Dysregulation of tissue homeostasis by cellular senescence in pathogenesis of aortic dissection

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H03743
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55030:Cardiovascular surgery-related
• Research Institution: Kurume University
• Principal Investigator: Aoki Hiroki 久留米大学, 付置研究所, 教授 (60322244)
• Co-Investigator(Kenkyū-buntansha): 田中 啓之 久留米大学, 医学部, 教授 (70197466)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 大動脈解離 / 細胞老化 / 増殖応答 / 炎症応答 / 平滑筋細胞

Outline of Final Research Achievements

Aortic dissection (AD) is a fatal disease of unknown cause. In this study, we found that proliferation and senescence of various cell types occurred in a mouse AD model. Inhibiting the proliferative response with rapamycin also inhibited cell senescence and prevented AD. Administration of the senolytic reagent ABT-263 to mice inhibited the appearance of senescent cells and the onset and progression of AD. In the aortic wall after AD-inducing stimulation, IL-6 was expressed before the onset of AD, and the phenotype of smooth muscle cells changed from contractile to secretory, which was suppressed by ABT-263. We conclude that AD is caused by rapamycin-dependent proliferative responses and cellular senescence through destructive inflammatory responses and transformation of smooth muscle cells.

Free Research Field

分子循環器学

Academic Significance and Societal Importance of the Research Achievements

大動脈解離は前触れのない強烈な痛みとともに発症し、急速に重症化して突然死を引き起こす原因不明の病気である。現時点では病気の成り立ちは不明で発症は予想できず、発症後は緊急手術以外に積極的な治療法はない。マウスの大動脈解離モデルで検討したところ、解離の発症に先立って大動脈壁の細胞に異常増殖と老化が起こることがわかった。薬で老化した細胞を取り除くと大動脈解離の発症や重症化を抑制できることがわかった。この研究をもとに解離の発症予測や治療ができるようになるかもしれない。