Anti-Inflammatory Effect for Atherosclerosis Progression by Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitor in a Normoglycemic Rabbit Model

Background and Objectives: We sought to investigate an anti-atherosclerotic and antiinflammatory effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in normoglycemic atherosclerotic rabbit model. Methods: Male New Zealand white rabbits (n=26) were fed with a 1% high-cholesterol diet for 7 weeks followed by normal diet for 2 weeks. After balloon catheter injury, the rabbits were administered with the Dapagliflozin (1mg/kg/day) or control-medium for 8 weeks (n=13 for each group). All lesions were assessed with angiography, optical coherence tomography (OCT), and histological assessment. Results: Atheroma burden (38.51 +/- 3.16% vs. 21.91 +/- 1.22%, p<0.01) and lipid accumulation (18.90 +/- 3.63% vs. 10.20 +/- 2.03%, p=0.047) was significantly decreased by SGLT-2 inhibitor treatment. The SGLT-2 inhibitor group showed lower macrophage infiltration (20.23 +/- 1.89% vs. 12.72 +/- 1.95%, p=0.01) as well as tumor necrosis factor (TNF)-alpha expression (31.17 +/- 4.40% vs. 19.47 +/- 2.10%, p=0.025). Relative area of inducible nitric oxide synthase' macrophages was tended to be lower in the SGLT-2 inhibitor-treated group (1.00 +/- 0.16% vs. 0.71 +/- 0.10%, p=0.13), while relative proportion of Arg1(+) macrophage was markedly increased (1.00 +/- 0.27% vs. 2.43 +/- 0.64%, p=0.04). As a result, progression of atherosclerosis was markedly attenuated in SGLT-2 inhibitor treated group (OCT area stenosis, 32.13 +/- 1.20% vs. 22.77 +/- 0.88%, p<0.01). Mechanistically, SGLT-2 treatment mitigated the inflammatory responses in macrophage. Especially, Toll-like receptor 4/nuclear factor-kappa B signaling pathway, and their downstream effectors such as interleukin-6 and TNF-alpha were markedly suppressed by SGLT-2 inhibitor treatment. Conclusions: These results together suggest that SGLT-2 inhibitor exerts an antiatherosclerotic effect through favorable modulation of inflammatory response as well as macrophage characteristics in non-diabetic situation.