title: Inactivation of CD73 promotes atherogenesis in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Physiology,  Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf,  Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Buchheiser
authors.forename: Annette
authors.initials: A
authors.lastname: Ebner
authors.forename: Sandra
authors.initials: S
authors.lastname: Burghoff
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Ding
authors.forename: Michael
authors.initials: M
authors.lastname: Romio
authors.forename: Claudia
authors.initials: C
authors.lastname: Viethen
authors.forename: Antje
authors.initials: A
authors.lastname: Lindecke
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schrader
mesh_terms: D015720:5'-Nucleotidase / Q000172:deficiency* / Q000235:genetics; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005230:Fatty Acids, Nonesterified / Q000097:blood; D058851:GPI-Linked Proteins / Q000172:deficiency / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005230:Fatty Acids, Nonesterified; D058851:GPI-Linked Proteins; D014280:Triglycerides; D002784:Cholesterol; D015720:5'-Nucleotidase; C548242:Nt5e protein, mouse; D000241:Adenosine