The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE-/- Mice

被引：143

作者：

Leng, Weiling ^{[1
]}

Ouyang, Xinshou ^{[2
]}

Lei, Xiaotian ^{[1
]}

Wu, Mingxia ^{[1
]}

Chen, Liu ^{[1
]}

Wu, Qinan ^{[1
]}

Deng, Wuquan ^{[1
]}

Liang, Ziwen ^{[1
]}

机构：

[1] Third Mil Med Univ, Dept Endocrinol, Affiliated Hosp 1, Chongqing 400038, Peoples R China

[2] Yale Univ Med, Sect Digest Dis, Dept Internal Med, New Haven, CT 06520 USA

来源：

MEDIATORS OF INFLAMMATION | 2016年 / 2016卷

基金：

中国国家自然科学基金;

关键词：

INADEQUATE GLYCEMIC CONTROL; INFLAMMATION; WEIGHT;

D O I：

10.1155/2016/6305735

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Background. Our study aimed to observe the effect of sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin on diabetic atherosclerosis and investigate the subsequent mechanism. Methods. Aortic atherosclerosis was induced in streptozotocin induced diabetic ApoE(-/-) mice by feeding with high-fat diet, and dapagliflozin was administrated intragastrically for 12 weeks as treatment. Effects of dapagliflozin on indices of glucose and fatmetabolism, IL-1 beta, IL-18, NLRP3 protein levels, and the reactive oxygen species (ROS) were measured. The atherosclerosis was evaluated by oil red O and hematoxylin-eosin staining. The effects of dapagliflozin on the IL-1 beta production in culturing primary macrophages of wild type and NLRP3(-/-)knockout mice were investigated for mechanism analyses. Results. Dapagliflozin treatment showed favorable effects on glucose and fat metabolism, partially reversed the formation of atherosclerosis, inhibited macrophage infiltration, and enhanced the stability of lesion. Also, reduced production of IL-1 beta, IL-18, NLRP3 protein, and mitochondrial ROS in the aortic tissues was detected with dapagliflozin treatment. In vitro, NLRP3 inflammasome was activated by hyperglucose and hyperlipid through ROS pathway. Conclusions. Dapagliflozin may be of therapeutic potential for diabetic atherosclerosis induced by high-fat diet, and these benefits may depend on the inhibitory effect on the secretion of IL-1 beta by macrophages via the ROS-NLRP3-caspase-1 pathway.

引用

页数：13

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