Pathophysiological role of inflammatory and metabolic signals during aortic aneurysm formation in Marfan syndrome
| Project/Area Number |
19K08484
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | マルファン症候群 / 動脈瘤 / マクロファージ / TGFβシグナル / ロイスディーツ症候群 / 大動脈瘤 |
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| Outline of Research at the Start |
マルファン症候群やそのロイス・ディーツ症候群（LDS）は、若年で致死的大動脈瘤・解離症を発症する遺伝性難治疾患である。動脈壁では組織脆弱性とTGFβ受容体シグナルの亢進を認めるが、動脈瘤発症・進展に至る分子機構は明らかでない。マルファン外来での臨床研究から、重症例ほど炎症細胞の浸潤が多くエネルギー代謝に関わる転写因子Xの発現が低値であること、妊娠や僅かな生活習慣病リスクが大動脈解離発症の危険因子となることを見出した。これらは、LDSでのTGFβパラドックスや周産期大動脈解離の病態を解明するためのキー現象と疑っている。本課題では、慢性炎症とX依存性シグナル異常が動脈瘤進展に果たす役割を検証する。
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| Outline of Final Research Achievements |
Increased transforming growth factor-β (TGF-β) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aorta. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-β type II receptor gene Tgfbr2 in myeloid cells of Fbn1 C1039G/+ MFS mice (Fbn1C1039G/+ ;Tgfbr2MyeKO ). Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+ ;Tgfbr2 MyeKO mice. In the aorta of Fbn1C1039G/+ ;Tgfbr2 MyeKO mice, and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-β enhanced the migration capacity of RAW264.7 macrophages. TGF-β signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.
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| Academic Significance and Societal Importance of the Research Achievements |
マルファン症候群では、大動脈瘤に対する降圧薬治療（ロサルタンなど）や自己弁温存大動脈基部置換術などの発達によりその予後は改善傾向にあるが、病態特異的な治療法がなく、依然として若年で致死的な大動脈解離に至る患者も少なくない。本課題において、炎症細胞におけるTGFβシグナル抑制がその治療標的となる可能性が示唆され、治療法が開発されることも期待できる。
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Report
(4 results)
Research Products
(36 results)
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[Journal Article] Vascular Ehlers-Danlos syndrome diagnosed in a patient initiating hemodialysis2019
Author(s)
Haruki Ouchi, Hiroshi Nishi, Motonobu Nakamura, Yosuke Hirakawa, Tetsuhiro Tanaka, Norifumi Takeda, Takafumi Akai, Yuichi Ohashi, Katsuyuki Hoshina, Toshio Takayama, Masaomi Nangaku
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Journal Title
Kidney International Reports
Volume: 4
Issue: 11
Pages: 1646-1648
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Xanthine oxidoreductase in adventitial macrophages exacerbates aortic aneurysm progression by amplifying ROS generation in a mouse model of Marfan syndrome2020
Author(s)
17.Hiroki Yagi, Hiroshi Akazawa, Qing Liu, Akiko Saga-Kamo, Chizuru Yabumoto, Masahiko Umei, Hiroshi Matsunaga, Hiroshi Kadowaki, Ryo Matsuoka, Norifumi Takeda, Issei Komuro
Organizer
第84回日本循環器学会学術集会
Related Report
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