Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis

Skiba, D. S. et al. (2017) Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis. British Journal of Pharmacology, 174(22), pp. 4055-4069. (doi:10.1111/bph.13685) (PMID:27935022) (PMCID:PMC5659999)

Skiba, D. S. et al. (2017) Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis. British Journal of Pharmacology, 174(22), pp. 4055-4069. (doi:10.1111/bph.13685) (PMID:27935022) (PMCID:PMC5659999)

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Abstract

Background and Purpose: Inflammation plays a key role in atherosclerosis. The protective role of angiotensin 1–7 (Ang-(1–7)) in vascular pathologies suggested the therapeutic use of low MW, non-peptide Ang-(1–7) mimetics, such as AVE0991. The mechanisms underlying the vaso-protective effects of AVE0991, a Mas receptor agonist, remain to be explored. Experimental Approach: We investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)−/− mice, in the context of vascular inflammation and plaque stability. Key Results: AVE0991 has significant anti-atherosclerotic properties in ApoE−/− mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using the descending aorta of chow-fed ApoE−/− mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (PVAT) and adventitial infiltration with macrophages and T-cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability (a measure of endothelial function). AVE0991 inhibited perivascular inflammation, by reducing chemokine expression in PVAT and through direct actions on monocytes/macrophages inhibiting their activation, characterized by production of IL-1β, TNF-α, CCL2 and CXCL10, and differentiation to M1 phenotype. Pretreatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in PVAT and in THP-1 cells in vitro, and the anti-inflammatory effects of AVE0991 were partly Mas dependent. Conclusions and Implications: The selective Mas receptor agonist AVE0991 exhibited anti-atherosclerotic and anti-inflammatory actions, affecting monocyte/macrophage differentiation and recruitment to the perivascular space during early stages of atherosclerosis in ApoE−/− mice. Linked Articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Montezano, Dr Augusto and Guzik, Professor Tomasz and Nosalski, Mr Ryszard and Skiba, Mr Dominik and Touyz, Professor Rhian and Rios, Dr Francisco and Mikolajczyk, Dr Tomasz
Authors: Skiba, D. S., Nosalski, R., Mikolajczyk, T. P., Siedlinski, M., Rios, F. J., Montezano, A. C., Jawien, J., Olszanecki, R., Korbut, R., Czesnikiewicz-Guzik, M., Touyz, R. M., and Guzik, T. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:British Journal of Pharmacology
Publisher:Wiley
ISSN:0007-1188
ISSN (Online):1476-5381
Published Online:01 February 2017
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in British Journal of Pharmacology 174(22): 4055-4069
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES
651771ImmunoTensionTomasz GuzikEuropean Commission (EC)631773RI CARDIOVASCULAR & MEDICAL SCIENCES