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Alamandine abrogates neutrophil degranulation in atherosclerotic mice.

Abstract：

BACKGROUND:Neutrophil-mediated inflammation was recently identified as an active contributor to athero-progression. Therapeutic strategies inhibiting neutrophil degranulation or recruitment were hypothesized to positively impact on plaque vulnerability. In this study, we investigated whether treatment with the recently discovered agonist of the Mas-related G-coupled receptor type D (MrgD) alamandine would impact on neutrophil degranulation in vivo and in vitro. MATERIALS AND METHODS:Fifteen-week-old ApoE-/- mice were fed with a Western-type diet for an additional 11 weeks. After the first 2 weeks of diet, mice were surgically implanted with a carotid 'cast' device that alters the blood shear stress and induces different carotid plaque phenotypes. During the last 4 weeks before euthanasia, mice were randomly assigned to subcutaneously receive vehicle (NaCl 0·15 M) or alamandine (24 μg/kg/h) by micropump. For in vitro experiments, neutrophils were obtained after thioglycollate intraperitoneal injection in ApoE-/- mice. RESULTS:Treatment with alamandine was well-tolerated, but failed to affect lipid, macrophage, neutrophil or collagen content within carotid and aortic root plaques. Also, treatment with alamandine did not affect Th-cell polarization in lymphoid organs. Conversely, alamandine administration was associated with a reduction in serum levels of neutrophil granule enzymes, such as MMP-9 and MPO as well as MMP-9 content within aortic root plaques. In vitro, preincubation with alamandine dose-dependently abrogated PMA-induced neutrophil degranulation of MMP-9 and MPO. CONCLUSION:These results suggest that treatment with the MrgD agonist alamandine led to a reduced release of neutrophil granule products, potentially interfering with pro-atherosclerotic neutrophil activation.

journal_name

Eur J Clin Invest

journal_title

European journal of clinical investigation

authors

Da Silva AR,Lenglet S,Carbone F,Burger F,Roth A,Liberale L,Bonaventura A,Dallegri F,Stergiopulos N,Santos RA,Mach F,Fraga-Silva RA,Montecucco F

doi

10.1111/eci.12708

subject

Has Abstract

pub_date

2017-02-01 00:00:00

pages

117-128

issue

eissn

0014-2972

issn

1365-2362

journal_volume

pub_type

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Alamandine abrogates neutrophil degranulation in atherosclerotic mice.