Alternative Autophagy is The Predominant Form of Autophagy in Regulating Arterial Senescence and Atherosclelosis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09250
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Kagoshima University
• Principal Investigator: Ikeda Yoshiyuki 鹿児島大学, 医歯学域医学系, 講師 (00573023)
• Co-Investigator(Kenkyū-buntansha): 赤崎 雄一 鹿児島大学, 医歯学域附属病院, 助教 (00631920) ; 大石 充 鹿児島大学, 医歯学域医学系, 教授 (50335345)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: オルタナティブオートファジー / マイトファジー / 血管老化 / エストロゲン

Outline of Final Research Achievements

Mitochondria plays a crucial role to regulate cellular senescence, which undergo mitophagy to maintain mitochondrial quality. Female C57BL6 mice with ovariectomy (Ovx) showed lower plasma estrogen level and fewer number of mitophagy, mitochondrial dysfunction and accelerated arterial senescence compared to C57BL6 with sham operation. Whereas protein expression of arterial LC3II/LC3I was not different between the 2 groups, that of Rab9 was significantly lower in Ovx than in sham mice. Administration of Estradiol (E2) to Ovx increased Rab9 and mitophagy, improved mitochondrial function and retarded arterial senescence.
In vitro experiment using HUVEC and VSMC demonstrated that E2 retarded cellular senescence and increased Lamp2 dots which co-localized with Rab9 and TOMM20 dots assessed by Immunohistochemistry, which was abolished by knockdown of Rab9. Rab9-induced alternative autophagy plays a crucial role in mediating Rab9-dependent mitophagy and retarding vascular senescence.

Free Research Field

循環器病、老年病

Academic Significance and Societal Importance of the Research Achievements

閉経に伴う血管老化・動脈硬化の進展機序にRab9-依存性オルタナティブオートファジーを主体にしたマイトファジーの低下が関与することが本研究により明らかとなった。現在、閉経女性に対してホルモン補充療法が施行されるが、様々な副作用の問題がある。今回の我々の研究成果は、ホルモン補充療法に代わる新たな治療方法の確立に寄与できるものと考えている。