Document Detail


Everolimus limits aortic aneurysm in the apolipoprotein E-deficient mouse by downregulating C-C chemokine receptor 2 positive monocytes.
MedLine Citation:
PMID:  23393391     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Corey S Moran; Roby J Jose; Joseph V Moxon; Alicia Roomberg; Paul E Norman; Catherine Rush; Heinrich Körner; Jonathan Golledge
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-02-07
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  33     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-14     Completed Date:  2013-05-02     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  814-21     Citation Subset:  IM    
Affiliation:
Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University Townsville, QLD, Australia.
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MeSH Terms
Descriptor/Qualifier:
Angiotensin II
Animals
Aorta, Abdominal / drug effects*,  enzymology,  immunology,  pathology
Aortic Aneurysm, Abdominal / chemically induced,  enzymology,  genetics,  immunology,  pathology,  prevention & control*
Apolipoproteins E / deficiency*,  genetics
Cell Movement / drug effects
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Flow Cytometry
Infusion Pumps, Implantable
Infusions, Subcutaneous
Interferon-gamma / metabolism
Macrophages / drug effects,  enzymology,  immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes / drug effects*,  enzymology,  immunology,  pathology
Protein Kinase Inhibitors / administration & dosage,  pharmacology*
Receptor, Macrophage Colony-Stimulating Factor / metabolism
Receptors, CCR2 / metabolism*
Sirolimus / administration & dosage,  analogs & derivatives*,  pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors*,  metabolism
Chemical
Reg. No./Substance:
0/Apolipoproteins E; 0/Ccr2 protein, mouse; 0/Protein Kinase Inhibitors; 0/Receptors, CCR2; 11128-99-7/Angiotensin II; 159351-69-6/everolimus; 53123-88-9/Sirolimus; 82115-62-6/Interferon-gamma; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse; EC 2.7.10.1/Receptor, Macrophage Colony-Stimulating Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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