Inactivation of CD73 promotes atherogenesis in apolipoprotein E-deficient mice

CD73 (ecto-5'-nucleotidase) is expressed by a broad range of immune cells and attenuates inflammation in several acute disease models. This study therefore explored the role of CD73-derived adenosine in a model of chronic vascular inflammation such as atherogenesis. CD73(-/-) mice were backcros...

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Bibliographic Details
Published in:Cardiovascular research 2011-11, Vol.92 (2), p.338-347
Main Authors: BUCHHEISER, Anja, EBNER, Annette, BURGHOFF, Sandra, ZHAOPING DING, ROMIO, Michael, VIETHEN, Claudia, LINDECKE, Antje, KÖHRER, Karl, FISCHER, Jens W, SCHRADER, Jürgen
Format: Article
Language:English
Subjects:
5'-Nucleotidase - deficiency
5'-Nucleotidase - genetics
Adenosine - metabolism
Animals
Aorta - enzymology
Aorta - immunology
Aorta - pathology
Apolipoproteins E - deficiency
Apolipoproteins E - genetics
Atherosclerosis (general aspects, experimental research)
Atherosclerosis - blood
Atherosclerosis - enzymology
Atherosclerosis - genetics
Atherosclerosis - immunology
Atherosclerosis - pathology
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Chemokine CCL2 - blood
Cholesterol - blood
Disease Models, Animal
Disease Progression
Fatty Acids, Nonesterified - blood
Gene Expression Profiling - methods
GPI-Linked Proteins - deficiency
GPI-Linked Proteins - genetics
Macrophages - enzymology
Macrophages - immunology
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Oligonucleotide Array Sequence Analysis
T-Lymphocytes - enzymology
T-Lymphocytes - immunology
Time Factors
Triglycerides - blood
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Summary:CD73 (ecto-5'-nucleotidase) is expressed by a broad range of immune cells and attenuates inflammation in several acute disease models. This study therefore explored the role of CD73-derived adenosine in a model of chronic vascular inflammation such as atherogenesis. CD73(-/-) mice were backcrossed into the apolipoprotein E (ApoE(-/-)) background. In CD73(-/-)/ApoE(-/-) double mutants, atherosclerotic lesion formation was increased by ∼50% compared with ApoE(-/-). However, the cellular composition and extracellular matrix of the plaques did not differ. Surprisingly, we found significant activity and expression of CD73 in the plaque of ApoE(-/-) mice which increased over time. CD73 co-localized with macrophages, Tregs, and cells of mesenchymal origin. Genome-wide microarray analysis of the aorta lacking CD73 revealed upregulation of endothelin-1 (Edn1) mRNA together with changes of genes in lipid metabolism and the Wnt and nuclear factor kappa B pathways. Measurement of plasma levels verified the upregulation of Edn1 in CD73(-/-) and double mutants. Plasma triglycerides (TG) were also found to be significantly elevated in the CD73(-/-)/ApoE(-/-) mice compared with ApoE(-/-) controls. Lack of CD73 promotes atherogenesis most likely by de-inhibition of resident macrophages and T cells. Elevated Edn1 and TG levels may have contributed. This establishes CD73-derived adenosine as a direct or indirect regulator of atherogenesis.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvr218