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

• Published in: British journal of pharmacology Vol. 174; no. 22; pp. 4055 - 4069
• Main 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, Guzik, T J
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-11-2017; John Wiley and Sons Inc
• Subjects: Adipocytes; Adipose tissue; Angiotensin; Angiotensin I; Animals; Anti-Inflammatory Agents - therapeutic use; Aorta; Aorta - drug effects; Aorta - immunology; Aorta - pathology; Apolipoprotein E; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - immunology; Atherosclerosis - pathology; Bioavailability; Cardiovascular diseases; Cell activation; Cell Line; Cell Line, Tumor; Collagen; CXCL10 protein; Cytokines - genetics; Endothelium; Female; Humans; Imidazoles - therapeutic use; Inflammation; Interleukin 1; Leukocyte migration; Leukocytes - drug effects; Leukocytes - immunology; Lymphocytes T; Macrophages; Macrophages - drug effects; Macrophages - immunology; Mice, Inbred C57BL; Mice, Knockout, ApoE; Monocyte chemoattractant protein 1; Monocytes; Peptide Fragments; Plaque, Atherosclerotic; Proto-Oncogene Mas; Proto-Oncogene Proteins - agonists; Receptors, G-Protein-Coupled - agonists; Research Paper; Themed Section: Research Papers; Tumor necrosis factor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13685

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