Dapagliflozin Attenuates High Glucose-Induced Endothelial Cell Apoptosis and Inflammation Through Ampk/Sirt1 Activation Publisher Pubmed



Faridvand Y^{1, 2, 3} ; Kazemzadeh H⁴ ; Vahedian V⁵ ; Mirzajanzadeh P⁶ ; Nejabati HR² ; Safaie N¹ ; Maroufi NF² ; Pezeshkian M¹ ; Nouri M^{1, 2} ; Jodati A¹ Show Affiliations
Source: Clinical and Experimental Pharmacology and Physiology Published:2022

Abstract

Hyperglycaemia is a major cause of pathophysiological processes such as oxidative stress, inflammation, and apoptosis in diabetes. Dapagliflozin (DAPA), a novel hypoglycaemic drug, has been shown to have anti-apoptotic, anti-inflammatory, and antioxidant effects in multiple experimental studies. In this study, we investigated the protective effects of DAPA in the hyperglycaemic condition to identify associated molecular mechanisms. human umbilical vein endothelial cells (HUVEC) endothelial cells were treated with 40 mM glucose for 72 h to establish an in vitro high glucose (HG) condition model, and then additional groups co-treated with or without DAPA before glucose treatment. Then, cell viability, reactive oxygen species (ROS), pro-inflammatory cytokines (IL-6 and TNF-α), apoptosis, and SIRT1 expression were measured. The results showed that DAPA pretreatment resulted in increased cell viability. Additionally, DAPA pretreatment decreased endothelial ROS, IL-6, and TNF-α levels in endothelial cells subjected to HG conditions. Moreover, DAPA pretreatment significantly prevented HG-induced apoptosis and caspase-3 activity in HUVECs. Furthermore, DAPA increased the expression of SIRT1, PGC-1α, and increased the phosphorylation levels of AMPK (p-AMPK) in a set of HG conditions in HUVECs. However, the endothelial protective effects of DAPA were abolished when cells were subjected to the SIRT1 inhibitor (EX-527) and AMPK inhibitor (Compound C). These findings suggest that DAPA can abrogate HG-induced endothelial cell dysfunction by AMPK/SIRT1 pathway up-regulation. Therefore, suggesting that the activation of AMPK/SIRT1 axis by DAPA may be a novel target for the treatment of HG-induced endothelial cell injury. © 2022 John Wiley & Sons Australia, Ltd.