Inhibition of Prolyl Hydroxylase Improves Myocardial Dysfunction Following Endotoxin Shock via Activation of Kynurenic Acid Production

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K20400
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Emergency medicine
• Research Institution: Keio University
• Principal Investigator: Ihara Naho 慶應義塾大学, 医学部(信濃町), 助教 (70573260)
• Research Collaborator: MINAMISHIMA Shizuka
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 低酸素応答 / 敗血症性ショック / 敗血症性心筋症 / プロリン水酸化酵素阻害剤 / キヌレン酸

Outline of Final Research Achievements

Inhibition of prolyl hydroxylase (PHD) has been reported to improve the survival rate of mice with endotoxin shock by reduction of the blood lactate level, or and ameliorate cardiac ischemia reperfusion injury, which led us examine the effect of PHD inhibition on Sepsis-induced cardiomyopathy. Adult male mice were intraperitoneally injected with 35 mg/kg of lipopolysaccharide (LPS) and treated with either PHD inhibitor FG-4592 (25 mg/kg) or vehicle by oral gavage. Administration of FG-4592 markedly improved survival rate 7 days after LPS injection, and ameliorated left ventricular dysfunction due to LPS-induced endotoxin shock at 24 hours after LPS injection. Serum level of KYNA was increased upon FG-4592 treatment in mice whereas circulating cytokines levels were not affected. Administration of KYNA promptly improved cardiac dysfunction due to LPS-induced endotoxin shock. Moreover, KYNA administration immediately after LPS reduced mortality on mice with endotoxin shock.

Free Research Field

麻酔学

Academic Significance and Societal Importance of the Research Achievements

PHD阻害剤（FG-4592）はエンドトキシンショック後の心機能不全を軽減し、生存率を改善した。PHD阻害剤の心筋保護作用には抗炎症効果だけではなく、血中キヌレン酸の増加が関与していることが示唆された。キヌレン酸はエンドトキシンショック後の心機能不全を軽減し、生存率を改善した。PHD阻害剤やキヌレン酸は敗血症性心筋症の新たな治療戦略の一つになりうるかもしれない。