Elucidation of the relationship of novel apoptosis-inducing substances to the pathophysiology of pulmonary arterial hypertension

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08519
• 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: Nagasaki University
• Principal Investigator: EGUCHI Masamichi 長崎大学, 病院(医学系), 助教 (70585405)
• Co-Investigator(Kenkyū-buntansha): 世古 義規 順天堂大学, 大学院医学研究科, 客員教授 (30240708) ; 前村 浩二 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90282649)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 肺動脈性肺高血圧症 / アポトーシス / 抗体医療

Outline of Final Research Achievements

Oxidative stress-Responsive Apoptosis Inducing Protein (ORAIP) is a substance identified as a secretory protein that induces apoptosis. In this study, we aimed to elucidate the involvement of ORAIP in the pathophysiology of pulmonary arterial hypertension (PAH). The PAH cases had higher blood ORAIP levels than the control cases.　Increased expression of ORAIP in lung tissue was observed in Monocrotaline (MCT) -PAH model rats, and anti-ORAIP neutralizing antibody therapy improve pulmonary hypertension. Furthermore, we created SUGEN hypoxia-PAH model rats, which are clinically similar models, and examined the effect of anti-ORAIP neutralizing antibody on improving pulmonary hypertension, but no effect was observed. In addition, a SUGEN hypoxia-PAH model was created using ORAIP receptor knockout rats and the degree of PAH was evaluated, but there was no difference in the degree of PAH between wild-type rats and knockout rats.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

ORAIPは低酸素負荷後再酸素化刺激された細胞から分泌されアポトーシスを誘導する分泌型タンパク質であり、モノクロタリンPAHモデルラットの肺組織でのORAIPの発現の上昇が認められ、anti-ORAIP中和抗体で肺高血圧の改善効果が認められた。そこで抗体医薬として肺動脈性肺高血圧症に対する用途特許を目指し、特許を取得した。しかし、より臨床に類似したSUGEN低酸素-PAHモデルラットでは、anti-ORAIP中和抗体での肺高血圧の改善効果は認められなかった。ORAIPのPAHへの病態への解明には、今後、さらなる検討が必要と考えられる。