Objective To investigate the effect of dapagliflozin on the formation of atherosclerosis (AS) in apolipoprotein E knockout (ApoE^{- / -}) mice and the mechanism associated with sodium-hydrogen exchanger 1 (NHE1). Methods 24 6-week-old male ApoE^{- / -} mice were randomly divided into ordinary diet group, high-fat diet group, high-fatdiet+dapagliflozin group (10 mg / (kg·d) gavage) and high-fat diet+glimepiride group (0. 5 mg / ( kg·d) gavage). AS plaques in mouse aorta was observed by using HE staining after 8 weeks. The expression of sodium-glucose cotransporter 2 (SGTL2) in the aorta was measured by quantitative PCR and Western blot. NHE1 expression was detected by immunohistochemistry. Then, mouse macrophage cell line RAW 264. 7 cells were treated with dapagliflozin (10 μmol / L), amiloride (20 μmol / L) and lipopolysaccharide (100 ng / mL) for 24 h. The expression of NHE1 protein was analyzed by Western blot. The recovery rate ( NHE1 activity) from the NH4Cl-induced acid load was assayed by SNARF-1/ AM fluorescence method. TNF-α, IL-1β, IL-6, IL-10 secretion were determined by enzyme-linked immunosorbent assay. Results The AS plaque area in the aorta of the high-fat diet+dapagliflozin group was significantly lower than that of the high-fat diet group (P<0. 05). The expression of SGLT2 in the aortic plaques of each group was significantly decreased (P<0. 05). The plaque NHE1 expression in the high-fat diet+dapagliflozin group was lower than that in the high-fat diet group (P<0. 05). Compared with the LPS group, the LPS+dapagliflozin group had a significantly lower NHE1 protein level in the RAW 264. 7 cells ( P< 0. 05). SNARF-1 fluorescence assay indicated dapagliflozin inhibited NHE1 activity with decreasing intracellular pH (P<0. 05). ELISA showed that the contents of TNF-α, IL-1β and IL-6 in the cell supernatant were significantly decreased, whereas the content of IL-10 was significantly increased ( P< 0. 05 ). Conclusions Dapagliflozin inhibits AS plaque development and cytokine release by inhibiting NHE1 expression and its activity.