Development of a treatment for pulmonary arterial hypertension focusing on inflammatory endothelial dysfunction

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16033
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Inagaki Tadakatsu 国立研究開発法人国立循環器病研究センター, 研究所, 研究員 (20638366)
• Research Collaborator: Masaki Takeshi ; Mori Hiroyoshi ; Fukushima Yasue
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 肺動脈性肺高血圧症 / 肺血管リモデリング / 右心不全 / Interleukin-6

Outline of Final Research Achievements

In this study, we used the severe PAH model (SuHx) to test the hypothesis that the onset of PAH and right heart failure involve inflammatory endothelial dysfunction in the lung and coronary blood vessels. In SuHx rats, Endothelium-dependent vasodilator responses were significantly attenuated in the middle and small arteries in the right coronary artery of SuHx rats. Endothelin receptor antagonist treatment recovered the endothelium-dependent vasodilator responses, improved the inflammatory state of the right ventricle and restored cardiac function. We also created IL-6 knockout (KO) rats using CRISPR/Cas9 genome editing. IL-6KO rats showed significant resistance to PAH. These results suggests that endothelial dysfunction of coronary arteries is involved in the onset of right heart failure, and that inhibition of inflammatory signals may be a promising new treatment for refractory PAH.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

本研究では肺高血圧症における肺血管リモデリングおよび右冠動脈の異常収縮には炎症を背景とする血管内皮機能障害が関与するかについて、肺高血圧症における炎症性シグナルの分子機序から明らかにすることを目的とし、既存の治療薬に適応しない重症疾患患者に対する新たな治療法の確立を目指すものであった。本研究により、IL-6阻害がこれまでの既存の薬剤に適応しない重症肺高血圧患者に対して右心不全の予防や予後改善にまで発展する可能性が期待された。