The DPP-4 inhibitor sitagliptin attenuates the progress of atherosclerosis in apolipoprotein-E-knockout mice via AMPK- and MAPK-dependent mechanisms.
The DPP-4 inhibitor sitagliptin attenuates the progress of atherosclerosis in apolipoprotein-E-knockout mice via AMPK- and MAPK-dependent mechanisms.
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DOI：
10.1186/1475-2840-13-32
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发表时间：
2014-02-04
影响因子：
9.3
通讯作者：
Xue Y
中科院分区：
文献类型：
--
作者：
Zeng Y;Li C;Guan M;Zheng Z;Li J;Xu W;Wang L;He F;Xue Y
二肽基肽酶-4抑制剂西格列汀是一种新型抗糖尿病药物，它通过增加胰高血糖素样肽-1的活性和作用时间而有效地治疗2型糖尿病。由于动脉粥样硬化是糖尿病心血管并发症的主要病理特征，因此研究西格列汀的抗动脉粥样硬化作用并探讨其相关机制具有重要意义。雄性载脂蛋白E基因敲除小鼠随机分为两组，分别饲喂高脂饲料(HFD)或高脂饲料加西格列汀(0.3%)，连续16周。测定体重、摄食量、血糖、血脂和黏附分子。用苏丹红染色和免疫组织化学方法分析动脉粥样硬化斑块面积及其组织学组成。用定量聚合酶链式反应和免疫印迹法分别检测主动脉炎症细胞因子(单核细胞趋化蛋白-1和白介素6)的表达及AMP-激活蛋白激酶(AMPK)和丝裂原活化蛋白激酶(MAPK)的激活。西格列汀治疗组小鼠动脉粥样硬化斑块形成较对照组少(7.64 ± 1.98%vs 12.91 ± 1.15%，p <； 0.001)，特别是在主动脉弓和腹主动脉，斑块分别减少了1.92倍和2.74倍(p <； 0.05和p <； 0.01)。西格列汀显著降低斑块中胶原纤维的含量(p <； )。此外，西格列汀显著降低主动脉单核细胞趋化蛋白-1和白介素6的表达(p <； 0.01和p <； 0.05)，以及血清可溶性血管细胞黏附分子-1和P-选择素的水平(p <； 0.05)。此外，西替格列汀可诱导主动脉AMPK和Akt的磷酸化(p <； 0.0 5和p <； 0.0 1)，而抑制p38和细胞外信号调节蛋白(ERK)1/2的磷酸化(p <； 0.0 5和p <； 0.0 1)。我们目前的研究表明，西格列汀可能通过调节AMPK和MAPK通路，从而减少白细胞与内皮细胞的相互作用和炎症反应，从而缩小动脉粥样硬化病变的面积。这些作用不依赖于减肥和降血糖的效果。
The dipeptidyl peptidase-4 inhibitor sitagliptin, a new anti-diabetic medicine, is effective in treating type 2 diabetes mellitus by increasing the activation and duration of action of glucagon-like peptide-1. Since atherosclerosis is the main pathological feature of diabetic cardiovascular complications, it is important to investigate the anti-atherosclerotic effect of sitagliptin and explore the relevant mechanisms. Male apolipoprotein-E-knockout mice were randomly divided into two groups and fed either high-fat diet (HFD) or HFD plus sitagliptin at a concentration of 0.3% for 16 weeks. Body weight, food intake, blood glucose, serum lipids and adhesion molecules were measured. The atherosclerotic plaque area and its histological composition were analyzed using Sudan staining and immunohistochemistry. The expression of inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6) and the activation of AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) in the aortas were determined using quantitative polymerase chain reaction and western blot, respectively. Mice treated with sitagliptin developed fewer atherosclerotic plaques than the control group (7.64 ± 1.98% vs 12.91 ± 1.15%, p < 0.001), particularly in the aortic arch and abdominal aorta, where plaques were decreased 1.92- and 2.74-fold, respectively (p < 0.05 and p < 0.01). Sitagliptin significantly reduced the content of collagen fiber in plaques 1.2-fold (p < 0.05). Moreover, sitagliptin significantly reduced the expression of monocyte chemoattractant protein-1 and interleukin-6 in the aorta (p < 0.01 and p < 0.05), as well as the serum levels of soluble vascular cell adhesion molecule-1 and P-selectin (both p < 0.05). In addition, Sitagliptin induced phosphorylation of AMPK and Akt (p < 0.05 and p < 0.01), while suppressed phosphorylation of p38 and extracellular signal-regulated kinase (Erk) 1/2 (p < 0.05 and p < 0.01) in aortas. Our present study indicates that sitagliptin can reduce the area of the atherosclerotic lesion, possibly by regulating the AMPK and MAPK pathways and then reducing leukocyte –endothelial cell interaction and inflammation reactions. These actions are independent of weight loss and glucose-reducing effects.
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影响因子：
16.2
作者：
Dicker D
通讯作者：
Dicker D
西他列汀超出血糖控制的影响：关注生活质量。
影响因子：
9.3
作者：
Sakamoto Y;Oyama J;Ikeda H;Kuroki S;Gondo S;Iwamoto T;Uchida Y;Kodama K;Hiwatashi A;Shimomura M;Taguchi I;Inoue T;Node K;S-DOG investigators
通讯作者：
S-DOG investigators
影响因子：
16.2
作者：
Luft VC;Schmidt MI;Pankow JS;Hoogeveen RC;Couper D;Heiss G;Duncan BB;Atherosclerosis Risk in Communities Investigators
通讯作者：
Atherosclerosis Risk in Communities Investigators
影响因子：
4.5
作者：
Kubota Y;Miyamoto M;Takagi G;Ikeda T;Kirinoki-Ichikawa S;Tanaka K;Mizuno K
通讯作者：
Mizuno K
影响因子：
1.8
作者：
Choi, Min-Koo;Jin, Qing-Ri;Song, Im-Sook
通讯作者：
Song, Im-Sook