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J Am Coll Cardiol. 2019 May 28;73(20):2567-2580. doi: 10.1016/j.jacc.2019.02.067.

Immunotherapy of Endothelin-1 Receptor Type A for Pulmonary Arterial Hypertension.

Author information

1
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 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.
2
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 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. Electronic address: qiu_zhihua512@163.com.
3
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 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. Electronic address: zzhua2001@163.com.

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PAH) is a chronic fatal disease. The treatment of PAH is less than ideal and the control is far from satisfactory worldwide. Vaccination provides a promising approach for treatment of PAH.

OBJECTIVES:

This study sought to find a vaccine against endothelin-1 (ET-1) receptor type A (ETAR) for treating PAH.

METHODS:

The ETRQβ-002 vaccine was screened and the specific antibodies against epitope ETR-002 belonging to the second extracellular loop of ETAR (including the polyclonal and monoclonal antibody) were produced. The effect of the antibodies on Ca2+-dependent signal transduction events was investigated. In vivo, ETRQβ-002 vaccine was used to vaccinate monocrotaline (MCT)- and Sugen/hypoxia-induced pulmonary hypertension animals. The monoclonal antibody (mAb) against ETR-002 was also injected into the PAH animals. The effect of ETRQβ-002 vaccine on pulmonary hypertension and remodeling of pulmonary arterioles and right ventricle (RV) was carefully evaluated. Further, the possible immune-mediated damage was detected in normal vaccinated animals.

RESULTS:

ETR-002 peptide has perfect immunogenicity and ETRQβ-002 vaccine could induce strong antibody production. In vitro, the anti-ETR-002 antibody bound to ETAR and inhibited Ca2+-dependent signal transduction events, including extracellular signal-regulated kinase phosphorylation and elevation of intracellular Ca2+ concentration induced by ET-1. In vivo, both ETRQβ-002 vaccine and the mAb significantly decreased the RV systolic pressure up to 20 mm Hg and 10 mm Hg in MCT-exposed rats and Sugen/hypoxia-exposed mice, respectively. Also, ETRQβ-002 vaccine/mAb obviously ameliorated pathological remodeling of pulmonary arterioles and hypertrophy of the RV in PAH animals. Additionally, no significant immune-mediated damage was detected in vaccinated animals.

CONCLUSIONS:

ETRQβ-002 vaccine/mAb attenuated remodeling of pulmonary arterioles and RV in MCT- and Sugen/hypoxia-induced PAH animals and decreased RV systolic pressure effectively through diminishing the pressure response and inhibiting signal transduction initiated by ET-1. ETRQβ-002 vaccine/mAb may provide a novel and promising method for PAH treatment.

KEYWORDS:

ET-1; ETAR; endothelin-1; endothelin-1 receptor type A; immunotherapy; pulmonary arterial hypertension; vaccine

PMID:
31118151
DOI:
10.1016/j.jacc.2019.02.067

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