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 anti-inflammatory 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)-α 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-α were markedly suppressed by SGLT-2 inhibitor treatment.


CONCLUSIONS
These results together suggest that SGLT-2 inhibitor exerts an anti-atherosclerotic effect through favorable modulation of inflammatory response as well as macrophage characteristics in non-diabetic situation.
['Lee|Seul Gee|SG|0000-0002-9176-3075', 'Lee|Seung Jun|SJ|0000-0002-9201-4818', 'Lee|Jung Jae|JJ|0000-0002-4478-1772', 'Kim|Jung Sun|JS|0000-0003-2263-3274', 'Lee|Oh Hyun|OH|0000-0001-7070-7720', 'Kim|Choong Ki|CK|0000-0001-5226-7290', 'Kim|Darae|D|0000-0003-3284-0904', 'Lee|Yong Ho|YH|0000-0002-6219-4942', 'Oh|Jaewon|J|0000-0002-4585-1488', 'Park|Seil|S|0000-0002-4949-8976', 'Jeon|Ok Hee|OH|0000-0002-5151-3653', 'Hong|Sung Jin|SJ|0000-0003-4893-039X', 'Ahn|Chul Min|CM|0000-0002-7071-4370', 'Kim|Byeong Keuk|BK|0000-0003-2493-066X', 'Ko|Young Guk|YG|0000-0001-7748-5788', 'Choi|Donghoon|D|0000-0002-2009-9760', 'Hong|Myeong Ki|MK|0000-0002-2090-2031', 'Jang|Yangsoo|Y|0000-0002-2169-3112']
Atherosclerosis Macrophages Sodium-glucose transporter 2 inhibitors Sodium-glucose transporter-2