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

Yong Dai; Zhihua Qiu; Wenrui Ma; Chang Li; Xiao Chen; Xiaoxiao Song; Zeyang Bai; Dingyang Shi; Jiayu Zheng; Guangwei Pan; Yuhua Liao; Mengyang Liao; Zihua Zhou

doi:10.3389/fcvm.2021.683436

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

Front Cardiovasc Med. 2021 Jun 17:8:683436. doi: 10.3389/fcvm.2021.683436. eCollection 2021.

Authors

Yong Dai^{1

2

3}, Zhihua Qiu^{1

2

3}, Wenrui Ma^{1

2

3}, Chang Li^{1

2

3}, Xiao Chen^{1

2

3}, Xiaoxiao Song^{1

2

3}, Zeyang Bai^{1

2

3}, Dingyang Shi^{1

2

3}, Jiayu Zheng^{1

2

3}, Guangwei Pan^{1

2

3}, Yuhua Liao^{1

2

3}, Mengyang Liao^{1

2

3}, Zihua Zhou^{1

2

3}

Affiliations

¹ Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

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% O₂). 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.

Keywords: durable efficacy; endothelin-A receptor; pulmonary arterial hypertension; vaccine therapy; vascular remodeling.