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)

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Background and Purpose: Inflammation plays a key role in atherosclerosis. A protective role of angiotensin-(1-7) in vascular pathologies opened a possibility for therapeutic use of small molecule non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms of these vaso-protective effects of a Mas receptor agonist, AVE0991, remain unclear. Experimental approach: We investigated the effects of AVE0991 on the spontaneous atherosclerosis in 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 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 as a measure of endothelial function. AVE0991 inhibited perivascular inflammation, through the reduction of chemokine expression in pVAT, as well as through direct actions on monocytes/macrophages inhibiting their activation, characterized by IL-1β, TNF-α, MCP-1 and CXCL10 and differentiation to M1 phenotype. Pre-treatment 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 anti-inflammatory effects of AVE0991 were partially Mas dependent. Conclusions & implications: Selective Mas receptor agonist AVE0991 possesses anti-atherosclerotic and anti-inflammatory properties, affecting monocyte/macrophage differentiation and recruitment to perivascular space at early stages of atherosclerosis in ApoE-/- mice.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Rios, Dr Francisco and Nosalski, Dr Ryszard and Mikolajczyk, Dr Tomasz and Skiba, Mr Dominik and Guzik, Professor Tomasz and Czesnikiewicz-Guzik, Dr Marta and Montezano, Dr Augusto and Touyz, Professor Rhian
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 > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School
Journal Name:British Journal of Pharmacology
ISSN (Online):1476-5381
Published Online:09 December 2016
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