs as compared with normal glucose (5 mM) control (12.01 ± 0.76% vs. 2.86 ± 0.55%; P < 0.001). Treatment with IGF1 attenuated hyperglycemia-induced apoptosis by 68% (3.23 ± 0.76% vs. 9.97 ± 1.29%; P < 0.001; n = 3) in comparison with the non-treated control. Treatment with PI3K inhibitor LY294002 enhanced hyperglycemia-induced apoptosis by 109% (20.83 ± 1.87% vs. 9.97 ± 1.29%; P < 0.001; n = 3) in comparison with the non-treated control. Over-expression of AKT by transduction with CA-AKT attenuated hyperglycemia-induced apoptosis by 47% (5.48 ± 0.35% vs.10.31 ± 0.94%; P < 0.001; n = 3) in comparison with the empty-vector control. Transduction with DN-AKT enhanced high glucose-induced apoptosis by 105% (21.13 ± 1.11% vs. 10.31 ± 0.94%; P < 0.001; n = 3) in comparison with the empty-vector control. Western blotting showed that high glucose induced a significant increase in FOXO3a nuclear localization. Luciferase reporter assay showed that high glucose induced a significant increase of 310% (P < 0.001; n = 3) in FOXO3a transcriptional activity against Fas ligand when NRVMs were transducted with TM-FOXO3a in comparison with the empty-vector control.    Conclusions:  The PI3K/AKT pathway mediated hyperglycemia-induced apoptosis of NRVMs through the translocation of FOXO3a to nuclei and the resultant enhanced transcriptional activity of FOXO3.

The PI3K/AKT Pathway and FOXO3a Transcription Factor Mediate High Glucose-Induced Apoptosis in Neonatal Rat Ventricular Myocytes