Activation peptide of coagulation factor IX protects vascular endothelial cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08380
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Nihon University
• Principal Investigator: HIDAI Chiaki 日本大学, 医学部, 教授 (70228732)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 脳梗塞 / 炎症反応 / 血液凝固因子

Outline of Final Research Achievements

It has been found that an inactive coagulation factor IX (F9) inhibits vascular permeability. This activity is localized to the activation peptide of F9, and intravenous administration of a chemically synthesized peptide (F9-AP) showed therapeutic effects in sepsis and brain contusion models. In this study, we investigated the mechanism of action of F9-AP. In the brain contusion model, acute reactants such as c-fos and VEGF and marker genes of inflammation were increased, which could not be considered as simple inhibition of inflammation. On the other hand, in experiments using vascular endothelial cells, F9-AP simultaneously suppressed signals from multiple ligands such as IL6 and thrombin, suggesting the involvement of lipid rafts as a possible mechanism. F9-AP-induced reduction of infarct nests was also observed in a cerebral infarction model.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

脳梗塞の治療では、発症から6時間以内の血流再開が虚血による一次的障害を抑制し、予後の改善に有効であると知られているが、その条件で病院にたどり着ける患者は全体の10％に満たない。一方、脳梗塞は、脳外傷同様に炎症による二次的障害が臨床上重要な意味を持つので、それを防止できるF9-APは、新たな脳梗塞の治療戦略の存在を示唆している。また、F9ーAPの抗炎症作用は、これまで知られている、NSAID、ステロイド、免疫抑制剤と異なる機序による可能性が高い。COVID19による肺炎など、炎症反応は未だ十分にはコントロールできていない反応であり、本研究の成果は新しい抗炎症薬の発明に寄与すると考えられる。