Angiogenesis inhibitor-specific hypertension increases the risk of developing aortic dissection

• Material Type: 博士論文
• Title: Angiogenesis inhibitor-specific hypertension increases the risk of developing aortic dissection
• Author/Editor: Tsujinaka, Kaito; Izawa-Ishizawa, Yuki; Miyata, Koji; Yoshioka, Toshihiko; Oomine, Kohei; Nishi, Honoka; Kondo, Masateru; Itokazu, Syuto; Miyata, Tatsumi; Niimura, Takahiro; Sato, Maki; Aizawa, Fuka; Yagi, Kenta; Chuma, Masayuki; Zamami, Yoshito; Goda, Mitsuhiro; Ishizawa, Keisuke
• Author Heading: Tsujinaka, Kaito; Izawa-Ishizawa, Yuki; Miyata, Koji; Yoshioka, Toshihiko; Oomine, Kohei; Nishi, Honoka; Kondo, Masateru; Itokazu, Syuto; Miyata, Tatsumi; Niimura, Takahiro; Sato, Maki; Aizawa, Fuka; Yagi, Kenta; Chuma, Masayuki; Zamami, Yoshito; Goda, Mitsuhiro; Ishizawa, Keisuke
• Publication, Distribution, etc.: Elsevier
• Publication Date: 2023-09-16
• Publication Date (W3CDTF): 2023-09-16
• Alternative Title: 血管新生阻害剤特異的な高血圧は大動脈解離発症のリスクを高める
• Periodical title: Biomedicine & Pharmacotherapy
• No. or year of volume/issue: 167
• Volume: 167
• Pages: 115504-
• ISSN (Periodical Title): ISSN : 0753-3322; ISSN : 1950-6007
• Degree grantor/type: 徳島大学
• Date Granted: 2024-03-22
• Dissertation Number: 甲第3798号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Angiogenesis inhibitors; Aortic dissection; Real-world database; Hypertension; FDA Adverse Event Reporting System
• Target Audience: 一般
• Note (General): Aortic dissection is an adverse event of angiogenesis inhibitors; however, the association between the drugs and aortic dissection is unclear. Therefore, we investigated if and how angiogenesis inhibitors increase the onset of aortic dissection using pharmacologically-induced aortic dissection-prone model (LAB) mice, cultured endothelial cells, and real-world databases, which is a novel integrated research approach. Disproportionality analysis was performed and calculated using the reporting odds ratio as a risk signal using a worldwide database of spontaneous adverse events to estimate the risk of adverse events. Angiogenesis inhibitors, but not other hypertension-inducing drugs, showed significant risk signals for aortic aneurysms and dissection. A retrospective cohort analysis using JMDC, a medical receipt database in Japan, showed that the history of atherosclerosis and dyslipidemia, but not hypertension, were significantly associated with the onset of aortic dissection during angiogenesis inhibitor medication administration. For in vivo studies, sunitinib (100 mg/kg/day) was administered to LAB mice. Sunitinib increased systolic blood pressure (182 mmHg vs. 288 mmHg with sunitinib; p＜0.01) and the incidence of aortic dissection (40% vs. 59% with sunitinib; p = 0.34) in mice. In vivo and in vitro studies revealed that sunitinib increased endothelin-1 expression and induced endothelial cell damage evaluated by intracellular- and vascular cell adhesion molecule-1 expressions. The increased risk of developing aortic dissection with angiogenesis inhibitors is associated with the development of drug-specific hypertension via endothelial cell damage and endothelin-1 expression. Our findings are invaluable in establishing safer anticancer therapies and strategies to prevent the development of vascular toxicity in high-risk patients.
• Access Restrictions: インターネット公開
• Rights (production): This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• Related Material (DOI): 10.1016/j.biopha.2023.115504
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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http://repo.lib.tokushima-u.ac.jp/files/public/11/119327/20240502144643414220/k3798_abstract.pdf fulltext

http://repo.lib.tokushima-u.ac.jp/files/public/11/119327/20240502144643505467/k3798_review.pdf fulltext

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