Abstract
Background and PurposeInflammation 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 ApproachWe investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)−/− mice, in the context of vascular inflammation and plaque stability.Key ResultsAVE0991 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 ImplicationsThe 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 ArticlesThis 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
Highlights
Immune activation and inflammation are known to modulate the development of atherosclerotic plaques (Libby et al, 2011; Weber and Noels, 2011; Back and Hansson, 2015) and to regulate plaque stability (Chen et al, 2013)
We focused on a strategy concomitantly known to modulate inflammation and vascular responses, such as activation of angiotensin 1–7 (Ang-(1–7)) receptors, as this could provide a viable alternative for anti-inflammatory interventions in atherosclerosis, as well as other vascular diseases, without concerns associated with significant systemic immunosuppression (Passos-Silva et al, 2013; Magalhaes et al, 2015)
Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al, 2010; McGrath & Lilley, 2015).Seventy eight female C57BL/6JBomTac mice and 104 female apolipoprotein E (ApoE)-/- mice (B6.129P2-Apoe N11) on the C57BL/6J background were obtained from Taconic (Ejby, Denmark)
Summary
Immune activation and inflammation are known to modulate the development of atherosclerotic plaques (Libby et al, 2011; Weber and Noels, 2011; Back and Hansson, 2015) and to regulate plaque stability (Chen et al, 2013). Much experimental evidence supports the role of the immune system of atherosclerosis, this has not been adequately translated into therapeutic strategies in humans (Libby et al, 2011; Weber and Noels, 2011; Back and Hansson, 2015) This is mainly caused by the view that systemic immunosuppression would be unacceptable for prevention and treatment of cardiovascular diseases. A limited number of clinical approaches are being studied, including systemic methotrexate or more recently, anti-cytokine (anti-IL-1β or anti-TNF-α) treatments (Ridker and Luscher, 2014) These are based on evidence of high concentrations of these cytokines in advanced plaques and their role as checkpoints in atherosclerosis formation in vivo and in vitro. We investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)À/À mice, in the context of vascular inflammation and plaque stability
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