The role of endothelial ADAM17 in NASH and cardiovascular disease

2019 Fiscal Year Final Research Report

• Project/Area Number: 18KK0437
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Research Field: Legal medicine
• Research Institution: Kyoto University
• Principal Investigator: Miyao Masashi 京都大学, 医学研究科, 助教 (90711466)
• Project Period (FY): 2018 – 2019
• Keywords: 法医病理学

Outline of Final Research Achievements

Angiotensin II(AngII) has a crucial role in cardiovascular pathologies. However, the precise molecular mechanism underlying aging-related endothelial inflammation induced by AngII remains elusive. We have tested a hypothesis in cultured rat aortic endothelial cells (ECs) that the removal of AngII-induced senescent cells, preservation of proteostasis, or inhibition of mitochondrial fission attenuates the pro-inflammatory EC phenotype. AngII stimulation in ECs resulted in cellular senescence. The AngII-induced senescence was attenuated by treatment with a senolytic drug, an ER stress inhibitor, or a mitochondrial fission inhibitor. Pro-inflammatory phenotype in EC induced by AngII was alleviated by these treatments. These findings suggest that mitochondrial fission and endoplasmic reticulum stress have causative roles in endothelial senescence-associated inflammatory phenotype induced by AngII exposure, thus providing potential therapeutic targets in age-related cardiovascular diseases.

Free Research Field

法医学

Academic Significance and Societal Importance of the Research Achievements

現在、全世界で人口の高齢化が進んでおり、高齢化に伴うヒトの健康障害、予防可能な死を抑制することが持続可能な社会の発展にとって重要である。私たちはヒトの予防可能な「加齢」にアンジオテンシンというホルモンが関連し、そのメカニズムにミトコンドリアの分裂、小胞体ストレス、炎症反応が重要であることを明らかにした。このように、ヒトの予防可能な「加齢」と心臓血管疾患の関係性を明らかにすることで、急速に進む人口の高齢化に伴う予防可能な死や健康障害を抑えるための実行可能性の高い予防、治療法の開発に繋げていきたい。