The study of the mechanisms of pulmonary hypertension based on abnormal MCU/NCLX transport

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16509
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Fukuoka University
• Principal Investigator: Tagashira Hideaki 福岡大学, 医学部, 准教授 (90735028)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: イオン輸送体 / 肺高血圧症

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is a severe and progressive disease that causes right heart failure. The pathogenesis of PAH is generally characterized by vasoconstriction, upregulated proliferation, migration, and pulmonary vascular remodeling in lung tissue. Recent studies using genetic analyses and experimental models have suggested that the hypercontraction of pulmonary arteries induced by Ca2+ signaling abnormality may be involved in the pathogenesis of PAH. However, the pathophysiological mechanisms of PAH via Ca2+ transporters are not clearly understood. Recently, MCU and NCLX have been identified as mitochondrial Ca2+ transporters. However, the physiological and pathophysiological role of these mitochondrial Ca2+ transporters are still unclear. In this study, we generated mitochondrial Ca2+ transporter gene altered mice and investigated the relationship between mitochondrial Ca2+ transporters and the pathogenesis of hypoxia-induced pulmonary hypertension.

Free Research Field

薬理学一般

Academic Significance and Societal Importance of the Research Achievements

これまでに、PAHの原因としてKCNK3（TASK1）やKv1.5の機能低下および非選択的陽イオンチャネルTRPC6の発現増加等が報告されており、PAHの発症・増悪には細胞膜K+チャネルやCa2+チャネルが関与することが示唆されている。本研究は、これまでに報告されている細胞膜チャネルではなく、細胞内オルガネラに発現しているミトコンドリアCa2+輸送体の各種遺伝子改変マウスならびに薬理学的ツールを用いて、肺血管平滑筋細胞のミトコンドリアCa2+輸送バランス異常による肺高血圧発症への関与を明らかとしたものである。肺血管過収縮や肺血管リモデリングの新しい病態機序として極めて興味深いものと考えられる。