Molecular mechanism of familial aortic dissection by smooth muscle myosin mutation and elucidation of vascular aging mechanism

• Project/Area Number: 18H02811
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Jichi Medical University
• Principal Investigator: Nagai Ryozo 自治医科大学, 医学部, 学長 (60207975)
• Co-Investigator(Kenkyū-buntansha): 相澤 健一 自治医科大学, 医学部, 准教授 (70436484) ; 仲矢 丈雄 自治医科大学, 医学部, 准教授 (80512277) ; 宮川 拓也 東京大学, 大学院農学生命科学研究科(農学部), 特任准教授 (50596559) ; 田之倉 優 東京大学, 大学院農学生命科学研究科(農学部), 特任教授 (60136786) ; 今井 靖 自治医科大学, 医学部, 教授 (20359631)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 平滑筋ミオシン / 家族性大動脈解離 / 血管老化機構

Outline of Final Research Achievements

We established a pathogenic variant of the myosin heavy chain (Myh11), known to cause familial thoracic aortic aneurysm and dissection (FTAAD), in the form of Myh11del1256 K mice. The Myh11ΔK/ΔK mice exhibited thickening of the vascular wall, microscopic structural abnormalities including decreased cell adhesion, and reduced contractility in the aorta. The Myh11ΔK/+ mice developed aortic dissection and intramural hematoma upon angiotensin stimulation. The underlying mechanism involved a decrease in the integrin subunit α2 (Itga2). The impact of reduced cell adhesion due to Itga2 depletion suggested a defect in aortic contraction.

Academic Significance and Societal Importance of the Research Achievements

急性大動脈解離は、突然大動脈壁に亀裂を生じ、大動脈破裂や血管の閉塞等の致命的な合併症を引き起こす致死性疾患である。FTAAD家系の38歳女性は第3子を妊娠中後期に胸部大動脈解離を発症し死亡している。幸い女児が誕生したが動脈管開存症(PDA)を有し、治療法開発が急がれる。予測や予防が非常に難しく、長年臨床医学上の問題とされてきた疾病の機構を明らかにし、治療法開発に繋げることは社会的に意義があると思われる。

Research Products

• [Journal Article] An Myh11 single lysine deletion causes aortic dissection by reducing aortic structural integrity and contractility (2022)
  • Author(s): Negishi Keita、Aizawa Kenichi、Shindo Takayuki、Suzuki Toru、Sakurai Takayuki、Saito Yuichiro、Miyakawa Takuya、Tanokura Masaru、Kataoka Yosky、Maeda Mitsuyo、Tomida Shota、Morita Hiroyuki、Takeda Norifumi、Komuro Issei、Kario Kazuomi、Nagai Ryozo、Imai Yasushi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41598-022-12418-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A deletion mutation in myosin heavy chain MYH11 reduces the contraction force of the aorta resulting in aortic dissection (2019)
  • Author(s): Keita Negishi, Kenichi Aizawa, Takayuki Shindo, Yuichiro Saito, Toru Suzuki, Kazuomi Kario, Ryozo Nagai, Yasushi Imai
  • Organizer: 第83回日本循環器学会学術集会
  • Int'l Joint Research