Dapagliflozin exerts anti-inflammatory effects via inhibition of LPS-induced TLR-4 overexpression and NF-κB activation in human endothelial cells and differentiated macrophages

• Published in: European journal of pharmacology 2022-03, Vol.918, p.174715-174715, Article 174715
• Main Authors: Abdollahi, Elaheh, Keyhanfar, Fariborz, Delbandi, Ali-Akbar, Falak, Reza, Hajimiresmaiel, Seyed Javad, Shafiei, Massoumeh
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - pharmacology; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - immunology; Atherosclerosis - pathology; Benzhydryl Compounds - pharmacology; Dapagliflozin; Gene Expression Regulation - drug effects; Glucosides - pharmacology; High glucose; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - immunology; Humans; HUVECs; Hypoglycemic Agents - pharmacology; Inflammation Mediators - antagonists & inhibitors; Macrophage Activation - drug effects; Macrophage polarization; Macrophages - drug effects; Macrophages - immunology; NF-kappa B - metabolism; SGLT-2 inhibitor; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Toll-Like Receptor 4 - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174715

Evidence has demonstrated that a new class of anti-diabetic drugs, sodium-glucose co-transporter 2 (SGLT2) inhibitors, could exert beneficial effects on atherosclerotic complications of diabetes. Atherosclerosis is widely accepted as an inflammatory disease. Therefore, we aimed to assess the direct anti-inflammatory effects of SGLT2 inhibitors dapagliflozin (DAPA) on two cell types involved in the process of atherogenesis. Human umbilical vein endothelial cells (HUVECs) and macrophages were exposed to DAPA and lipopolysaccharide (LPS 20 ng/mL) for 24 h under normal (5.5 mmol/L, NG) or high glucose (25 mmol/L, HG) conditions. Then, levels of TLR-4/p–NF–κB, inflammatory cytokines, inflammation-related miR-146a and miR-155 as well as alteration in the ratio of M1/M2 macrophage polarization was assessed. DAPA (0.5 μM) could significantly attenuate LPS-induced TLR-4 overexpression (23.9% and 33.1% under NG and HG conditions in HUVECs and 53.3% and 52.4% under NG and HG states in macrophages, respectively). NF-κB p65 phosphorylation was also significantly decreased to 30.1% under NG condition in HUVECs and 51.9% and 34.5% under NG and HG states in macrophages by 0.5 μM DAPA. Moreover, DAPA elevated expression levels of anti-inflammatory miR-146a, while values of miR-155 decreased in those cells. DAPA also caused a shift from inflammatory M1 macrophages toward M2-dominant macrophages. These data suggest that regardless of glucose concentrations, DAPA could exert direct anti-inflammatory effects, at least partly, by inhibiting the expression of TLR-4 and activation of NF-κB along with the secretion of pro-inflammatory mediators. [Display omitted] •Dapagliflozin attenuated expression of TLR-4 and p–NF–κB p65 in HUVECs and macrophages.•Dapagliflozin reduced secretion of inflammatory cytokines from HUVECs and macrophages.•Dapagliflozin increased expression levels of anti-inflammatory miR-146a.•Dapagliflozin decreased values of pro-inflammatory miR-155.•Dapagliflozin promoted M2 but restraining M1 macrophage phenotype polarization.