The roles of smooth muscle cell autophagy

• Project/Area Number: 16K01833
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied health science
• Research Institution: Juntendo University
• Principal Investigator: Mita Tomoya 順天堂大学, 医学部, 准教授 (90532557)
• Research Collaborator: OSONOI yusuke ; MASUYAMA atsushi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: オートファジー / 平滑筋細胞 / 動脈硬化 / 細胞死 / 細胞老化 / プラーク破綻 / 血管平滑筋細胞 / 動脈瘤 / 血管平滑筋 / 大動脈瘤

Outline of Final Research Achievements

Defective autophagy has been implicated in various human diseases, including cardiovascular diseases. In this study, we aimed to elucidate the role of autophagy in vascular smooth muscle cells (SMCs) on atherosclerosis.SMCs cultured from mice with SMC-specific deletion of the essential autophagy gene atg7 (Atg7cKO) by 7-ketocholestrerol exposure showed enhanced apoptotic cell death and cellular senescence. Atg7cKO mice crossed with Apoe-deficient mice showed a reduced survival rate, increased plaque area, and aneurysm formation. In addition, we investigated the role of autophagy in SMCs on plaque instability in vivo. To generate a mouse model of plaque instability, we conducted to form a tandem stenosis in the carotid artery of Atg7cKO:apoeKO mice. Our data suggest that defective autophagy in SMCs enhances plaque instability and the risk of plaque rupture.Thus,we suggest that activation of SMCs autophagy may be a new therapeutic target to reduce cardiovascular disease.

Academic Significance and Societal Importance of the Research Achievements

全世界において心血管イベント抑制は重要な課題である。様々な動脈硬化の発症進展を抑制する薬が開発され、患者の生命予後は改善してきているものの十分ではないのが現状である。本研究の平滑筋細胞のオートファジーが動脈硬化抑制的に作用しているという結果は、今後、オートファジーをターゲットとした新しい動脈硬化抑制薬の開発につながる可能性があり、意義の高い研究であると考えている。

Research Products

• [Journal Article] Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis. (2018)
  • Author(s): Osonoi Y, Mita T, Azuma K, Nakajima K, Masuyama A, Goto H, Nishida Y, Miyatsuka T, Fujitani Y, Koike M, Mitsumata M, Watada H.
  • Journal Title: Autophagy Volume: 14 Issue: 11 Pages: 1991-2006
  • DOI: 10.1080/15548627.2018.1501132
  • Peer Reviewed / Open Access
• [Journal Article] Defective autophagy in vascular smooth muscle cells enhances atherosclerotic plaque instability. (2018)
  • Author(s): Masuyama A, Mita T, Azuma K, Osonoi Y, Nakajima K, Goto H, Nishida Y, Miyatsuka T, Mitsumata M, Watada H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 505 Issue: 4 Pages: 1141-1147
  • DOI: 10.1016/j.bbrc.2018.09.192
  • Peer Reviewed / Open Access