Journal
EUROPEAN HEART JOURNAL
Volume 40, Issue 9, Pages 768-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehy881
Keywords
Myeloid cell; Endothelin; Hypertension
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Funding
- British Heart Foundation [FS/11/78/29328, FS/13/30/29994, FS/16/54/32730]
- Kidney Research UK [IN10/2010]
- Institut National de Santeet de la Recherche Medicale (INSERM)
- European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant [107037]
- MRC [MR/R017840/1] Funding Source: UKRI
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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 phi 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 (LysMET(B)(-/-)), we explored the effects of modifying M phi 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 phi depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human M phi expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of M phi with exogenous ET-1 did not polarize M phi phenotype. Interestingly, both mouse and human M phi cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. M phi depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMET(B)(-/-) mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received M phi depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. Conclusion M phi and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.
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