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

Dai, Yue; Xiao, Chen; Song, Xiaoxiao; Chen, Xijun; Ma, Wenrui; Lin, Jianwen; Wu, Hailang; Hu, Xiajun; Zhou, Yanzhao; Zhang, Hongrong; Liao, Yuhua; Qiu, Zhihua; Zhou, Zihua

doi:10.1016/j.jacc.2019.02.067

Cited by 42 publications

(38 citation statements)

References 30 publications

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“…Liao's team also developed the first vaccine against endothelin-1 receptor type A (ETAR) (ETRQβ-002 vaccine) to treat the pulmonary arterial hypertension (PAH) (Dai et al, 2019). In monocrotaline-induced PAH rats and Sugen/hypoxia-induced PAH mice, the ETRQβ-002 vaccine was injected to generate antibodies against ETR-002 (the second extracellular loop of ETAR).…”

Section: Peptidesmentioning

confidence: 99%

Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era

Zhang²,

Song

2021

Front. Pharmacol.

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Targeted therapy refers to exploiting the specific therapeutic drugs against the pathogenic molecules (a protein or a gene) or cells. The drug specifically binds to disease-causing molecules or cells without affecting normal tissue, thus enabling personalized and precision treatment. Initially, therapeutic drugs included antibodies and small molecules, (e.g. nucleic acid drugs). With the advancement of the biology technology and immunotherapy, the gene editing and cell editing techniques are utilized for the disease treatment. Currently, targeted therapies applied to treat cardiovascular diseases (CVDs) mainly include protein drugs, gene editing technologies, nucleic acid drugs and cell therapy. Although targeted therapy has demonstrated excellent efficacy in pre-clinical and clinical trials, several limitations need to be recognized and overcome in clinical application, (e.g. off-target events, gene mutations, etc.). This review introduces the mechanisms of different targeted therapies, and mainly describes the targeted therapy applied in the CVDs. Furthermore, we made comparative analysis to clarify the advantages and disadvantages of different targeted therapies. This overview is expected to provide a new concept to the treatment of the CVDs.

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Section: Peptidesmentioning

confidence: 99%

Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era

Zhang²,

Song

2021

Front. Pharmacol.

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“…ETRQβ-002 vaccine was prepared as previously described (10). Male C57BL/6 mice (Vital River, Beijing, China) aged 6 weeks were randomly divided into five groups: (1) a control group received only vehicle (Con, n = 14); (2) a hypoxia-and Su5416exposed group (SuHx, n = 26); (3) a SuHx + ETRQβ-002(s) group (simultaneous vaccination and SuHx exposure) (n = 26); (4) a SuHx + ETRQβ-002(e) group (vaccination after established PAH) (n = 26); (5) a SuHx + VLP group (n = 26).…”

Section: Vaccine Preparation and Experimental Ph Modelmentioning

confidence: 99%

“…Our previous study has demonstrated that a therapeutic vaccine targeting ETAR (termed ETRQβ-002) effectively decreases right ventricular systolic pressure (RVSP) in experimental PAH rodent animals. In addition, ETRQβ-002 vaccine alleviates pathological remodeling of PAs and right ventricular, while exhibiting a satisfactory safety profile (10). However, in the previous research, the period of observation was relatively short in PAH animals, rendering it difficult to evaluate the durable efficacy of ETRQβ-002.…”

Section: Introductionmentioning

confidence: 98%

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

Dai

Qiu

et al. 2021

Front. Cardiovasc. Med.

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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.

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“…In a study for a novel PAH treatment, Dia et al developed a vaccine (ETRQβ-002) against the ET-1 receptor (ET A ) ET A peptide (ET A -002, second extracellular loop of ET A receptor, conjugated to the Qβ bacteriophage virus-like particle carrier protein, ETRQβ-002) [ 82 ]. Effects of the antibodies on Ca 2+ -dependent signal transduction events were examined in monocrotaline (MCT) and Sugen/hypoxia-induced pulmonary hypertension rats [ 82 ]. Monoclonal antibodies to ET A -002 reduced remodeling of pulmonary arterioles and the right ventricle in MCT- and Sugen/hypoxia-induced PAH animals and decreased right ventricular systolic pressure [ 82 ].…”

Section: Potential Therapeutics For Et-1 Dysregulation In Admentioning

confidence: 99%

“…Effects of the antibodies on Ca 2+ -dependent signal transduction events were examined in monocrotaline (MCT) and Sugen/hypoxia-induced pulmonary hypertension rats [ 82 ]. Monoclonal antibodies to ET A -002 reduced remodeling of pulmonary arterioles and the right ventricle in MCT- and Sugen/hypoxia-induced PAH animals and decreased right ventricular systolic pressure [ 82 ]. This is a novel therapeutic approach to treat PAH, a chronic fatal disease that is associated with ET-1 dysregulation.…”

Section: Potential Therapeutics For Et-1 Dysregulation In Admentioning

confidence: 99%

Dysregulation of Endothelin-1: Implications for Health Disparities in Alzheimer’s Disease

Alcendor

2020

JPM

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Alzheimer’s disease (AD) and related dementias disproportionately impact racial and ethnic minorities. The racial and ethnic disparities in AD could be explained by differences in cerebral vascular disease pathology. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide that regulates smooth muscle, endothelial cell, and pericyte contractions that may result in cerebral vascular constriction, leading to cerebral hypoperfusion; over time, ET-1 may result in neuronal injury contributing to the pathology of AD. Upregulation of the ET-1 system has been observed in African Americans when compared with non-Hispanic Whites. The role of the ET-1 system as a driver of ethnic disparities in AD requires further investigation. Targeting of the ET-1 system as a therapeutic intervention that could impact AD progression also needs further study. Dysregulation of ET-1 in Hispanic/Latino populations largely have been unexplored. Genetics linking ET-1 dysregulation and racial disparities in AD also needs further investigation. In this review, I examine how AD effects underserved minority populations and how dysregulation of the ET-1 system specifically predisposes ethnic minorities to AD. In addition, I examine the molecular interactions of the ET-1 system and amyloid beta, the role the ET-1 system in neurodegeneration, potential therapeutics for ET-1 dysregulation, and the impact on AD progression.

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

Cited by 42 publications

References 30 publications

Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era

Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era

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

Dysregulation of Endothelin-1: Implications for Health Disparities in Alzheimer’s Disease

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