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

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 vasoprotective 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)À/À mice, in the context of vascular inflammation and plaque stability. KEY RESULTSAVE0991 has significant anti-atherosclerotic properties in ApoEÀ/À mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using the descending aorta of chow-fed ApoEÀ/À 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 ApoEÀ/À mice.

Gestational intermittent hypoxia induces endothelial dysfunction, reduces perivascular adiponectin and causes epigenetic changes in adult male offspring

“…Local inflammation has an important role in PVAT dysfunction, as shown by findings that PVAT inflammation preceded atherosclerotic plaque formation and endothelial dysfunction in apolipoprotein E −/− mice (Skiba et al . ). Dysfunctional PVAT obtained from animal models with obesity increases the expression of inflammatory cytokines and chemokines such as TNF, monocyte chemoattractant protein 1, interleukin‐6 and interferon gamma (Chatterjee et al .…”

The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases

“…AVE0991 was found to be 10-fold more potent than ANG (1–7) in competing for [ 125 I]-ANG (1–7) binding to, and 5-fold more potent than ANG (1–7) to induce NO release from bovine aortic endothelial cells [207], suggesting that AVE0991 may act as a nonpeptide agonist for the Mas receptor [208,209]. Subsequent in vivo studies have reported that AVE0991 significantly protected postischemic heart failure in rats [210], prevented diabetes-induced cardiovascular dysfunction [211], inhibited atherogenesis in apoE-knockout mice [212,213], ameliorated inflammation in experimental arthritis [214], and attenuated cardiac hypertrophy [215]. Despite these reported protective effects in different animal models or diseases, no clinical trial for AVE0991 is currently registered since it was developed more than 10 years ago [207].…”

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…82 Nox2 NADPH oxidase mediates M1/M2 polarization and regulates their participation in vascular damage, inflammation, and fibrosis. 83,84 The interaction between tumor necrosis factor-α-like weak inducer of apoptosis (Tnfsf12) regulates vascular damage by stimulating ROS production in an Nox2-dependent manner in macrophages and can, therefore, promote accelerated vascular aging 85 and cognitive impairment. 86 There is increasing interest in unraveling the mechanisms of activation of immune cells in the vascular wall.…”