A novel role for myeloid endothelin-B receptors in hypertension.
Endothelin
Hypertension
Myeloid cell
Journal
European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
30
03
2018
revised:
04
09
2018
accepted:
10
12
2018
pubmed:
19
1
2019
medline:
12
9
2020
entrez:
19
1
2019
Statut:
ppublish
Résumé
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. In vitro, Mφ 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 Mφ 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 Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ 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 Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.
Identifiants
pubmed: 30657897
pii: 5289586
doi: 10.1093/eurheartj/ehy881
pmc: PMC6396028
doi:
Substances chimiques
Endothelin-1
0
Receptor, Endothelin A
0
Receptor, Endothelin B
0
Angiotensin II
11128-99-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
768-784Subventions
Organisme : British Heart Foundation
ID : FS/11/78/29328
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/13/30/29994
Pays : United Kingdom
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.
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