Salim, Hotimah Masdan Tokushima University
Higashikuni, Yasutomi The University of Tokyo
Tanaka, Kimie The University of Tokyo
Hirata, Yoichiro The University of Tokyo
Soeki, Takeshi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Sata, Masataka Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Thesis or Dissertation
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 b 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 b 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 eNOSSer1177 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.
本論文は, 著者Hotimah Masdan Salimの学位論文として提出され, 学位審査・授与の対象となっている。
|DOI (Published Version)|
|URL ( Publisher's Version )|
LID201705191026.pdf 366 KB
k3007_fulltext.pdf 1.1 MB
|MEXT report number||
Doctor of Medical Science