Pathophysiological role of inflammatory and metabolic signals during aortic aneurysm formation in Marfan syndrome

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08484
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokyo
• Principal Investigator: TAKEDA NORIFUMI 東京大学, 医学部附属病院, 助教 (60436483)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: マルファン症候群 / 動脈瘤 / マクロファージ / TGFβシグナル

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.

Free Research Field

循環器内科学

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。