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

Authors
 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  ;  Yangsoo Jang 
Citation
 KOREAN CIRCULATION JOURNAL, Vol.50(5) : 443-457, 2020-05 
Journal Title
 KOREAN CIRCULATION JOURNAL 
ISSN
 1738-5520 
Issue Date
2020-05
Keywords
Atherosclerosis ; Macrophages ; Sodium-glucose transporter 2 inhibitors ; Sodium-glucose transporter-2
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.
Files in This Item:
T202001998.pdf Download
DOI
10.4070/kcj.2019.0296
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Ko, Young Guk(고영국) ORCID logo https://orcid.org/0000-0001-7748-5788
Kim, Byeong Keuk(김병극) ORCID logo https://orcid.org/0000-0003-2493-066X
Kim, Jung Sun(김중선) ORCID logo https://orcid.org/0000-0003-2263-3274
Ahn, Chul Min(안철민)
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Jang, Yang Soo(장양수) ORCID logo https://orcid.org/0000-0002-2169-3112
Choi, Dong Hoon(최동훈) ORCID logo https://orcid.org/0000-0002-2009-9760
Hong, Myeong Ki(홍명기) ORCID logo https://orcid.org/0000-0002-2090-2031
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179231
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