期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 918, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174715
关键词
Atherosclerosis; Dapagliflozin; SGLT-2 inhibitor; High glucose; HUVECs; Macrophage polarization
Evidence suggests that the new class of anti-diabetic drugs, SGLT2 inhibitors, can have beneficial effects on atherosclerotic complications of diabetes. This study aimed to evaluate the direct anti-inflammatory effects of the SGLT2 inhibitor dapagliflozin (DAPA). The results showed that DAPA could attenuate inflammation by inhibiting the expression of TLR-4 and activation of NF-kappa B, as well as shifting macrophage polarization from an inflammatory state to an anti-inflammatory state.
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 athemgenesis. 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-kappa B, 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 mu M) 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-kappa B 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 mu M 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-kappa B along with the secretion of pro-inflammatory mediators.
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