Necroptosis-tartgeted therapy for heart failure

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08544
• 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: Sapporo Medical University
• Principal Investigator: Yano Toshiyuki 札幌医科大学, 医学部, 講師 (40444913)
• Co-Investigator(Kenkyū-buntansha): 丹野 雅也 札幌医科大学, 医学部, 准教授 (00398322) ; 久野 篤史 札幌医科大学, 医学部, 准教授 (30468079)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 心不全 / 細胞死

Outline of Final Research Achievements

We found increased cardiomyocyte expression of nuclear p-MLKL, an executor of necroptosis, in patients with nonischemic dilated cardiomyopathy (NICM), but its clinical significance remains unclear. Endomyocardial biopsy specimens were obtained from 57 patients with NICM (56±15 years old, 68% male). Nuclear p-MLKL levels were determined by immunostaining against phospho-Ser358-MLKL. Using median nuclear p-MLKL expression levels, patients were classified into a high nuclear p-MLKL group and a low nuclear p-MLKL group.　Adverse event was defined as composite of death or admission for heart failure or ventricular arrhythmia.　Results of Kaplan-Meier survival curve analyses showed that the adverse event-free survival rate was lower in the high nuclear p-MLKL group than in the low nuclear p-MLKL group (4% vs. 31%, p=0.021). Enhanced expression of nuclear p-MLKL in cardiomyocytes predicts future adverse events, suggesting possible involvement of necroptosis in progression of NICM.

Free Research Field

心不全

Academic Significance and Societal Importance of the Research Achievements

癌治療においては発現している分子や遺伝子をガイドに分子標的治療が行われ、一定の成果をあげている。心不全においても動物実験レベルでは様々な分子標的が想定されているが臨床応用されておらず、症状や心不全進行の程度に応じた薬物治療が今なお主体となっている。本研究は申請者による“心不全のテーラーメイド治療プロジェクト”の一環であり、心筋生検組織からリン酸化MLKL亢進群を抽出し、分子標的治療を行うことが最終目標である。心不全に対する分子標的治療の最初の一歩となり、今後の波及効果にも期待を持てるプロジェクトになると考えている。