Dataset Information

A novel role for myeloid endothelin-B receptors in hypertension.

ABSTRACT:

Aims

Hypertension is common. Recent data suggest that macrophages (M?) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying M? number and phenotype.

Methods and results

In vitro, M? ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying M? number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of M? depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human M? expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of M? with exogenous ET-1 did not polarize M? phenotype. Interestingly, both mouse and human M? cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. M? depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received M? depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies.

Conclusion

M? and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.

SUBMITTER: Czopek A

PROVIDER: S-EPMC6396028 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel role for myeloid endothelin-B receptors in hypertension.

Czopek Alicja A Moorhouse Rebecca R Guyonnet Léa L Farrah Tariq T Lenoir Olivia O Owen Elizabeth E van Bragt Job J Costello Hannah M HM Menolascina Filippo F Baudrie Véronique V Webb David J DJ Kluth David C DC Bailey Matthew A MA Tharaux Pierre-Louis PL Dhaun Neeraj N

European heart journal 20190301 9

<h4>Aims</h4>Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype.<h4>Methods and results</h4>In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Usi ...[more]

PMID: 30657897

Similar Datasets

Project description:BackgroundPulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension.ObjectivesTo evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension.Search methodsWe searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012.Selection criteriaWe included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension.Data collection and analysisFive review authors independently selected studies, assessed study quality and extracted data.Main resultsWe included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide.Authors' conclusionsEndothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.

Dataset Information

A novel role for myeloid endothelin-B receptors in hypertension.

Aims

Methods and results

Conclusion

Publications

A novel role for myeloid endothelin-B receptors in hypertension.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets