Investigation of the pathogenesis of pulmonary arterial hypertension using tissue-specific Ahr knockout mice

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08484
• 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: National Cardiovascular Center Research Institute
• Principal Investigator: Okazawa Makoto 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (40414130)
• Co-Investigator(Kenkyū-buntansha): 中岡 良和 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (90393214)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肺高血圧症 / 肺動脈性肺高血圧症 / アリルハイドロカーボン受容体 / 組織特異的遺伝子欠損マウス

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is a severe disease that causes occlusion in the small pulmonary arteries, leading to elevation of pulmonary arterial pressure and eventually to right-sided heart failure. All current therapeutic drugs for PAH target vasodilation. The PAH patients with advanced stages still have poor prognoses. Therefore, the development of a novel therapeutic drug other than vasodilators has been awaited. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various cells. In this study, we demonstrated that AHR is an essential transcription factor for the pathogenesis of PAH using several PAH model animals and human peripheral blood mononuclear cells. Our results suggest that AHR and its downstream signal molecules are novel therapeutic targets for PAH.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

肺動脈性肺高血圧症（Pulmonary Arterial Hypertension：PAH）は肺動脈に原因不明の狭窄・閉塞を来して肺動脈圧の上昇から右心不全に至る予後不良の厚労省指定難病である。PAH治療に使用可能な血管拡張薬には限界があり、別の機序に基づく創薬が待たれている。本研究では、芳香族炭化水素受容体（aryl hydrocarbon receptor: AHR）に着目し、種々の動物モデルを駆使し、関与する組織・細胞とAHRの下流分子を同定した。本研究成果から、AHRの下流分子がPAHの新規創薬ターゲットとなり得ることが示唆された。