Cargando…

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

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 AVE0...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Guzik, T J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659999/
https://www.ncbi.nlm.nih.gov/pubmed/27935022
http://dx.doi.org/10.1111/bph.13685
_version_ 1783274217759834112
author 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
Guzik, T J
author_facet 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
Guzik, T J
author_sort Skiba, D S
collection PubMed
description 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
format Online
Article
Text
id pubmed-5659999
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-56599992017-11-01 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 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 Guzik, T J Br J Pharmacol Themed Section: Research Papers 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 John Wiley and Sons Inc. 2017-02-01 2017-11 /pmc/articles/PMC5659999/ /pubmed/27935022 http://dx.doi.org/10.1111/bph.13685 Text en © 2016 The Authors. British Journal of Pharmacology published by John Wiley & Son Ltd on behalf of British Pharmacological Society This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Themed Section: Research Papers
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
Guzik, T J
Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
title Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
title_full Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
title_fullStr Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
title_full_unstemmed Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
title_short Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
title_sort anti‐atherosclerotic effect of the angiotensin 1–7 mimetic ave0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis
topic Themed Section: Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659999/
https://www.ncbi.nlm.nih.gov/pubmed/27935022
http://dx.doi.org/10.1111/bph.13685
work_keys_str_mv AT skibads antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT nosalskir antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT mikolajczyktp antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT siedlinskim antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT riosfj antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT montezanoac antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT jawienj antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT olszaneckir antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT korbutr antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT czesnikiewiczguzikm antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT touyzrm antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis
AT guziktj antiatheroscleroticeffectoftheangiotensin17mimeticave0991ismediatedbyinhibitionofperivascularandplaqueinflammationinearlyatherosclerosis