一种二肽基肽酶-4 抑制剂，去氟西他滨，可改善载脂蛋白 E 缺陷小鼠的内皮功能并减少动脉粥样硬化病变的形成。

A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice.

机构信息

Department of Cardiovascular Medicine, Faculty of Life Sciences, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

出版信息

J Am Coll Cardiol. 2012 Jan 17;59(3):265-76. doi: 10.1016/j.jacc.2011.07.053.

DOI:10.1016/j.jacc.2011.07.053

PMID:22240132

Abstract

OBJECTIVES

The aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS).

BACKGROUND

The new class of anti-type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1.

METHODS

Endothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E-deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease.

RESULTS

DFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10(-4) mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001).

CONCLUSIONS

A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium.

摘要

目的

本研究旨在探讨二肽基肽酶-4 抑制剂地氟列汀（DFS）的抗动脉粥样硬化作用。

背景

新型抗 2 型糖尿病药物二肽基肽酶-4 抑制剂通过增加活性胰高血糖素样肽（GLP）-1 的水平来改善葡萄糖代谢。

方法

通过用乙酰胆碱诱导主动脉环内皮依赖性血管舒张来检测内皮功能，并在喂食高脂肪饮食的载脂蛋白 E 缺陷小鼠的整个主动脉中观察动脉粥样硬化病变的发展，同时在培养的人巨噬细胞和内皮细胞中研究 DFS 的抗动脉粥样硬化作用。测量有或无冠心病患者的血浆中活性 GLP-1 的水平。

结果

与载体处理相比，DFS 可显著改善内皮功能障碍（10-4mol/L 乙酰胆碱时的舒张率为 89.9%±3.9%，p<0.05），同时伴有内皮型一氧化氮合酶磷酸化增加和动脉粥样硬化病变面积减少（17.7%[15.6%至 25.8%]比 24.6%[19.3%至 34.6%]，p<0.01）。在培养的人巨噬细胞中，DFS 与 GLP-1 单独使用相比，显著增加 GLP-1 诱导的环磷酸腺苷胞质水平，通过环磷酸腺苷/蛋白激酶 A 途径抑制 c-jun N-末端激酶和细胞外信号调节激酶 1/2 和核因子-κB p65 的核转位，并抑制促炎细胞因子（即白细胞介素-1β、白细胞介素-6 和肿瘤坏死因子-α）和单核细胞趋化蛋白-1 的产生对脂多糖的反应。与 GLP-1 单独使用相比，DFS 增强的 GLP-1 活性可维持内皮一氧化氮合酶磷酸化并减少内皮衰老和凋亡。在人类研究中，冠心病患者的空腹活性 GLP-1 水平明显低于无冠心病患者（3.10pmol/L[2.40 至 3.62pmol/L]比 4.00pmol/L[3.10 至 5.90pmol/L]，p<0.001）。