Dulaglutide inhibits high glucose- induced endothelial dysfunction and NLRP3 inflammasome activation

• Published in: Archives of biochemistry and biophysics 2019-08, Vol.671, p.203-209
• Main Authors: Luo, Xiaojia, Hu, Yongmei, He, Sen, Ye, Qiran, Lv, Zhengbing, Liu, Jianxiong, Chen, Xiaoping
• Format: Article
• Language: English
• Subjects: CARD Signaling Adaptor Proteins - metabolism; Cardiovascular diseases; Carrier Proteins - metabolism; Caspase 1 - metabolism; Dulaglutide; Endothelial Cells - drug effects; Endothelial dysfunction; Glucagon-Like Peptides - analogs & derivatives; Glucagon-Like Peptides - pharmacology; Glucose - pharmacology; Human Umbilical Vein Endothelial Cells; Humans; IL-18; Immunoglobulin Fc Fragments - pharmacology; Inflammasomes - drug effects; Inflammasomes - metabolism; L-Lactate Dehydrogenase - metabolism; NADPH Oxidase 4 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Oxidative Stress - drug effects; Protein Carbonylation - drug effects; Reactive Oxygen Species - metabolism; Recombinant Fusion Proteins - pharmacology; Sirtuin 1 - metabolism; Type 2 diabetes mellitus
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2019.07.008

Activation of the NLRP3 inflammasome plays an important role in high glucose- induced endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). Dulaglutide, a newly developed glucagon-like peptide-1 receptor (GLP-1R) agonist, has been approved for the management of T2DM. In the current study, we aimed to investigate whether dulaglutide possesses a protective effect against high glucose- induced activation of the NLRP3 inflammasome. Our results indicate that dulaglutide treatment prevented high glucose- induced generation of reactive oxygen species (ROS) and protein carbonyl, as well as the expression of NADPH oxidase 4 (NOX-4) in human umbilical vein endothelial cells (HUVECs). Dulaglutide treatment could inhibit high glucose- induced release of lactate dehydrogenase (LDH) and the expression of TXNIP. Dulaglutide suppressed high glucose- induced activation of NLRP3 inflammasome by reducing the expression of NLRP3, ASC, and cleaved caspase 1 (P10). Notably, dulaglutide treatment suppressed high glucose- induced maturation of IL-1β and IL-18. Mechanistically, our findings indicate that SIRT1 was involved in this process by showing that knockdown of SIRT1 by transfection with SIRT1 siRNA abolished the inhibitory effects of dulaglutide on IL-1β and IL-18 secretion via suppression of NLRP3, ASC, and p10. These data suggest that dulaglutide might serve as a potential drug for the treatment of cardiovascular complications in T2DM patients.