A Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Improves Endothelial Function and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Deficient Mice

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• 作者：Junichi Matsubara ; MD ; PhD<sup>?/sup><sup> ; sup><sup>&sect ; sup> ; Seigo Sugiyama ; MD ; PhD<sup>?/sup><sup> ; sup><sup>ssugiyam@kumamoto-u.ac.jpsup> ; Koichi Sugamura ; MD ; PhD<sup>?/sup> ; Taishi Nakamura ; MD ; PhD<sup>&dagger ; sup> ; Yukio Fujiwara ; PhD<sup>&Dagger ; sup> ; Eiichi Akiyama ; MD<sup>?/sup> ; Hirofumi Kurokawa ; MD<sup>?/sup> ; Toshimitsu Nozaki ; MD ; PhD<sup>?/sup> ; Keisuke Ohba ; MD<sup>?/sup> ; Masaaki Konishi ; MD<sup>?/sup> ; Hirofumi Maeda ; MD<sup>?/sup> ; Yasuhiro Izumiya ; MD ; PhD<sup>?/sup> ; Koichi Kaikita ; MD ; PhD<sup>?/sup> ; Hitoshi Sumida ; MD ; PhD<sup>?/sup><sup> ; sup><sup>?/sup> ; Hideaki Jinnouchi ; MD ; PhD<sup>¶ ; sup><sup> ; sup><sup>#sup> ; Kunihiko Matsui ; MD ; PhD<sup>??sup> ; Shokei Kim-Mitsuyama ; MD ; PhD<sup>&dagger ; sup> ; Motohiro Takeya ; MD ; PhD<sup>&Dagger ; sup> ; Hisao Ogawa ; MD ; PhD<sup>?/sup>
• 关键词：atherosclerosis ; dipeptidyl peptidase-4 inhibitors ; endothelium ; glucagon-like peptide 1 receptor ; inflammation ; receptors
• 刊名：Journal of the American College of Cardiology
• 出版年：2012
• 出版时间：17 January, 2012
• 年：2012
• 卷：59
• 期：3
• 页码：265-276
• 全文大小：4084 K

文摘

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ss=""h4"">Objectives

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

ss=""h4"">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.

ss=""h4"">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.

ss=""h4"">Results

DFS significantly improved endothelial dysfunction (89.9 ¡À 3.9 % vs. 79.2 ¡À 4.3 % relaxation at 10<sup>?sup> 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).

ss=""h4"">Conclusions

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