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ID 114201
Title Alternative
P2Y12阻害薬チカグレロールはアポリポ蛋白E欠損マウスの血管障害を軽減して動脈硬化形成を抑制する
Author
Ganbaatar, Byambasuren Tokushima University
Salim, Hotimah Masdan Tokushima University
Nishimoto, Sachiko Tokushima University
Tanaka, Kimie The University of Tokyo
Higashikuni, Yasutomi The University of Tokyo
Hirata, Yoichiro The University of Tokyo
Keywords
Atherosclerosis
Inflammation
Endothelial function
P2Y12
Ticagrelor
Content Type
Thesis or Dissertation
Description
Background and aims: Ticagrelor reduces cardiovascular events in patients with acute coronary syndrome (ACS). Recent studies demonstrated the expression of P2Y12 on vascular cells including endothelial cells, as well as platelets, and suggested its contribution to atherogenesis. We investigated whether ticagrelor attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein E-deficient (apoe-/-) mice.
Methods: Eight-week-old male apoe-/- mice were fed a western-type diet (WTD) supplemented with 0.1% ticagrelor (approximately 120 mg/kg/day). Non-treated animals on WTD served as control. Atherosclerotic lesions were examined by en-face Sudan IV staining, histological analyses, quantitative RT-PCR analysis, and western blotting. Endothelial function was analyzed by acetylcholine-dependent vasodilation using aortic rings. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments.
Results: Ticagrelor treatment for 20 weeks attenuated atherosclerotic lesion progression in the aortic arch compared with control (p < 0.05). Ticagrelor administration for 8 weeks attenuated endothelial dysfunction (p < 0.01). Ticagrelor reduced the expression of inflammatory molecules such as vascular cell adhesion molecule-1, macrophage accumulation, and lipid deposition. Ticagrelor decreased the phosphorylation of JNK in the aorta compared with control (p < 0.05). Ticagrelor and a JNK inhibitor ameliorated impairment of endothelium-dependent vasodilation by adenosine diphosphate (ADP) in wild-type mouse aortic segments. Furthermore, ticagrelor inhibited the expression of inflammatory molecules which were promoted by ADP in HUVEC (p < 0.001). Ticagrelor also inhibited ADP-induced JNK activation in HUVEC (p < 0.05).
Conclusions: Ticagrelor attenuated vascular dysfunction and atherogenesis through the inhibition of inflammatory activation of endothelial cells. These effects might be a potential mechanism by which ticagrelor decreases cardiovascular events in patients with ACS.
Journal Title
Atherosclerosis
ISSN
00219150
NCID
AA00553457
AA11522036
Publisher
Elsevier
Volume
275
Start Page
124
End Page
132
Published Date
2018-05-31
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Byambasuren Ganbaatar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3353号
Diploma Number
甲医第1436号
Granted Date
2020-03-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences