Molecular mechanisms of uric acid for promoting atherosclerosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08418
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Teikyo University
• Principal Investigator: Kono Hajime 帝京大学, 医学部, 教授 (60585074)
• Co-Investigator(Kenkyū-buntansha): 本田 善一郎 お茶の水女子大学, 保健管理センター, 教授 (70238814)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 動脈硬化 / 尿酸 / AMPK / インフラマソーム / HIF-1α / ミトコンドリア活性酸素 / IL-1

Outline of Final Research Achievements

Uric acid is supposed but not yet determined to be associated with atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. The secretion of IL-1β from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.

Free Research Field

動脈硬化

Academic Significance and Societal Importance of the Research Achievements

高尿酸血症は動脈硬化における増悪因子と想定されており、実際痛風患者では心血管イベントが高頻度に発生する。しかし動脈硬化を阻止するために尿酸を低下させるのが良いのかどうかは明らかではなかった。我々はマウスと細胞を用いた基礎実験において尿酸が炎症を引き起こし、動脈硬化を促進させる事を解明した。また、その分子機序も明らかとなった。本研究の結果、動脈硬化の進展阻止において尿酸降下療法の裏付けが得られ、新たな治療介入点も明らかとなった。