Endothelin-1 受体 A 型肺动脉高压的免疫治疗,Journal of the American College of Cardiology

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Endothelin-1 受体 A 型肺动脉高压的免疫治疗
Journal of the American College of Cardiology ( IF 21.7 ) Pub Date : 2019-05-01 , DOI: 10.1016/j.jacc.2019.02.067
Yong Dai , Xiao Chen , Xiaoxiao Song , Xijun Chen , Wenrui Ma , Jibin Lin , Hailang Wu , Xiajun Hu , Yanzhao Zhou , Hongrong Zhang , Yuhua Liao , Zhihua Qiu , Zihua Zhou

背景肺动脉高压(PAH)是一种慢性致死性疾病。PAH 的治疗效果并不理想，在世界范围内的控制也不尽如人意。疫苗接种为治疗多环芳烃提供了一种有前景的方法。目的本研究旨在寻找一种针对内皮素-1 (ET-1) A 型受体 (ETAR) 的疫苗，用于治疗多环芳烃。方法筛选ETRQβ-002疫苗，制备针对ETAR第二胞外环表位ETR-002的特异性抗体（包括多克隆抗体和单克隆抗体）。研究了抗体对Ca 2+ 依赖性信号转导事件的影响。在体内，ETRQβ-002 疫苗用于接种野百合碱 (MCT) 和 Sugen/缺氧诱导的肺动脉高压动物。针对 ETR-002 的单克隆抗体 (mAb) 也被注射到 PAH 动物中。仔细评估了 ETRQβ-002 疫苗对肺动脉高压和肺小动脉和右心室 (RV) 重塑的影响。此外，在正常接种疫苗的动物中检测到可能的免疫介导的损伤。结果 ETR-002 肽具有完美的免疫原性，ETRQβ-002 疫苗可诱导强抗体产生。在体外，抗 ETR-002 抗体与 ETAR 结合并抑制 Ca2+ 依赖性信号转导事件，包括细胞外信号调节激酶磷酸化和由 ET-1 诱导的细胞内 Ca2+ 浓度升高。在体内，ETRQβ-002 疫苗和 mAb 均显着降低了 MCT 暴露大鼠和 Sugen/缺氧暴露小鼠的 RV 收缩压，分别高达 20 毫米汞柱和 10 毫米汞柱。此外，ETRQβ-002疫苗/ mAb明显改善了PAH动物肺小动脉的病理重塑和RV肥大。此外，在接种疫苗的动物中未检测到显着的免疫介导的损伤。结论 ETRQβ-002 疫苗/mAb 减弱了 MCT 和 Sugen/缺氧诱导的 PAH 动物肺小动脉和 RV 的重塑，并通过减少压力反应和抑制由 ET-1 启动的信号转导有效降低了 RV 收缩压。ETRQβ-002 疫苗/mAb 可能为 PAH 治疗提供一种新的、有前景的方法。结论 ETRQβ-002 疫苗/mAb 减弱了 MCT 和 Sugen/缺氧诱导的 PAH 动物肺小动脉和 RV 的重塑，并通过减少压力反应和抑制由 ET-1 启动的信号转导有效降低了 RV 收缩压。ETRQβ-002 疫苗/mAb 可能为 PAH 治疗提供一种新的、有前景的方法。结论 ETRQβ-002 疫苗/mAb 减弱了 MCT 和 Sugen/缺氧诱导的 PAH 动物肺小动脉和 RV 的重塑，并通过减少压力反应和抑制由 ET-1 启动的信号转导有效降低了 RV 收缩压。ETRQβ-002 疫苗/mAb 可能为 PAH 治疗提供一种新的、有前景的方法。

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

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.

更新日期：2019-05-01

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