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

Korean Circulation Journal 2020년 50권 5호 p.443 ~ 457
이슬기, 이승준, Lee Jung-Jae, 김정순, 이오현, 김충기, 김다래, 이영호, 오재원, 박세일, 전옥희, 홍성진, 안철민, 김병극, 고영국, 최동훈, 홍명기, 장양수,
소속 상세정보
이슬기 ( Lee Seul-Gee ) - Yonsei University College of Medicine Yonsei Cardiovascular Research Institute
이승준 ( Lee Seung-Jun ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
 ( Lee Jung-Jae ) - Yonsei University Graduate Program in Science for Aging
김정순 ( Kim Jung-Sun ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
이오현 ( Lee Oh-Hyun ) - Yonsei University College of Medicine Yongin Severance Hospital Division of Cardiology
김충기 ( Kim Choong-Ki ) - Hanyang University Seoul Hospital Department of Cardiology
김다래 ( Kim Da-Rae ) - Sungkyunkwan University School of Medicine Samsung Medical Center Department of Medicine
이영호 ( Lee Yong-Ho ) - Yonsei University College of Medicine Severance Hospital Department of Internal Medicine
오재원 ( Oh Jae-Won ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
박세일 ( Park Se-Il ) - Yonsei University College of Medicine Cardiovascular Product Evaluation Center
전옥희 ( Jeon Ok-Hee ) - Yonsei University College of Medicine Cardiovascular Product Evaluation Center
홍성진 ( Hong Sung-Jin ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
안철민 ( Ahn Chul-Min ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
김병극 ( Kim Byeong-Keuk ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
고영국 ( Ko Young-Guk ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
최동훈 ( Choi Dong-Hoon ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
홍명기 ( Hong Myeong-Ki ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology
장양수 ( Jang Yang-Soo ) - Yonsei University College of Medicine Severance Cardiovascular Hospital Division of Cardiology

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.

키워드

Atherosclerosis; Sodium-glucose transporter-2; Sodium-glucose transporter 2 inhibitors; Macrophages

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