title: Anti-atherosclerotic effect of the angiotensin 1-7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)-/- mice, in the context of vascular inflammation and plaque stability.
  
  
  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
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Krakow, Poland.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
authors.forename: D S
authors.initials: DS
authors.lastname: Skiba
authors.affiliation: Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Krakow, Poland.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
authors.forename: R
authors.initials: R
authors.lastname: Nosalski
authors.affiliation: Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Krakow, Poland.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
authors.forename: T P
authors.initials: TP
authors.lastname: Mikolajczyk
authors.affiliation: Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Siedlinski
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
authors.forename: F J
authors.initials: FJ
authors.lastname: Rios
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: Department of Pharmacology, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Jawien
authors.affiliation: Department of Pharmacology, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Olszanecki
authors.affiliation: Department of Pharmacology, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Korbut
authors.affiliation: Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Czesnikiewicz-Guzik
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
authors.forename: R M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Krakow, Poland.|Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Guzik
mesh_terms: D000803:Angiotensin I; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D010446:Peptide Fragments; D058226:Plaque, Atherosclerotic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000819:agonists; D043562:Receptors, G-Protein-Coupled / Q000819:agonists
chemical_list: C469726:AVE 0991; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007093:Imidazoles; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; C118790:angiotensin I (1-7)