The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE(-/-) Mice.
The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE(-/-) Mice.
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DOI：
10.1155/2016/6305735
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发表时间：
2016
影响因子：
4.6
通讯作者：
Liang Z
中科院分区：
文献类型：
--
作者：
Leng W;Ouyang X;Lei X;Wu M;Chen L;Wu Q;Deng W;Liang Z
背景本研究旨在观察钠葡萄糖协同转运蛋白2（SGLT-2）抑制剂达格列净对糖尿病动脉粥样硬化的影响，并探讨其作用机制。方法.在链脲佐菌素诱导的糖尿病ApoE−/−小鼠中，通过喂食高脂饲料诱导主动脉粥样硬化，并灌胃给予达格列净12周作为治疗。测定达格列净对糖和脂肪代谢指标、IL-1β、IL-18、NLRP 3蛋白水平和活性氧（ROS）的影响。油红O染色和苏木精-伊红染色评价动脉粥样硬化。研究了达格列净对野生型和NLRP 3 −/−敲除小鼠培养的原代巨噬细胞中IL-1β产生的影响，以进行机制分析。结果达格列净治疗对糖和脂肪代谢有良好的影响，部分逆转动脉粥样硬化的形成，抑制巨噬细胞浸润，增强病变的稳定性。此外，在达格列净治疗中检测到主动脉组织中IL-1β、IL-18、NLRP 3蛋白和线粒体ROS的产生减少。高糖高脂通过ROS途径激活NLRP 3炎性小体。结论.达格列净可能对高脂饮食诱导的糖尿病动脉粥样硬化具有治疗潜力，这些益处可能取决于通过ROS-NLRP 3-caspase-1途径抑制巨噬细胞分泌IL-1β。
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 fat metabolism, IL-1β, 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-1β 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-1β, 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-1β by macrophages via the ROS-NLRP3-caspase-1 pathway.
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