Dapagliflozin attenuates high glucose-induced endothelial cell apoptosis and inflammation through AMPK/SIRT1 activation.
AMP-Activated Protein Kinases
/ metabolism
Anti-Inflammatory Agents
/ pharmacology
Apoptosis
Benzhydryl Compounds
Glucose
/ metabolism
Glucosides
Human Umbilical Vein Endothelial Cells
Humans
Hyperglycemia
/ metabolism
Inflammation
/ drug therapy
Interleukin-6
/ metabolism
Oxidative Stress
Reactive Oxygen Species
/ metabolism
Sirtuin 1
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
Dapagliflozin
HUVECs
ROS
SIRT1
high glucose
Journal
Clinical and experimental pharmacology & physiology
ISSN: 1440-1681
Titre abrégé: Clin Exp Pharmacol Physiol
Pays: Australia
ID NLM: 0425076
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
revised:
30
10
2021
received:
20
06
2021
accepted:
18
11
2021
pubmed:
12
3
2022
medline:
26
5
2022
entrez:
11
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35274762
doi: 10.1111/1440-1681.13638
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Benzhydryl Compounds
0
Glucosides
0
Interleukin-6
0
Reactive Oxygen Species
0
Tumor Necrosis Factor-alpha
0
dapagliflozin
1ULL0QJ8UC
AMP-Activated Protein Kinases
EC 2.7.11.31
SIRT1 protein, human
EC 3.5.1.-
Sirtuin 1
EC 3.5.1.-
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
643-651Informations de copyright
© 2022 John Wiley & Sons Australia, Ltd.
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