title: Everolimus limits aortic aneurysm in the apolipoprotein E-deficient mouse by downregulating C-C chemokine receptor 2 positive monocytes.
abstract: OBJECTIVE
  We aimed to determine the effect of mechanistic target of rapamycin inhibitor everolimus on abdominal aortic aneurysm within the angiotensin II (A2)-infused apolipoprotein E-deficient mouse model.
  
  
  RESULTS
  Abdominal aortic aneurysm was induced via subcutaneous infusion of A2. Flow cytometry demonstrated increased circulating and aortic C-C chemokine receptor 2 (CCR2) monocytes during A2 infusion. The number of CCR2 monocytes present within the aorta was positively correlated with suprarenal aortic diameter. Simultaneous infusion of everolimus via a second subcutaneous osmotic micropump inhibited A2-induced aortic dilatation. Using flow cytometry and Western blot analysis, decreased aortic dilatation was associated with reduced development of CCR2 bone marrow monocytes, fewer numbers of circulating CCR2 monocytes, and lower aortic CCR2 concentration. In vitro, everolimus inhibited A2-stimulated production of interferon (IFN)-γ and IFNγ-induced CCR2 expression in apolipoprotein E-deficient mouse bone marrow monocytes. Further, everolimus diminished IFNγ/lipopolysaccharide-stimulated M1 polarization in apolipoprotein E-deficient mouse bone marrow monocyte-differentiated macrophages.
  
  
  CONCLUSIONS
  Systemic administration of everolimus limits aortic aneurysm in the A2-infused apolipoprotein E-deficient mouse model via suppressed development of bone marrow CCR2 monocytes and reduced egress of these cells into the circulation.
authors: Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University Townsville, QLD, Australia.
authors: Corey S
authors: CS
authors: Moran
authors: Roby J
authors: RJ
authors: Jose
authors: Joseph V
authors: JV
authors: Moxon
authors: Alicia
authors: A
authors: Roomberg
authors: Paul E
authors: PE
authors: Norman
authors: Catherine
authors: C
authors: Rush
authors: Heinrich
authors: H
authors: Körner
authors: Jonathan
authors: J
authors: Golledge
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005434:Flow Cytometry; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C515335:Ccr2 protein, mouse; D047428:Protein Kinase Inhibitors; D054390:Receptors, CCR2; D000804:Angiotensin II; D007371:Interferon-gamma; D000068338:Everolimus; C546843:mTOR protein, mouse; D016186:Receptor, Macrophage Colony-Stimulating Factor; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus