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

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)-? 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-? 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.

SUBMITTER: Lee SG

PROVIDER: S-EPMC7098824 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Lee Seul Gee SG Lee Seung Jun SJ Lee Jung Jae JJ Kim Jung Sun JS Lee Oh Hyun OH Kim Choong Ki CK Kim Darae D Lee Yong Ho YH Oh Jaewon J Park Seil S Jeon Ok Hee OH Hong Sung Jin SJ Ahn Chul Min CM Kim Byeong Keuk BK Ko Young Guk YG Choi Donghoon D Hong Myeong Ki MK Jang Yangsoo Y

Korean circulation journal 20200212 5

<h4>Background and objectives</h4>We sought to investigate an anti-atherosclerotic and anti-inflammatory effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in normoglycemic atherosclerotic rabbit model.<h4>Methods</h4>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 gr ...[more]

PMID: 32153145

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Project description:BackgroundSGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late-INa) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-INa.MethodsElectrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question.ResultsThe SGLT2 inhibitor empagliflozin reduced late-INa in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations R1623Q or ΔKPQ. Empagliflozin, dapagliflozin, and canagliflozin are all potent and selective inhibitors of H2O2-induced late-INa (half maximal inhibitory concentration = 0.79, 0.58, and 1.26 µM, respectively) with little effect on peak sodium current. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-INa activator veratridine in a similar manner to tetrodotoxin, ranolazine, and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a three-dimensional homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia.ConclusionsOur results provide evidence that late-INa may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.

Dataset Information

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

Publications

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

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