Antiatherosclerotic effect of Ang- (1-7) non-peptide mimetic (AVE 0991) is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis.

Skiba, D.S. et al. (2017) Antiatherosclerotic effect of Ang- (1-7) non-peptide mimetic (AVE 0991) 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) Antiatherosclerotic effect of Ang- (1-7) non-peptide mimetic (AVE 0991) 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. 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
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Czesnikiewicz-Guzik, Dr Marta and 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
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School
Journal Name:British Journal of Pharmacology
Publisher:Wiley
ISSN:0007-1188
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