期刊
VASCULAR PHARMACOLOGY
卷 79, 期 -, 页码 16-23出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2015.08.011
关键词
DPP-4 inhibitor; Linagliptin; GLP-1; Endothelial function; Inflammation; Oxidative stress
资金
- JSPS Kakenhi [25460369, 25860586, 25860843, 23591314, 24659392, 22390159, 25670390, 25293184]
- MEXT KAKENHI Grant [21117007]
- Vehicle Racing Commemorative Foundation
- Boehringer Ingelheim, Japan [J171500100]
- Grants-in-Aid for Scientific Research [25860586, 24659392, 21117007, 25293184, 25860843, 25460369, 22390159] Funding Source: KAKEN
Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have vasoprotective effects. This study investigated whether a recently approved DPP-4 inhibitor, linagliptin (Lina), suppresses atherogenesis in non-diabetic apolipoprotein-E deficient (ApoE(-/-)) mice, and examined its effects on endothelial function. Methods and results: Lina (10 mg/kg/day) was administered orally to ApoE(-/-) mice for 20 weeks. Lina reduced atherogenesis without alteration of metabolic parameters including blood glucose level compared with control (P < 0.05). Results of immunohistochemical analyses and quantitative RT-PCR demonstrated that Lina significantly decreased inflammatory molecule expression and macrophage infiltration in the atherosclerotic aorta. Lina administration to ApoE(-/-) mice for 9 weeks ameliorated endothelium-dependent vasodilation compared with that in untreated mice. Plasma active glucagon-like peptide-1 (GLP-1) level was significantly higher in the treated group (P < 0.05). Exendin-4 (Ex-4), a GLP-1 analog, ameliorated endothelium-dependent vasodilation impaired by palmitic acid (PA) in wild-type mouse aortic segments. Ex-4 promoted phosphorylation of eNOS(Ser1177) and Akt, both of which were abrogated by PA, in human umbilical vein endothelial cells. In addition, Lina administration to ApoE(-/-) mice decreased oxidative stress, as determined by urinary 8-OHdG secretion and NADPH oxidase subunit expression in the abdominal aorta. Conclusion: Lina inhibited atherogenesis in non-diabetic ApoE(-/-) mice. Amelioration of endothelial dysfunction associated with a reduction of oxidative stress by GLP-1 contributes to the atheroprotective effects of Lina. (C) 2015 Elsevier Inc. All rights reserved.
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