Elucidation of the mechanism of cardiac remodeling and arrhythmogenesis via toll-like receptor (TLR) 9

• Project/Area Number: 18K08077
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: The University of Tokushima
• Principal Investigator: SOEKI Takeshi 徳島大学, 大学院医歯薬学研究部(医学域), 特任教授 (60393211)
• Co-Investigator(Kenkyū-buntansha): 佐田 政隆 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (80345214) ; 植松 悦子 徳島大学, 大学院医歯薬学研究部(医学域), 教務補佐員 (10352080)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 循環器 / Toll-like 受容体 / 心房細動 / 不整脈 / 慢性炎症

Outline of Final Research Achievements

Several evidences suggest that toll-like receptor (TLR) 9 recognizes bacterial DNA, activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. This study aimed to assess whether TLR9 contributes to the atrial inflammation and AF arrhythmogenesis. TLR9 deficient (TLR9-/-) and wild-type mice were infused with angiotensin II (Ang II) or vehicle for 4 weeks. Ang II-treated TLR9-/- mice showed lower incidence of AF compared with wild-type mice treated with Ang II. Genetic deletion of TLR9 significantly reduced the interstitial fibrosis in atrium of Ang II-treated mice. TLR9-/- mice also showed less mRNA expressions of inflammatory and fibrosis-related biomarkers in atrium compared with wild-type mice. In addition, plasma concentration of cell-free DNA was significantly higher in AF patients than control subjects. In conclusion, TLR9 might contribute to the AF arrhythmogenesis associated with atrial inflammation.

Academic Significance and Societal Importance of the Research Achievements

慢性炎症の要因として注目されている肥満が心房細動の独立した危険因子として最近注目されているが、それらを結びつけるものは不明であった。今回の研究で、肥満などにおいて増加するDNA断片が心房におけるTLR9を介してサイトカイン産生や炎症細胞浸潤に寄与し心房細動の発症に関与するという可能性が示唆された。今回の結果は、新しいアプローチでの心房細動の診断・治療法の開発に寄与することが期待される。

Research Products

• [Presentation] Toll-like receptor 9 is a novel therapeutic target to prevent atrial fibrillation (2020)
  • Author(s): Soeki T, Matsumoto K, Fukuda D, Uematsu E, Matsuura T, Tobiume T, Kusunose K, Ise T, Yamaguchi K, Yagi S, Yamada H, Wakatsuki T, Sata M
  • Organizer: European Society of Cardiology 2020
  • Int'l Joint Research