Anti-inflammatory effect for atherosclerosis progression by sodium-glucose cotransporter 2 (SGLT-2) inhibitor in a normoglycemic rabbit model

Seul Gee Lee, Seung Jun Lee, Jung Jae Lee, Jung Sun Kim, Oh Hyun Lee, Choong Ki Kim, Darae Kim, Yong Ho Lee, Jaewon Oh, Seil Park, Ok Hee Jeon, Sung Jin Hong, Chul Min Ahn, Byeong Keuk Kim, Young Guk Ko, Donghoon Choi, Myeong Ki Hong, Yansoo Jang

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Abstract

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.

Original languageEnglish
Pages (from-to)443-457
Number of pages15
JournalKorean Circulation Journal
Volume50
Issue number5
DOIs
Publication statusPublished - 2020 Jan 1

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All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Lee, S. G., Lee, S. J., Lee, J. J., Kim, J. S., Lee, O. H., Kim, C. K., Kim, D., Lee, Y. H., Oh, J., Park, S., Jeon, O. H., Hong, S. J., Ahn, C. M., Kim, B. K., Ko, Y. G., Choi, D., Hong, M. K., & Jang, Y. (2020). Anti-inflammatory effect for atherosclerosis progression by sodium-glucose cotransporter 2 (SGLT-2) inhibitor in a normoglycemic rabbit model. Korean Circulation Journal, 50(5), 443-457. https://doi.org/10.4070/kcj.2019.0296