Novel therapeutic strategy for atherosclerosis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09589
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nippon Medical School (2018-2019); Tokyo Medical and Dental University (2017)
• Principal Investigator: Oishi Yumiko 日本医科大学, 大学院医学研究科, 大学院教授 (80435734)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: マクロファージ

Outline of Final Research Achievements

Recent studies unraveled that cellular metabolism is tightly linked to activation of immune cells. While accumulation of extracellular/intracellular cholesterol has been shown to lead to macrophage activation and dysfunction, the underlying mechanisms remain incompletely understood. Here, we provide evidence that cellular cholesterol is required for macrophage activation. Accordingly, suppression of cholesterol accumulation by a novel supramolecular compound, polyrotaxane (PRX) inhibited Myd88-dependent macrophage inflammatory activation. Moreover, PRX treatment inhibited atherosclerotic plaque formation in Ldlr-/- mice. The finding that dynamic changes in cellular cholesterol directly regulate Myd88-dependent inflammatory programs in macrophages suggests the potential for new therapeutic and diagnostic approaches for chronic inflammatory diseases, such as atherosclerosis.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

血清コレステロール量が過剰になると、動脈硬化プラークの形成が促進されることは以前から知られていた。ところが、本検討の結果、血清レベルのみならず、マクロファージの細胞内コレステロールの増加が、マクロファージの活性化に必須であることが明らかとなった。細胞内コレステロール量の制御による、動脈硬化に対する新たな治療法の開発へと展開しうる、重要な意義をもつ。