Dasatinib suppresses atherosclerotic lesions by suppressing cholesterol uptake in a mouse model of hypercholesterolemia

• Material Type: 博士論文
• Title: Dasatinib suppresses atherosclerotic lesions by suppressing cholesterol uptake in a mouse model of hypercholesterolemia
• Author/Editor: 髙羽, 理光
• Author Heading: 髙羽, 理光
• Publication Date: 2022-07
• Publication Date (W3CDTF): 2022-07
• Alternative Title: 高脂血症モデルマウスにおいてダサチニブはコレステロールの取り込みを抑制し動脈硬化病変を抑制する
• Degree grantor/type: 浜松医科大学
• Date Granted: 2022-09-16
• Date Granted (W3CDTF): 2022-09-16
• Dissertation Number: 甲第915号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Atherosclerosis; Cardiovascular event; Cd36; Dasatinib; Sortilin
• Target Audience: 一般
• Note (General): doctoral; 医学系研究科; Although the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia is known to cause vascular adverse events (VAEs), the frequency of VAEs during dasatinib administration is not high, and the same holds for atherosclerosis-related VAEs. However, its effect on atherosclerosis remains controversial. In this study, our primary objective was to investigate how dasatinib affects atherosclerosis. Ldlr-/-/Apobec1-/- mice, which are highly prone to develop atherosclerosis, were administered dasatinib. After 16 weeks, we evaluated their atherosclerotic lesions. We used bone-marrow-derived macrophages to investigate the uptake of oxidized low-density lipoprotein (LDL) complexed with DiI dye (DiI-oxLDL). RNA sequencing and quantitative reverse transcription polymerase chain reaction (RTqPCR) were performed to explore the potential effects of dasatinib on cholesterol metabolism. Dasatinib administration significantly reduced atherosclerotic lesions (P<0.001 and P=0.013) and DiI-oxLDL uptake (P<0.001) unlike other TKIs. RNA sequencing and RT-qPCR suggested that Sort1, which encodes sortilin, a known regulator of LDL uptake, and Cd36 were potential targets of dasatinib. In conclusion, dasatinib induced elevated LDL-C levels, but oxLDL uptake in macrophages were suppressed, resulting in reducing atherosclerotic lesions. These results further our understanding of the differences in VAEs between dasatinib and other TKIs.
• Persistent ID (NDL): info:ndljp/pid/12694248; https://dl.ndl.go.jp/pid/12694248
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2023-03-07T16:07:55+09:00
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
• Availability of remote photoduplication service: 可
• Periodical Title (URI): http://hdl.handle.net/10271/00004269; https://hama-med.repo.nii.ac.jp/records/4147
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp

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