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ID 110139
Title Alternative
DPP-4阻害薬のひとつリナグリプチンは,正常血糖アポリポ蛋白E欠損マウスにおける血管内皮機能を改善し,動脈硬化を抑制する
Author
Salim, Hotimah Masdan Tokushima University
Higashikuni, Yasutomi The University of Tokyo
Tanaka, Kimie The University of Tokyo
Hirata, Yoichiro The University of Tokyo
Keywords
DPP-4 inhibitor
Endothelial function
GLP-1
Inflammation
Linagliptin
Oxidative stress
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Vascular Pharmacology
ISSN
15371891
NCID
AA11703926
AA12726778
Publisher
Elsevier
Volume
79
Start Page
16
End Page
23
Published Date
2015-08-13
Remark
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨:LID201705191026.pdf
論文本文:k3007_fulltext.pdf
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。
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3007号
Diploma Number
甲医第1311号
Granted Date
2017-03-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences