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

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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. (2017)
  • Publisher: Wiley
  • Journal: British Journal of Pharmacology (issn: 0007-1188, vol: 174, pp: 4,055-4,069)
  • Related identifiers: pmc: PMC5659999, doi: 10.1111/bph.13685
  • Subject: Research Paper | Themed Section: Research Papers

Background and Purpose: \ud \ud 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.\ud Experimental Approach: \ud \ud We investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)−/− mice, in the context of vascular inflammation and plaque stability.\ud Key Results: \ud \ud 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.\ud Conclusions and Implications: \ud \ud 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.\ud Linked Articles: \ud \ud 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 and
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