Rg1 Protects H9C2 Cells from High Glucose-/palmitate-induced Injury Via Activation of AKT/GSK-3β/Nrf2 Pathway

Our previous studies have assessed ginsenoside Rg1 (Rg1)-mediated protection in a type 1 diabetes rat model. To uncover the mechanism through which Rg1 protects against cardiac injury induced by diabetes, we mimicked diabetic conditions by culturing H9C2 cells in high glucose/palmitate. Rg1 had no toxic effect, and it alleviated the high glucose/palmitate damage in a dose-dependent manner, as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release to the culture medium. Rg1 prevented high glucose/palmitate-induced cell apoptosis, assessed using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling staining. Rg1 also reduced high glucose-/palmitate-induced reactive oxygen species formation and increased intracellular antioxidant enzyme activity. We found that Rg1 activates protein kinase B (AKT)/glycogen synthase kinase-3 (GSK-3β) pathway and antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, indicated by increased phosphorylation of AKT and GSK-3β, and nuclear translocation of Nrf2. We used phosphatidylinositol-3-kinase inhibitor Ly294002 to block the activation of the AKT/GSK-3β pathway and found that it partially reversed the protection by Rg1 and decreased Nrf2 pathway activation. The results suggest that Rg1 exerts a protective effect against high glucose and palmitate damage that is partially AKT/GSK-3β/Nrf2-mediated. Further studies are required to validate these findings using primary cardiomyocytes and animal models of diabetes.