Long-Term Effect of a Vaccine Targeting Endothelin-1 Receptor Type A in Pulmonary Arterial Hypertension

• Published in: Frontiers in cardiovascular medicine Vol. 8; p. 683436
• Main Authors: Dai, Yong, Qiu, Zhihua, Ma, Wenrui, Li, Chang, Chen, Xiao, Song, Xiaoxiao, Bai, Zeyang, Shi, Dingyang, Zheng, Jiayu, Pan, Guangwei, Liao, Yuhua, Liao, Mengyang, Zhou, Zihua
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 17.06.2021
• Subjects: Cardiovascular Medicine; durable efficacy; endothelin-A receptor; pulmonary arterial hypertension; vaccine therapy; vascular remodeling
• ISSN: 2297-055X; 2297-055X
• DOI: 10.3389/fcvm.2021.683436

Background: Previously, we invented a therapeutic vaccine targeting the endothelin-A receptor (termed ETRQβ-002). ETRQβ-002 successfully prevented the remodeling of pulmonary arterioles (PAs) and right ventricle (RV) without significant immune-mediated damage in experimental pulmonary arterial hypertension (PAH) mice models. Objective: Here, we aim to further evaluate the long-term effects of ETRQβ-002. Methods: PAH mice model was induced by a combination of subcutaneous injection with Sugen5416 and chronic hypoxic conditions (10% O 2 ). PAH mice were immunized with ETRQβ-002 at different time points, and the experiment lasted for 21 weeks. Hemodynamic, histological, and biochemical analyses were conducted to evaluate the long-term effects of ETRQβ-002. Results: We demonstrated that the titer of the specific antibody against ETR-002 could be maintained chronically after periodic booster immunization in PAH mice. Long-term reduction of right ventricular systolic pressure and amelioration of PA remodeling by ETRQβ-002 were confirmed. Moreover, we found that ETRQβ-002 also exerted antiproliferation, anti-inflammation, and antifibrosis effects in PA remodeling. Besides, ETRQβ-002 durably limited pathological RV hypertrophy and fibrosis. Finally, no immune-mediated damage was observed in hepatic or renal function or by pathology in liver and kidney during the long-term administration of ETRQβ-002. Conclusion: Our findings indicate that ETRQβ-002 provides long-term therapeutic effects in Sugen/hypoxia-induced PAH animals and offers a promising clinical prospect for PAH treatment.