Cardiology Group, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain.
Cardiovascular Area and Coronary Unit, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain.
Cardiovasc Res. 2018 Feb 1;114(2):336-346. doi: 10.1093/cvr/cvx186.
In patients with cardiovascular disease, epicardial adipose tissue (EAT) is characterized by insulin resistance, high pro-inflammatory chemokines, and low differentiation ability. As dapagliflozin reduces body fat and cardiovascular events in diabetic patients, we would like to know its effect on EAT and subcutaneous adipose tissue (SAT).
Adipose samples were obtained from 52 patients undergoing heart surgery. Sodium-glucose cotransporter 2 (SGLT2) expression was determined by real-time polymerase chain reaction (n = 20), western blot, and immunohistochemistry. Fat explants (n = 21) were treated with dapagliflozin and/or insulin and glucose transporters expression measured. Glucose, free fatty acid, and adipokine levels (by array) were measured in the EAT secretomes, which were then tested on human coronary endothelial cells using wound healing assays. Glucose uptake was also measured using the fluorescent glucose analogue (6NBDG) in differentiated stromal vascular cells (SVCs) from the fat pads (n = 11). Finally, dapagliflozin-induced adipocyte differentiation was assessed from the levels of fat droplets (AdipoRed staining) and of perilipin. SGLT2 was expressed in EAT. Dapagliflozin increased glucose uptake (20.95 ± 4.4 mg/dL vs. 12.97 ± 4.1 mg/dL; P < 0.001) and glucose transporter type 4 (2.09 ± 0.3 fold change; P < 0.01) in EAT. Moreover, dapagliflozin reduced the secretion levels of chemokines and benefited wound healing in endothelial cells (0.21 ± 0.05 vs. 0.38 ± 0.08 open wound; P < 0.05). Finally, chronic treatment with dapagliflozin improved the differentiation of SVC, confirmed by AdipoRed staining [539 ± 142 arbitrary units (a.u.) vs. 473 ± 136 a.u.; P < 0.01] and perilipin expression levels (121 ± 10 vs. 84 ± 11 a.u.).
Dapagliflozin increased glucose uptake, reduced the secretion of pro-inflammatory chemokines (with a beneficial effect on the healing of human coronary artery endothelial cells), and improved the differentiation of EAT cells. These results suggest a new protective pathway for this drug on EAT from patients with cardiovascular disease.
在心血管疾病患者中，心外膜脂肪组织 (EAT) 的特点是胰岛素抵抗、高促炎趋化因子和低分化能力。由于达格列净可降低糖尿病患者的体脂和心血管事件风险，我们想了解其对 EAT 和皮下脂肪组织 (SAT) 的影响。
对 52 例行心脏手术的患者进行脂肪样本采集。通过实时聚合酶链反应（n=20）、蛋白质印迹和免疫组化检测钠-葡萄糖共转运蛋白 2 (SGLT2) 的表达。用达格列净和/或胰岛素处理脂肪外植体（n=21），并测量葡萄糖转运体的表达。通过微阵列检测 EAT 分泌组中的葡萄糖、游离脂肪酸和脂肪因子水平，然后使用划痕愈合试验在人冠状动脉内皮细胞上进行检测。使用荧光葡萄糖类似物（6NBDG）还测量了分化的基质血管细胞（SVCs）中的葡萄糖摄取（n=11）。最后，通过脂肪滴（AdipoRed 染色）和 perilipin 的水平评估达格列净诱导的脂肪细胞分化。EAT 中表达 SGLT2。达格列净增加了 EAT 的葡萄糖摄取（20.95±4.4mg/dL 比 12.97±4.1mg/dL；P<0.001）和葡萄糖转运蛋白 4（2.09±0.3 倍变化；P<0.01）。此外，达格列净降低了趋化因子的分泌水平，并有益于内皮细胞的伤口愈合（0.21±0.05 比 0.38±0.08 开放伤口；P<0.05）。最后，达格列净的慢性治疗通过 AdipoRed 染色证实改善了 SVC 的分化[539±142 任意单位（a.u.）比 473±136 a.u.；P<0.01]和 perilipin 表达水平（121±10 比 84±11 a.u.）。
达格列净增加了葡萄糖摄取，减少了促炎趋化因子的分泌（对人冠状动脉内皮细胞的愈合有有益作用），并改善了 EAT 细胞的分化。这些结果表明，这种药物对心血管疾病患者的 EAT 具有新的保护途径。
