Investigation for the role of hypoxic responses in mitochondrial dysfunction in heart failure

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15892
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyushu University
• Principal Investigator: IKEDA MASATAKA 九州大学, 医学研究院, 特任助教 (10567382)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 虚血性心臓病 / 虚血再灌流傷害 / 低酸素誘導因子 / Hif-1α / ミトコンドリア / 酸素消費量

Outline of Final Research Achievements

In this study, we investigated the suppressive effect of hypoxia-inducible factor-1 (Hif-1α) using roxadustat, which is a first-in-class prolyl hydroxylase domain-containing protein (PHD) inhibitor, on an oxygen consumption in cardiomyocytes and infarct size in a murine ischemic/reperfusion model. The treatment with roxadustat in isolated cardiomyocytes significantly lowers an oxygen consumption in mitochondria, and suppressed cell death induced by hypoxia/reoxygenation. Notably, the pretreatment with roxadustat markedly suppressed infarct size in a murine ischemia reperfusion model. Roxadustat will be a new therapeutic strategy against ischemic heart disease by lowering an oxygen consumption and thereby producing an ischemic tolerance.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

低酸素誘導因子（Hif）を分解するプロリル水酸化酵素の阻害により腎性貧血を治療することを目的として開発されたfirst-in-classの薬剤であるroxadustatを用いることで、薬理学的に酸素代謝を抑制し、虚血耐性を誘導し得ることを明らかにした。本機序を利用することで、虚血性心疾患のみならず、心臓外科手術時（体外循環中）や臓器移植の際の臓器保護への応用も検討されることから、本薬剤の幅広い臨床応用の可能性が示唆された。