Everolimus limits aortic aneurysm in the apolipoprotein E-deficient mouse by downregulating C-C chemokine receptor 2 positive monocytes

Corey S Moran; Roby J Jose; Joseph V Moxon; Alicia Roomberg; Paul E Norman; Catherine Rush; Heinrich Körner; Jonathan Golledge

doi:10.1161/ATVBAHA.112.301006

Everolimus limits aortic aneurysm in the apolipoprotein E-deficient mouse by downregulating C-C chemokine receptor 2 positive monocytes

Arterioscler Thromb Vasc Biol. 2013 Apr;33(4):814-21. doi: 10.1161/ATVBAHA.112.301006. Epub 2013 Feb 7.

Authors

Corey S Moran¹, Roby J Jose, Joseph V Moxon, Alicia Roomberg, Paul E Norman, Catherine Rush, Heinrich Körner, Jonathan Golledge

Affiliation

¹ Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University Townsville, QLD, Australia.

PMID: 23393391
DOI: 10.1161/ATVBAHA.112.301006

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.

Approach and 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II
Animals
Aorta, Abdominal / drug effects*
Aorta, Abdominal / enzymology
Aorta, Abdominal / immunology
Aorta, Abdominal / pathology
Aortic Aneurysm, Abdominal / chemically induced
Aortic Aneurysm, Abdominal / enzymology
Aortic Aneurysm, Abdominal / genetics
Aortic Aneurysm, Abdominal / immunology
Aortic Aneurysm, Abdominal / pathology
Aortic Aneurysm, Abdominal / prevention & control*
Apolipoproteins E / deficiency*
Apolipoproteins E / genetics
Cell Movement / drug effects
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Everolimus
Flow Cytometry
Infusion Pumps, Implantable
Infusions, Subcutaneous
Interferon-gamma / metabolism
Macrophages / drug effects
Macrophages / enzymology
Macrophages / immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes / drug effects*
Monocytes / enzymology
Monocytes / immunology
Monocytes / pathology
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacology*
Receptor, Macrophage Colony-Stimulating Factor / metabolism
Receptors, CCR2 / metabolism*
Sirolimus / administration & dosage
Sirolimus / analogs & derivatives*
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Apolipoproteins E
Ccr2 protein, mouse
Protein Kinase Inhibitors
Receptors, CCR2
Angiotensin II
Interferon-gamma
Everolimus
mTOR protein, mouse
Receptor, Macrophage Colony-Stimulating Factor
TOR Serine-Threonine Kinases
Sirolimus